Conditions: Multiple Sclerosis, Relapsing-Remitting
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1225
Healthy volunteers: no

Brief summary:
This is a prospective, multicenter, open-label, single-arm, phase 3b study which evaluates effectiveness and safety of ocrelizumab in participants with early stage RRMS. The study will consist of an open-label treatment period of 192 weeks and follow-up period of at least 48 weeks.

The optional shorter infusion substudy will evaluate the safety of a shorter infusion of ocrelizumab in a subgroup of participants with early stage RRMS enrolled in the main MA30143 study. Approximately 700 patients will be enrolled in the substudy, and will receive additional 600 mg ocrelizumab administered in a shorter time frame.

Detailed description:

Arms:
arm 1: Ocrelizumab will be administered intravenously (IV) as two 300-milligram (mg) infusions (infusion length=2.5 hours) on Days 1 and 15, followed by one 600-mg infusion dose every 24 weeks (+/- 14 days) for a maximum of 8 doses throughout the 192 weeks treatment period. arm 2: At week 24 of the main study, eligible participants will be randomized to receive 600 mg ocrelizumab infused over approximately 3.5 hours every 24 weeks for the remainder of the study duration arm 3: At week 24 of the main study, eligible participants will be randomized to receive 600 mg ocrelizumab infused over approximately 2 hours followed by sodium chloride given as a slow infusion over the remaining 1.5 hours to mimic the standard-length infusion (3.5 hour) every 24 weeks for the remainder of the study duration

Interventions: intervention 1: Ocrelizumab
Intervention descriptions: intervention 1: Ocrelizumab will be administered via IV infusion as specified throughout the treatment period.

Protocol document:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Ocrelizumab—F. Hoffmann-La Roche Ltd
Protocol MA30143, Version 10.0
PROTOCOL
TITLE:
AN OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE 
THE EFFECTIVENESS AND SAFETY OF 
OCRELIZUMAB IN PATIENTS WITH EARLY STAGE
RELAPSING REMITTING MULTIPLE SCLEROSIS 
PROTOCOL NUMBER:
MA30143
VERSION NUMBER:
10.0
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
NCT NUMBER:
NCT03085810
TEST PRODUCT:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
SPONSOR:
F. HOFFMANN-LA ROCHE LTD
Grenzacherstrasse 124,
4070 Basel, Switzerland
DATE FINAL:
Version 1.0: 7 October 2016
DATES AMENDED:
Version 2.0: 22 November 2016
Version 3.0: 28 March 2017
Version 4.0: 27 July 2017
Version 5.0: 30 July 2018
Version 6.0: 30 December 2018
Version 7.0: 23 April 2019
Version 8.0: 28 April 2020
Version 9.0: 17 September 2020
Version 10.0: See electronic stamp below
 
23-Mar-2021 18:13:17
Title
Approver's Name
Company Signatory
Date and Time (UTC)




Ocrelizumab—F. Hoffmann-La Roche Ltd
3/Protocol MA30143, Version 10.0
visit). For those patients presenting with an Expanded Disability Status Scale (EDSS)
change at the end of the treatment period and who roll over to the long-term extension 
(LTE) study LIBERTO (Study MN39158), the 24-week and 48-week CDP confirmation 
visits will occur during the LTE study (Study MN39158). For patients who discontinue the 
study (e.g., move onto commercial ocrelizumab, or start treatment with another disease 
modifying treatment [DMT]), the EDSS CDP confirmatory assessments will not be 
performed.
Inclusion Criteria (Section 4.1.1)

Section 4.1.1 (Inclusion Criteria) has been updated to list the optional contraceptive 
methods which are considered highly effective.
Study Assessments

The requirement of a structured telephone interview post ocrelizumab infusion to 
collect information on any possible infusion-related reactions (IRRs) or any other 
changes in the patient’s health status which may have occurred after the discharge
(previous Section 4.5.13) has been removed.

Section 4.5.13 has been added to include the optional procedure of collecting blood
samples for analysis of immune responses to SARS-CoV-2 vaccine.
Statistical considerations and analysis plan

Section 6.4.1 has been updated to clarify that with respect to CDP confirmation 
visits, only EDSS data at all the visits occurring in the treatment period of the study 
and LTE study (for patients who roll over to study MN39158) will be used. 
Appropriate statistical methods to account for missing confirmation visits will be 
defined in the statistical analysis plan (SAP).

Section 6.6: It has been added that exploratory immunology analyses of SARS-CoV-
2 antibody titers and SARS-CoV-2 T cell responses will be analyzed as appropriate 
and details will be specified in a separate Biomarker Analysis Plan.
Appendix 1
Appendix 1 has been updated to reflect the changes in the protocol
Appendix 2

Appendix 2 has been updated to reflect the changes in the protocol. 

Magnetic resonance imaging (MRI) and telephone follow-up (every 8 weeks) 
have been removed from the Schedule of Assessments during the follow-up 
period.
Appendix 3
The National MS EDSS has been replaced with Neurostatus


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Appendix 7
The Infant Health Questionnaire (IHQ) has been replaced with the recent version 
(September 2020), which was updated to correct the inconsistencies noticed between 
the protocol Section 5.4.3.1 and the IHQ. 
Appendix 8

The safety follow-up period has been updated as per the main study.
Appendix 9

The safety follow-up period has been updated as per the main study.

The volume of additional blood samples in cases of relapse, de novo vaccination 
or severe infection has been corrected to 6 x 9 mL EDTA blood and 1 x 9 mL
serum samples [total blood volume of 63 mL]).
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics. The amendment represents cumulative 
changes to the original protocol.


Ocrelizumab—F. Hoffmann-La Roche Ltd
5/Protocol MA30143, Version 10.0
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 24
1.1
Background on Multiple Sclerosis.......................................... 24
1.2
Background on Ocrelizumab ................................................. 25
1.3
Study Rationale and Benefit-Risk Assessment...................... 29
2.
OBJECTIVES AND ENDPOINTS ............................................................... 30
3.
STUDY DESIGN......................................................................................... 33
3.1
Description of the Study......................................................... 33
3.1.1
Overview of Study Design ..................................................... 34
3.1.2
Screening .............................................................................. 34
3.1.3
Treatment Period................................................................... 34
3.1.4
Safety Follow-up Period.......................................................... 37
3.1.5
Planned Total Sample Size ................................................... 38
3.2
End of Study and Length of Study......................................... 38
3.3
Rationale for Study Design.................................................... 38
3.3.1
Rationale for Ocrelizumab Dose and Schedule..................... 41
3.3.2
Rationale for Patient Population ............................................ 41
4.
MATERIALS AND METHODS .................................................................... 42
4.1
Patients.................................................................................. 42
4.1.1
Inclusion Criteria.................................................................... 42
4.1.2
Exclusion Criteria................................................................... 43
4.2
Method of Treatment Assignment and Blinding..................... 45
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 46
4.3.1
Study Treatment Formulation and Packaging........................ 46
4.3.1.1
Ocrelizumab .......................................................................... 46
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 46
4.3.2.1
Ocrelizumab .......................................................................... 46
4.3.3
Prophylactic Treatment.......................................................... 49


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4.3.4
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 49
4.3.5
Continued Access to Ocrelizumab......................................... 50
4.4
Concomitant Therapy ............................................................ 51
4.4.1
Prohibited Therapy ................................................................ 51
4.5
Study Assessments ............................................................... 52
4.5.1
Informed Consent Forms and Screening Log........................ 52
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 52
4.5.3
Physical Examinations........................................................... 52
4.5.4
Vital Signs.............................................................................. 53
4.5.5
Neurological Examinations .................................................... 53
4.5.6
Assessment of Disability........................................................ 54
4.5.7
Brain Magnetic Resonance Imaging...................................... 55
4.5.8
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 56
4.5.9
Patient-Reported Outcomes .................................................. 57
4.5.10
BICAMS................................................................................. 58
4.5.11
Telephone Interviews ............................................................ 58
4.5.12
Patient Diary (optional) .......................................................... 58
4.5.13
Analysis of immune responses following SARS-CoV-
2 vaccination (Optional Procedure)............................................ 59
4.6
Optional Samples for Research Biosample 
Repository ............................................................................. 60
4.6.1
Overview of the Research Biosample Repository.................. 60
4.6.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 61
4.6.3
Sample Collection.................................................................. 61
4.6.4
Confidentiality........................................................................ 62
4.6.5
Consent to Participate in the Research 
Biosample Repository............................................................ 62
4.6.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 62
4.6.7
Monitoring and Oversight....................................................... 63
4.7
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 63


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4.7.1
Study Treatment Discontinuation........................................... 63
4.7.2
Patient Discontinuation from Study........................................ 64
4.7.3
Study Discontinuation............................................................ 64
4.7.4
Site Discontinuation............................................................... 65
5.
ASSESSMENT OF SAFETY....................................................................... 65
5.1
Safety Plan ............................................................................ 65
5.1.1
Risks associated with corticosteroids .................................... 66
5.1.2
Risks associated with antihistamines .................................... 66
5.1.3
Risks Associated with Ocrelizumab....................................... 66
5.1.3.1
Identified Risks and Adverse Drug Reactions........................ 66
5.1.3.2
Potential Risks....................................................................... 68
5.1.4
Management of Patients Who Experience 
Specific Adverse Events........................................................ 69
5.2
Safety Parameters and Definitions ........................................ 70
5.2.1
Adverse Events ..................................................................... 70
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 71
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 72
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 72
5.3.1
Adverse Event Reporting Period ........................................... 72
5.3.2
Eliciting Adverse Event Information....................................... 73
5.3.3
Assessment of Severity of Adverse Events ........................... 73
5.3.4
Assessment of Causality of Adverse Events ......................... 73
5.3.5
Procedures for Recording Adverse Events............................ 74
5.3.5.1
Infusion-Related Reactions.................................................... 74
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 75
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 75
5.3.5.4
Persistent or Recurrent Adverse Events................................ 75
5.3.5.5
Abnormal Laboratory Values ................................................. 76
5.3.5.6
Abnormal Vital Sign Values ................................................... 76
5.3.5.7
Abnormal Liver Function Tests.............................................. 77


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5.3.5.8
Deaths ................................................................................... 77
5.3.5.9
Preexisting Medical Conditions.............................................. 78
5.3.5.10
Lack of Efficacy or Worsening of Relapsing 
Remitting Multiple Sclerosis................................................... 78
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 78
5.3.5.12
Cases of Accidental Overdose or Medication 
Error....................................................................................... 79
5.3.5.13
Patient-Reported Outcome Data ........................................... 80
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 81
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 81
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 82
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 82
5.4.2.2
Events That Occur after Study Drug Initiation........................ 82
5.4.3
Reporting Requirements for Pregnancies.............................. 82
5.4.3.1
Pregnancies in Female Patients............................................ 82
5.4.3.2
Abortions ............................................................................... 83
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 83
5.5
Follow-Up of Patients after Adverse Events .......................... 84
5.5.1
Investigator Follow-Up........................................................... 84
5.5.2
Sponsor Follow-Up ................................................................ 84
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 84
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 84
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 85
6.1
Determination of Sample Size ............................................... 86
6.2
Summaries of Conduct of Study............................................ 86
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 87
6.4
Effectiveness Analyses.......................................................... 87
6.4.1
Effectiveness Endpoints ........................................................ 87


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6.4.2
Exploratory Endpoints............................................................ 88
6.5
Safety Analyses..................................................................... 88
6.5.1
Safety Outcome Measures .................................................... 88
6.5.2
Safety Analyses..................................................................... 88
6.6
Other Analysis ....................................................................... 89
6.7
Subgroup AnaLysis ............................................................... 89
6.8
Handling of Missing Data....................................................... 89
6.9
Interim Analysis ..................................................................... 89
7.
DATA COLLECTION AND MANAGEMENT ............................................... 89
7.1
Data Quality Assurance......................................................... 89
7.2
Electronic Case Report Forms............................................... 90
7.3
Source Data Documentation.................................................. 90
7.4
Use of Computerized Systems .............................................. 91
7.5
Retention of Records............................................................. 91
8.
ETHICAL CONSIDERATIONS.................................................................... 91
8.1
Compliance with Laws and Regulations ................................ 91
8.2
Informed Consent.................................................................. 92
8.3
Institutional Review Board or Ethics Committee.................... 93
8.4
Confidentiality........................................................................ 93
8.5
Financial Disclosure .............................................................. 94
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 94
9.1
Study Documentation ............................................................ 94
9.2
Protocol Deviations................................................................ 95
9.3
Management of Study Quality ............................................... 95
9.4
Site Inspections ..................................................................... 95
9.5
Administrative Structure......................................................... 95
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 96
9.7
Protocol Amendments ........................................................... 96
10. REFERENCES ........................................................................................... 98


Ocrelizumab—F. Hoffmann-La Roche Ltd
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LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 30
Table 2
Overview of Ocrelizumab Dosing................................................ 48
Table 3
Ocrelizumab infusion rates for Conventional and Shorter 
Infusions in absence of IRRs ...................................................... 48
Table 4
Guidelines for Management of Specific Adverse Events ............ 70
Table 5
Adverse Event Severity Grading Scale for IRRs and Other 
Events Not Specifically Listed in NCI CTCAE............................. 73
Table 6
Causal Attribution Guidance ....................................................... 74
LIST OF FIGURES
Figure 1
Overview of Study Procedures.................................................... 34
Figure 2
Overview of End of Treatment Period......................................... 37
Figure 3
Overview of Sample Collection for SARS-CoV-2 Vaccine 
Immunological Assessments for Optional Procedure......................... 60
LIST OF APPENDICES
APPENDIX 1 Schedule of Assessments: Screening through the End of 
Treatment Period ...................................................................... 102
APPENDIX 2 Safety Follow-up Schedule of Assessments .............................. 108
APPENDIX 3 Expanded Disability Status Scale (EDSS) ................................ 109
APPENDIX 4 Telephone Interviews................................................................ 113
APPENDIX 5 Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy............................................................... 115
APPENDIX 6 Patient Reported Outcomes...................................................... 118
APPENDIX 7 Pregnancy Outcome and Infant Health Information on First 
Year of Life................................................................................ 125
APPENDIX 8 T and B Cells Impact Substudy Protocol................................... 132
APPENDIX 9 Immune Substudy Protocol....................................................... 161
APPENDIX 10Ocrelizumab Shorter Infusion Substudy Protocol...................... 178


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL, SINGLE-ARM STUDY TO 
EVALUATE THE EFFECTIVENESS AND SAFETY 
OF OCRELIZUMAB IN PATIENTS WITH EARLY 
STAGE RELAPSING REMITTING MULTIPLE 
SCLEROSIS 
PROTOCOL NUMBER:
MA30143
VERSION NUMBER:
10.0
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
NCT NUMBER:
NCT03085810
TEST PRODUCT:
Ocrelizumab (RO4964913)  
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files. Please return a copy as 
instructed by the CRO.
{Name} 
{Address}




Ocrelizumab—F. Hoffmann-La Roche Ltd
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Objectives
Corresponding Endpoints
Proportion of patient relapse free by week 48, 96, 144 
and 192
Proportion of patients with no evidence of protocol-
defined disease activity (NEDA) over week 96, week 
144 and week 192 where disease activity is defined 
as at least one the following events: protocol-defined 
relapse; CDP based on increases in EDSS; a T1 
Gadolinium (Gd)-enhanced lesion after Week 8; or a 
new and/or enlarging T2 hyperintense lesion on 
magnetic resonance imaging (MRI) after Week 8 
compared to the Week 8 MRI scan.
Proportion of patients with no evidence of progression 
(NEP) defined as no progression sustained for at least 
24 weeks on all of the following three components
(CDP; 20% increase in timed 25 Foot Walk Test 
[T25FWT]; 20% increase in timed 9 hole peg test 
[9HPT]) between baseline and week 96/192
Proportion of patients with no evidence of progression 
sustained for at least 24 weeks and no active disease 
(NEPAD) defined as no progression on all of the three 
components of NEP (CDP, T25FWT, 9HPT), no new
relapse and no enlarging or new T2 or T1 Gd-
enhancing lesion between baseline and week 96/192
Change from baseline of Multiple Sclerosis Functional 
Composite (MSFC) and its composites (T25FW, 9HP, 
and Paced Auditory Serial Addition Test [PASAT]) 
over time
Change from baseline in cognitive performance as 
measured by Brief International Cognitive Assessment 
for Multiple Sclerosis (BICAMS) performed annually
Related to MRI
Total number of T1 Gd-enhancing lesions as detected 
by brain MRI over time
Total number of new and/or enlarging T2 lesion as 
detected by brain MRI over time
Change in total T1 hypointense lesion volume over 
time
Total number of fluid-attenuated inversion-recovery 
(FLAIR) late enhancing lesions as detected by brain 
MRI over time
Change in brain volume (including white and grey 
matter fractions) as detected by brain MRI over time
Other measures related to MS disease:
Time to treatment discontinuation/switch
Patient reported outcomes:
Employment status (Work Productivity and Activity 
Impairment Questionnaire [WPAI])
SymptoMScreen 
Quality of life (Multiple Sclerosis Impact Scale [MSIS]-
29)




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The study will consist of the following periods:

Screening period:  Up to 4 weeks

Treatment period:  Open-label treatment period of 192 weeks (i.e. 24 weeks after the last 
dose of ocrelizumab, which will be administered at Week 168). Patients will be allowed to 
switch from the conventional ocrelizumab infusion (3.5 hours) to the shorter ocrelizumab
infusion (2.0 hours) at any visit after the Week 24 visit based on the schedules of infusion 
as per the protocol, after providing written informed consent and in agreement with their 
treating physician, provided they have not experienced any previous serious infusion-related 
reactions (IRRs) with ocrelizumab treatment. While on the shorter infusion, the patients can 
switch back to the conventional infusion in agreement with their treating physician. If patients 
develop a serious IRR while on the shorter infusion, they will be switched to the conventional 
infusion and should not be restarted on the shorter infusion at any following infusion visit.

A safety follow-up period of 48 weeks after the last infusion of the study drug, as explained 
below
Safety Follow-up Period:  Patients who discontinue treatment early for any reason and patients who 
complete the study treatment period and do not continue in a separate long-term extension (LTE) study,
will be followed up for 48 weeks after the last infusion of study drug. When patients begin an 
alternative treatment for MS (see section 4.4.1 "Prohibited Therapy'), they will be discontinued from the 
study.
Patients who discontinue study treatment and switch to commercially marketed ocrelizumab, 
either after completion of the 192 weeks Treatment Period or after early discontinuation of the 
192 weeks Treatment Period, will not enter the safety Follow-up Period.
A structured telephone interview will be conducted by site personnel every 8 weeks between the 
study visits (starting after the site visit at 8 weeks) during the treatment period to identify and 
collect information on any changes in the patient’s health status that warrant an unscheduled visit
(including new or worsening neurological symptoms) and possible events or infections.
Number of Patients
The main study was initially planned to enroll at least 600 patients with early stage RRMS. 
Approximately 550 additional patients were to be enrolled in the shorter infusion substudy. They 
would also be enrolled in the main study (see Appendix 10 for more details). Therefore, the 
main study would enroll a total of at least 1,100 patients. A total of 1,225 patients (678 in the 
main study and 547 in the shorter infusion substudy) were enrolled in the study.
Target Population
UInclusion 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 RRMS, as per the revised McDonald 2010 criteria (Polman et al. 
2011)

Have a length of disease duration, from first documented clinical attack consistent with MS 
disease of ≤ 3 years

Within the last 12 months: 
One or more clinically reported relapse(s) 
OR
One or more signs of MRI activity 

EDSS of 0.0 to 3.5 inclusive, at screening

For women of childbearing potential:  agreement to use an acceptable birth control method 
during the treatment period and for at least 6 months or longer after the last dose of 
ocrelizumab as applicable in the ocrelizumab package leaflet.


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A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment
with local guidelines or requirements.
The following are acceptable contraceptive methods (failure rate >1% as defined by the 
Clinical Trial Facilitation Group [CTFG] guidelines): (1) progestogen-only oral hormonal 
contraception, where inhibition of ovulation is not the primary mode of action, (2) male or 
female condom with or without spermicide, (3) cap, diaphragm, or sponge with spermicide, 
(4) combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier methods). 
Birth control methods that are highly effective (i.e. failure rate <1% [CTFG]) may also be used but are 
not required, and include: (1) oral, intravaginal or transdermal combined hormonal contraception 
associated with inhibition of ovulation; (2) oral, injectable or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation; (3) intrauterine device; (4) intrauterine 
hormone-releasing system; (5) bilateral tubal occlusion; (6) vasectomised partner; (7) sexual 
abstinence. 
UExclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Secondary progressive multiple sclerosis (SPMS) or history of primary progressive or 
progressive relapsing MS

Inability to complete an MRI (contraindications for MRI include but are not restricted to 
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, claustrophobia, weight>140 kg, 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 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, sarcoidosis)

History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression)
UExclusions Related to General Health

Pregnancy or lactation

Patients intending to become pregnant during the study or within 6 months after the last dose 
of the study drug

Any concomitant disease that may require chronic treatment with systemic corticosteroids or 
immunosuppressants during the course of the study

History or currently active primary or secondary immunodeficiency

Lack of peripheral venous access


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
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies

Significant or uncontrolled somatic disease or any other significant disease that may preclude 
patient from participating in the study

Congestive heart failure (New York Heart Association [NYHA] III or IV functional severity)

Known active bacterial, viral, fungal, mycobacterial infection or other infection, (excluding 
fungal infection of nail beds) or any major episode of infection requiring hospitalization or 
treatment with intravenous (IV) antibiotics within 4 weeks prior to screening or oral antibiotics 
2 weeks prior to screening
Note: Active infections should be treated and effectively controlled before possible inclusion 
in the study

History of major opportunistic infections (i.e. cryptococcosis, Pneumocystis pneumonia, 
progressive multifocal leukoencephalopathy [PML])

History or known presence of recurrent or chronic infection (e.g., human immunodeficiency 
virus [HIV], syphilis, tuberculosis [TB])

History of malignancy, including solid tumors and hematological malignancies, except basal 
cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the 
cervix of the uterus that have been previously completely excised with documented, clear 
margins

History of alcohol or drug abuse within 24 weeks prior to baseline

History or laboratory evidence of coagulation disorders
UExclusions Related to Medications

Received any prior approved DMT with a label for MS, for example, interferons, glatiramer 
acetate, natalizumab, alemtuzumab, daclizumab, fingolimod, teriflunomide and 
dimethylfumarate.

Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the baseline visit.
In rare cases when patient requires vaccination with a live vaccine, the screening period may 
be extended but cannot exceed 8 weeks.

Treatment with any investigational agent within 24 weeks of screening (Visit 1) or five half-
lives of the investigational drug (whichever is longer) or treatment with any experimental 
procedures for MS (e.g., treatment for chronic cerebrospinal venous insufficiency).

Contraindications to or intolerance of oral or IV corticosteroids, including methylprednisolone 
administered IV, according to the country label, including:
a) Psychosis not yet controlled by a treatment
b) Hypersensitivity to any of the constituents.

Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, 
belimumab, or ofatumumab).

Systemic corticosteroid therapy within 4 weeks prior to screening.

Any previous treatment with immunosuppressants/ immunomodulators/ antineoplastic 
therapies (cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, 
methotrexate, cladribine, mitoxantrone, laquinimod, total body irradiation, or bone marrow 
transplantation).

Treatment with IV immunoglobulins (Ig) within 12 weeks prior to baseline.

Treatment with investigational DMT

History of recurrent aspiration pneumonia requiring antibiotic therapy

Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stable dose for ≥ 
30 days prior to screening. Wherever possible, patients should remain on stable doses 
throughout the 96-week treatment period.


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UExclusions Related to Laboratory Findings*

Positive serum β human chorionic gonadotropin (hCG) measured at screening

Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, or 
positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA 
polymerase chain reaction [PCR]) 

Lymphocyte count below lower limit of normal (LLN)

CD4 count<250/μL.

Aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) or 
alanine aminotransferase (ALT) /serum glutamic pyruvic transaminase (SGPT)≥ 3.0 × the 
upper limit of normal (ULN)

Serum creatinine >1.4 mg/dL (> 124 μmol/L) for women or > 1.6 mg/dL (> 141μmol/L) for 
men

Hemoglobin < 8.5 g/dL (< 5.15 mmol/L)

Platelet count <100,000/μL (<100 × 109/L)

Absolute neutrophil count <1.0 × 103/μL
*URe-testing before baseline: any abnormal screening laboratory value that is clinically relevant 
should be retested in order to rule out any progressive or uncontrolled underlying condition. The 
last value before randomization must meet study criteria. 
UPlease note: based on local Ethics Committees or National Competent Authority requirements, 
additional diagnostic testing may be required for selected patients or selected centers to exclude 
tuberculosis, Lyme disease, HTLV-1 associated myelopathy (HAM), acquire immunodeficiency 
syndrome (AIDS), hereditary disorders, connective tissue disorders, or sarcoidosis. Other specific 
diagnostic tests may be requested when deemed necessary by the Investigator.
End of Study
The end of the main study is defined as the last patient last visit in the Safety Follow-up period or 
last patient Week 192 visit, whichever occurs later.
The end of the study treatment period has been defined as the date on which the last patient 
receiving the full study treatment reached the 192 week visit. After the end of treatment period visit 
of the last enrolled patient, approximately 24 weeks and 48 weeks may be needed to allow the confirmation 
of the last event of the 24week and 48week-CDP (CDP/CDI confirmation visit). For those patients 
presenting with an EDSS change at the end of the treatment period and who roll over to the LTE study
LIBERTO (Study MN39158), the 24-week and 48-week CDP confirmation visits will occur during the 
LTE study (Study MN39158). For patients who discontinue the study (e.g., move onto commercial 
ocrelizumab, or start treatment with another DMT), the EDSS CDP confirmatory assessments will not be 
performed.
Length of Study
The total length of the main study, from screening of the first patient to the end of the study 
depends on the recruitment rate and is expected to be approximately 356 weeks (7 years). This 
includes an enrolment period of 116 weeks.
UInvestigational Medicinal Products
Test Product (Investigational Drug)
The first dose of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) in 
250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15), followed by one 
600-mg IV infusion in 500 mL 0.9% sodium chloride every subsequent doses (i.e., every 
24 weeks ± 14 days) for a maximum of 8 doses.


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UNon-Investigational Medicinal Products
The following premedications must be administered prior to each infusion of ocrelizumab to 
reduce the frequency and severity of infusion-related reactions (IRRs):

100 mg intravenous methylprednisolone (or an equivalent), administered by slow IV 
infusion, to be completed approximately 30 minutes and not less than 25 minutes prior to 
each ocrelizumab infusion.

Antihistamine via oral, intramuscular or IV route to be completed approximately 30-
60 minutes and not less than 25 minutes prior to each infusion of ocrelizumab (the 
antihistamine should be the first premedication to be administered).  

The addition of an antipyretic (e.g., acetaminophen/ paracetamol) may also be 
considered.
UStatistical Methods
Primary Analysis
The main study is an open-label single-arm study. No formal confirmatory hypothesis test will be 
conducted. 
The intent-to-treat (ITT) population will include all enrolled patients who received any dose of 
ocrelizumab and will be used for the primary analyses of effectiveness and safety. The per-
protocol (PP) population will include all ITT patients without major protocol deviations deemed to 
potentially affect the effectiveness endpoints.  The PP population will be used for supportive 
effectiveness analyses. Safety population is defined as all enrolled patients who received any 
dose or part of a dose of ocrelizumab in the study. After the Week 192 visit of the last enrolled 
patient, approximately 24 weeks and 48 weeks may be needed to allow the confirmation of the last 
event of the 24 week and 48 week-CDP (CDP/CDI confirmation visit). The analysis will be 
performed after the last CDP and CDI confirmation visit. With respect to CDP confirmation visits, 
only EDSS data at all the visits occurring in the treatment period of the study and LTE study (for patients 
who roll over to study MN39158) will be used. Appropriate statistical methods to account for missing 
confirmation visits will be defined in the statistical analysis plan (SAP).
The evaluation of the clinical effectiveness of ocrelizumab will be based upon the events and 
assessments in-between the baseline and week 192.The MRI activity will be evaluated from 
week 8 (baseline for MRI-based endpoints) to week 192. For the patients who do not have an 
event, time-to-event endpoints will be censored at the time of last visit in the study.  A descriptive 
analysis based on the Kaplan-Meier method will be performed for the time to CDP and other 
time-to-event endpoints, such as the time to first relapse or to first event of disease activity. 
Change of EDSS from baseline at week 192 will be analyzed based on mixed models for 
repeated measures. Details will be specified in the SAP.
Determination of Sample Size  
Sample size considerations for the main study are based on pooled data from two ocrelizumab 
phase III trials in RRMS (OPERA I and II). Based on extrapolations from these studies, we can 
conservatively expect 15% of patients (or less) to have a CDP event and approximately the same 
number of patients to be censored (including the patients who drop out during the study) by week 
192. In this case, for 1,100 patients, the precision (half-width of the 95% confidence interval) of 
the estimated CDP rate by study end is expected to be approximately 1.8% i.e., the 95% 
confidence interval will be (13.2%, 16.8%).  In OPERA the EDSS improvement at 2 years had a 
standard deviation of 0.74, based on 240 patients from the ocrelizumab group, who were 
previously treatment-naïve with disease duration ≤3 years and EDSS ≤3.5.  The standard 
deviation was rather stable over time and is assumed to remain stable after four years of 
treatment.  A sample size of 1,100 patients is expected to provide a precision for the estimate of 
the EDSS change from baseline of about 0.037, assuming a standard deviation of 0.75. 
Assuming no EDSS change from baseline to week 196, with 1,100 patients, the 95% confidence 
interval will be (-0.074, 0.074).


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The main study was initially planned to enroll at least 600 patients. Approximately 550 additional 
patients were to be enrolled in the shorter infusion substudy. They would also be enrolled in the 
main study (see Appendix 10 for more details). Therefore, the main study would enroll a total of 
at least 1,100 patients. A total of 1,225 patients (678 in the main study and 547 in the shorter 
infusion substudy) were enrolled in the study.
Interim Analyses
Exploratory analyses of selected endpoints (including CDP and safety analysis) will be performed 
during the course of the study, for example, after all patients have completed the first 48 weeks of 
the treatment phase and the necessary data are available.


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ULIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
AE
Anti-drug antibodies
Adverse event
AIDS
Acquire immunodeficiency syndrome
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ARR
Annual relapse rate
AST
Aspartate aminotransferase
-hCG
Beta subunit human chorionic gonadotropin
BICAMS
Brief International Cognitive Assessment for Multiple Sclerosis
BRC
Biological Reso 9u 9rce center
BVMT-R
Brief Visuospatial Memory Test Revised
CCOD
Clinical cut-off date
CDI
Confirmed disability improvement
CDP
Confirmed disability progression
CI
Confidence interval
CNS
Central nervous system
CRO
Contract research organization
CSF
Cerebrospinal fluid
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CVLT-II
California Verbal Learning Test 2
DMT
Disease modifying treatment
DRB
Data Review Board
EC
Ethics committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic data capture
EDSS
Expanded Disability Status Scale
EU
European Union
FDA
Food and Drug Administration
FLAIR
Fluid-attenuated inversion-recovery
FSH
Follicle stimulating hormone
FSS
Functional Systems Score
GA
Glatiramer acetate
GCP
Good Clinical Practice
Gd
Gadolinium
GGT
Gamma-glutamyl transpeptidase
GPA
Granulomatosis with polyangiitis
HAM
HTLV-1 associated myelopathy


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Abbreviation
Definition
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HEENT
Head, eye, ear, nose, and throat
HIV
Human immunodeficiency virus
9HPT
9 Hole peg test
HR
Hazard ratio
HTLV-1
Human T-lymphotropic virus 1
IA
Interim analysis
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
iDCC
Independent Data Coordinating Center
iDMC
Independent Data Monitoring Committee
IFN-
Interferon beta
IFNg
Interferon gamma
Ig
Immunoglobulin
IMP
Investigational medicinal product
IND
Investigational New Drug 
IRB
Institutional Review Board
IRR
Infusion-related reaction
ITT
intent-to-treat
IV
Intravenous
IxRS
Interactive voice/Web response system
JCV
John Cunningham virus
LLN
Lower limit of normal
LPLV
Last patient, last visit
LTE
Long term extension
MELAS
Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke
MMRM
Mixed model with repeated measure
MRI
Magnetic resonance imaging
MS
Multiple sclerosis
MSFC
Multiple sclerosis functional composite
MSIS-29
Multiple Sclerosis Impact Scale (29-item scale)
NCI
National Cancer Institute
NEDA
No evidence of disease activity
NEP
No evidence of progression
NEPAD
No evidence of progression or active disease
NfL
Neurofilament light chain
NGS
Next generation sequencing
NYHA
New York Heart Association
OCB
Oligoclonal band


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Abbreviation
Definition
ON
Optic neuritis
PASAT
Paced Auditory Serial Addition Test
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PK
Pharmacokinetic
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
RBC
Red blood cell
RBR
Research Biosample Repository
RMS
Relapsing multiple sclerosis
RRMS
Relapsing remitting multiple sclerosis
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
SDMT
SGOT
SGPT
Standard deviation
Symbol digit modalities test
Serum glutamic oxaloacetic transaminase
Serum glutamic pyruvic transaminase
SIs
Serious infections
SPMS
Secondary progressive multiple sclerosis
TB
Tuberculosis
T25FWT
Timed 25 foot walk test
ULN
Upper limit of normal
U.S.
United States
USP
United States Pharmacopeia
WBC
White blood cell
WES
Whole Exome Sequencing
WGS
Whole Genome Sequencing
WPAI
Work productivity and activity impairment questionnaire


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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 (55Tullman et al. 201355). MS primarily 
affects young adults, with 70%80% of patients having an age of onset (i.e., initial visit 
to a physician) between 20 and 40 years (55Anderson et al. 199255; 55Noonan et al. 200255), 
and has a strong gender bias, with approximately 64%70% of diagnosed patients 
being women (55Goodin 201455). 
MS is subcategorized into three main phenotypes of the disease course: relapsing-
remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS 
(SPMS; Lublin et al. 201455T); 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).
The clinical signs in MS can occur in isolation or in combination, and can include 
weakness, spasticity, gait and coordination imbalances, sensory dysfunction, vision loss, 
sexual dysfunction, fatigue, depression, chronic pain, sleep disorders, and cognitive 
impairment (Tanasescu et al. 2014). Current diagnosis of definite MS involves both 
clinical (history and neurological exam) and paraclinical (for example, Magnetic 
Resonance Imaging [MRI], Spinal Tap, Evoked potentials) evidence. The revised 2010 
McDonald MRI criteria for demonstration of lesion dissemination of space include ≥1 T2 
lesion in at least two of the following four areas of the CNS: periventricular, juxtacortical, 
infratentorial, and spinal cord; and demonstration of lesion dissemination in time include 
the following: a new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with 
reference to a baseline scan, irrespective of the timing of the baseline MRI; and 
simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing 
lesions at any time (Polman et al. 2011).
MS treatments tackle separately the acute exacerbations and their prevention. 
Symptomatic management of relapses involves the use of corticosteroids, while 
disease-modifying treatments (DMTs) aim to decrease the clinical relapse rate and 
concomitant inflammation within the CNS (Tanasescu et al. 2014). DMTs, which include 
immunomodulatory, anti-inflammatory, and immunosuppressive drugs, are used to slow 
the development of MS-related neurological damage and disability progression. By 
providing a more effective approach to MS treatment, DMTs may improve quality of life 
for individuals with MS (Weinstock-Guttman 2013).
The therapeutic landscape of MS is changing rapidly. After several years in which 
first-line DMTs – glatiramer acetate (GA) and interferon beta (IFNβ) – constituted the 
principal treatment options, a variety of new agents for MS treatment are now approved 
by regulatory authorities or in phase II and III clinical trials (Tanasescu et al. 2014). In 


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2004 natalizumab was approved for relapsing forms of MS and in 2014, alemtuzumab 
and peg IFNβ-1a. 3Fingolimod was the first oral DMT approved by 3Food and Drug 
Administration3 (FDA) in 2010 for relapsing forms of MS (RMS) followed by teriflunomide 
in 2012 and dimethyl fumarate in 2013 3(wwww.mymsaa.org).
Suppression of disease activity and disability progression as early as possible remains 
an important goal of therapy in MS (Noyes and Weinstock-Guttman 2013; Ziemssen et 
al. 2015). With the emergence of more efficacious therapies and a better understanding 
of the consequences of subclinical and early disease activity, physicians have a lower 
tolerance for allowing disease activity to persist because what is lost in MS cannot 
typically be regained. The potential risk of irreversible disease progression is therefore 
an important factor in the therapeutic decision making of patients and their physicians. 
Although there are now several approved therapies for RMS, some lack sufficient 
efficacy to quell progression of disability (Coles et al. 2008), while more effective 
therapies are often reserved for later use because of serious risks (Ziemssen et al. 
2015). Thus there remains a need for highly effective therapies with a benefit-risk profile 
that supports its expeditious use at any time during the course of disease to preserve 
CNS tissue and neurological function, stem accrual of irreversible disability, and improve 
the quality of life for people living with MS. 
1.2
BACKGROUND ON OCRELIZUMAB
Ocrelizumab is a recombinant humanized anti-human monoclonal antibody that 
selectively targets and eliminates CD20-expressing B cells (55Klein et al. 201355), 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 (55Stashenko et al. 198055; 
55Loken et al. 198755; 55Tedder and Engel 199455). While ocrelizumab selectively depletes 
CD20-expressing B cells (55Kappos et al. 201155), the capacity of B-cell reconstitution and 
pre-existing humoral immunity are preserved (55Martin and Chan 200655; 55DiLillo et al. 
200855). In addition, innate immunity and total T-cell numbers are not affected (55WA21493 
Clinical Study Report55).
See the Ocrelizumab Investigator's Brochure (IB) for additional details on nonclinical and 
clinical studies.
Summary of Clinical Studies of Ocrelizumab in MS
In two double-blind, double-dummy Phase III global RMS trials (Studies WA21092 and 
WA21093), ocrelizumab 600 mg demonstrated superior efficacy over subcutaneous 
IFNβ-1a 44 g (Hauser et al. 2015). Efficacy outcomes were consistent between trials 
and across the primary and key clinical and imaging secondary endpoints. Ocrelizumab 
600 mg demonstrated statistically significant superiority compared with IFNβ-1a on each 
of the following major efficacy endpoints:


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
Relative reductions of 46% and 47% (both p0.0001) in the protocol-defined annual 
relapse rate (ARR) in Studies WA21092 and WA21093, respectively (primary 
endpoint)

A 40% relative reduction in both the 12-week confirmed disability progression [CDP] 
(Hazards ratio [HR] 0.60 [95% confidence interval [CI]: 0.45, 0.81], p0.0006) and 
24-week CDP (HR 0.60 [95% CI: 0.43, 0.84], p=0.0025) in the pooled analysis of 
Studies WA21092 and WA21093. Each individual trial also demonstrated a 
significant relative risk reduction of 12-week CDP and 24-week CDP (43% reduction 
for both 12- and 24-week CDP in Study WA21092 and 37% reduction for both 12-
and 24-week CDP in Study WA21093)

Relative reductions of 94% and 95% (both p<0.0001) in the number of 
T1- gadolinium (Gd)-enhancing lesions per scan at Weeks 24, 48 and 96 in 
Study WA21092 and Study WA21093, respectively

Relative reductions of 77% and 83% (both p0.0001) in the total number of new 
and/or enlarging T2 hyperintense lesions per scan at Weeks 24, 48 and 96 in 
Study WA21092 and Study WA21093, respectively
In a Phase III global PPMS trial (Study WA25046), ocrelizumab 600 mg demonstrated 
statistically significant superiority compared with placebo on each of the following major 
efficacy endpoints (Montalban et al. 2015)

A 24% relative risk reduction in 12-week CDP, the primary endpoint (HR0.76 [95% 
CI: 0.59, 0.98], p0.0321)

A 25% relative risk reduction in 24-week CDP (HR0.75 [95% CI: 0.58, 0.98],
p0.0365)

Relative reduction of 29% in the progression rate of timed 25-foot walk from 
baseline to Week 120 (p0.0404)

A decrease in the volume of T2 lesions by 3.4% over 120 weeks, compared with the 
placebo group in which the T2 lesion volume increased by 7.4% (p0.0001)

Relative reduction of 17.5% in whole brain volume loss from Week 24 to Week 120 
(p0.0206).
Clinical Safety
The safety data included are from five studies in MS: two Phase III studies in RMS
(Studies WA21092 and WA21093), one Phase III study in PPMS (Study WA25046); one 
Phase II study in RRMS (Study WA21493) and one substudy (shorter infusion substudy) 
of the Phase IIIb study in early stage RRMS (Study MA30143).
The four studies WA21092, WA21093, WA25046, and WA21493 have completed the 
controlled treatment period and are in open-label extension phase.


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In the two double-blind, double-dummy RMS Phase III studies (pooled data of Studies 
WA21092 and WA21093) during the 96-week controlled treatment period, the rates of 
treatment discontinuations for adverse events (AEs) were lower in patients treated with 
ocrelizumab 600 mg (3.5%) than in patients receiving IFNβ-1a (6.2%). The proportion of 
patients with AEs (83.3% in both groups) as well as the total number of AEs were similar 
in the ocrelizumab and the IFNβ -1a treatment groups over the 96-week treatment 
period. The proportion of patients reporting infections was higher in the ocrelizumab 
group compared with the IFNβ-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 IFNβ -1a 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 (SAEs) was lower in the ocrelizumab treatment group than in the IFNβ-1a 
treatment group (6.9% in the ocrelizumab treatment group versus 8.7% in the IFNβ-1a 
treatment group). Overall, the proportion of patients with serious infections was lower in 
the ocrelizumab group (1.3%) than in the IFNβ-1a group (2.9%). Two serious infusion-
related reactions (IRRs) were reported; one in the IFNβ -1a group (severe balance 
disorder and other symptoms; Grade 3) and one in the ocrelizumab group (life 
threatening bronchospasm; 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 
IFNβ -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. Three deaths occurred in Studies WA21092 and WA21093; 2 patients 
(suicide and mechanical ileus) in the IFNβ -1a treatment group and 1 patient (suicide) in 
the ocrelizumab treatment group. 
In the PPMS Phase III double blind placebo controlled Study WA25046, the proportion of 
patients with AEs leading to discontinuation from treatment was similar in ocrelizumab 
(4.1%) and placebo (3.3%) groups. The proportion of patients who experienced at least 
one AE 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 AEs experienced by patients with an AE 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 IRRs 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 
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 


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(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 SAEs (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). 
The primary analysis of the shorter infusion substudy of the main MA30143 study (a 
phase IIIb study in early stage RRMS) suggested that the frequency/severity of IRRs 
were comparable between the conventional ocrelizumab infusion (administered over 
3.5 hours) and the shorter ocrelizumab infusion (administered over .0 hours); no new 
safety signals were detected. As of September 2019, 291 and 289 patients were 
randomized to the conventional and shorter infusion groups, respectively. Following the 
first randomized infusion, 67 patients (23.1%) in the conventional and 71 patients 
(24.6%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild 
or moderate; >98% of all IRRs resolved without sequelae in both groups. No IRRs were 
life-threatening, serious, or fatal; one severe IRR occurred in both the conventional 
(laryngeal inflammation [second randomized dose]) and shorter infusion groups (fatigue 
[first randomized dose]). No IRR-related discontinuations occurred. During the first 
randomized dose, 14 (4.8%) and 25 (8.7%) patients in the conventional and shorter 
infusion groups had IRRs leading to infusion interruption/slowing, respectively (data on 
file).
All Exposure Population
The safety data from controlled periods of Studies WA21092 (Phase III, RMS), 
WA21093 (Phase III, RMS), WA25046 (Phase III, PPMS), and Study WA21493 (Phase 
II, RRMS) as well as BN29739, MA30005, MA30143, ML29966, MN30035, MN39158 
and MN39159 are included up to a clinical cut-off date (CCOD) of January 2020. A total
of 5,680 patients exposed to ocrelizumab, accounting for 18,218 patient years (PY), are 
included in this section (MS All Exposure Population).
The most common AEs were IRRs which were manageable using appropriate 
measures, and infections, mostly Grade 1 or Grade 2 in intensity. The overall rate of 
serious infections (SIs) remains low and stable. Urinary tract infection and pneumonia
remained the SIs events reported with the highest rates per 100PY. The event rate per 
100PY of SIs appears to increase numerically with fluctuation over time driven solely by 
the PPMS population subset. The majority of SIs were of Grade 3 intensity or below, 
resolved without sequelae, within ≤ 2 weeks and were not treatment limiting. Though 
malignancy remains a potential risk and needs to be further characterized, the incidence 


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rate of malignancy in ocrelizumab treated patients remained consistent with that of the 
general MS population. 
For more detailed information on safety from clinical trials and post-marketing settings, 
please refer to the most recent version of the IB.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
It is widely understood that the clinical course of MS consists of two major phases; an 
early, focal inflammatory phase and a later, progressive, inflammatory-independent 
neurodegeneration phase (Leray et al. 2010). Focal damage manifests clinically mainly 
as relapses, whereas diffuse damage has been more closely associated with disability 
progression and cognitive decline (Ziemssen et al. 2015). Studies have shown, however, 
that neurodegeneration can in fact begin early in the disease course and can contribute 
to ongoing disease activity, but this may not always be clinically evident in the initial 
stages (Ziemssen et al. 2015). It is argued that once neurodegenerative features are 
clinically detectable, permanent damage has already accumulated making it difficult to 
improve outcomes (Freedman 2011). Furthermore, each relapse that patients with 
RRMS experience may be associated with accumulation of irreversible neurological 
damage and disability (Noyes and Weinstock-Guttman 2013). For example, in the 
natural history RRMS cohort study, patients were stratified according to number of 
relapses in the first 2 years, first inter-attack interval and number of relapses from year 3 
to onset of progression. More relapses in the first 2 years were related to a higher 
probability to convert to SPMS (HR = 1.1; p = 0.003) and latency between disease onset 
and onset of progression was significantly longer in groups with 1 versus ≥3 relapses 
during the first 2 years (p = 0.014) (Scalfari et al. 2010). One of the early studies 
including patients with RRMS (Jacobs et al. 1996) early in the disease (Expanded 
Disability Status Scale [EDSS] at baseline 1.0 – 3.5) demonstrated that the IFNβ-1a 
treatment reduced the CDP significantly after two years compared to placebo. An eight-
year follow-up of these patients (Rudick et al. 2005) could demonstrate that patients who 
received the initial IFNβ-1a treatment had a significant lower risk at reaching an EDSS of 
6.0 compared to the initial placebo group. This demonstrated that the delay in start of 
DMT therapy did not allow to catch up on the progression of the disability on long term. 
Therefore, optimizing treatment early in MS may prevent the accumulation of irreversible 
neurological damage and reduce the risk of disease progression (Ziemssen et al. 2015). 
The majority of the clinical trials of DMTs in MS target patients who are already 
progressed, for example the mean duration of disease is around six years for many 
clinical trials (Wiendl and Meuth. 2015). There is, however, evidence suggesting that 
early intervention might be effective in reducing the rate of relapses in patients with 
RRMS and in slowing the course of MS progression (Noyes and Weinstock-Guttman 
2013). 
A follow-up of the phase 3 clinical trial (n = 160) of IFNβ-1a vs. placebo in early RRMS 
patients described above, patients randomized to IFNβ-1a (n=79) were significantly less 




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Objectives
Corresponding Endpoints
Proportion of patients who have confirmed disability 
improvement (CDI), CDP for at least 24 weeks and 48 
weeks at year 1, 2 and 4 
Proportion of patients who have improved, stable or 
worsened disability compared with baseline measured 
by EDSS annually
Mean change from baseline in EDSS score over the 
course of the study
Other clinical measures and composite endpoints:
Time to first protocol-defined event of disease activity
Time to first relapse 
Annualized relapse rate 
Proportion of patient relapse free by week 48, 96, 144 
and 192
Proportion of patients with no evidence of protocol-
defined disease activity (NEDA) over week 96, week 
144 and week 192 where disease activity is defined 
as at least one the following events: protocol-defined 
relapse; CDP based on increases in EDSS; a T1 Gd-
enhanced lesion after Week 8; or a new and/or 
enlarging T2 hyperintense lesion on MRI after Week 8 
compared to the Week 8 MRI scan.
Proportion of patients with no evidence of progression 
(NEP) defined as no progression sustained for at least 
24 weeks on all of the following three components
(CDP; 20% increase in timed 25 Foot Walk Test 
[T25FWT]; 20% increase in timed 9 hole peg test 
[9HPT]) between baseline and week 96/192
Proportion of patients with no evidence of progression 
sustained for at least 24 weeks and no active disease 
(NEPAD) defined as no progression on all of the three 
components of NEP (CDP, T25FWT, 9HPT), no new
relapse and no enlarging or new T2 or T1 Gd-
enhancing lesion between baseline and week 96/192
Change from baseline of Multiple Sclerosis Functional 
Composite (MSFC) and its composites (T25FW, 9HP, 
and Paced Auditory Serial Addition Test [PASAT]) 
over time
Change from baseline in cognitive performance as 
measured by Brief International Cognitive 
Assessment for Multiple Sclerosis (BICAMS) 
performed annually
Related to MRI
Total number of T1 Gd-enhancing lesions as detected 
by brain MRI over time
Total number of new and/or enlarging T2 lesion as 
detected by brain MRI over time
Change in total T1 hypointense lesion volume over 
time




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Objectives
Corresponding Endpoints
Ocrelizumab shorter infusion substudy 
(approximately 700 patients: of which 
approximately 550 additional patients 
and approximately 150 currently 
participating in the main study)
Proportion of patients with IRRs occurring during or 
within 24 hours following the first infusion after 
randomization to the shorter infusion substudy
The definition of a protocol-defined event of disease activity is the occurrence of Uat least 
one of the following while on treatment with ocrelizumab:

a protocol-defined relapse as defined in Section 4.5.5

CDP based on increases in EDSS (see Section 4.5.6)

a T1 Gd-enhanced lesion after Week 8

a new and/or enlarging T2 hyperintense lesion on MRI after Week 8 
compared to the Week 8 MRI scan
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
The main study is a prospective, multicenter, open-label, single-arm effectiveness and 
safety study in patients with early stage RRMS. The first dose of ocrelizumab will be 
administered as an initial dose of two 300-mg infusions (600 mg total) in 250 mL 0.9% 
sodium chloride each separated by 14 days (i.e., Days 1 and 15) followed by one 600-
mg infusion in 500 mL 0.9% sodium chloride every 24 weeks (± 14 days) for the 
remainder of the study duration. 
Patients will be assessed for effectiveness and safety every 24 weeks as described in 
the Schedule of Assessments presented in 55Appendix55 1.
The study will consist of the following periods:

Screening period:  Up to 4 weeks

Treatment period:  Open-label treatment period of 192 weeks (i.e. 24 weeks after 
the last dose of ocrelizumab, which will be administered at Week 168)

A safety follow-up period of 48 weeks after the last infusion of the study drug, as 
explained below
Safety Follow-up Period: Patients who discontinue treatment early for any reason and 
patients who complete the study treatment period and do not continue in a separate long-term 
extension (LTE) study, will be followed up for 48 weeks after the last infusion of study 
drug. When patients begin an alternative treatment for MS (see section 4.4.1 “Prohibited 
Therapy”), they will be discontinued from the study.
Patients who discontinue study treatment and switch to commercially marketed 
ocrelizumab, either after completion of the 192 weeks Treatment Period or after early 
discontinuation of the 192 weeks Treatment Period, will not enter the safety Follow-up 
Period.


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A structured telephone interview will be conducted by site personnel every 8 weeks 
between the study visits (starting after the site visit at 8 weeks) during the treatment 
period to identify and collect information on any changes in the patient’s health status 
that warrant an unscheduled visit (including new or worsening neurological symptoms) 
and possible events or infections.
3.1.1
Overview of Study Design
Figure 1 presents an overview of the study procedures. A schedule of assessments is 
provided in 55Appendix55 1.
Figure 1
Overview of Study Procedures
MRI magnetic resonance imaging; OCR = ocrelizumab; NEDA = no evidence of disease activity
3.1.2
Screening
After providing written informed consent, patients will enter a screening period (up to 4-
weeks) to be evaluated for eligibility. 
Re-screening of patients is allowed in this protocol.
3.1.3
Treatment Period
Eligible patients will be treated with an initial dose of two 300-mg infusions (600 mg total) 
in 250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15) 
followed by one 600-mg infusion in 500 mL 0.9% sodium chloride every 24 weeks (±14 
days) for the remainder of study duration.


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Additional patients enrolled into the shorter infusion sub-study were randomized into 2 
groups at week 24 visit. One group received 600 mg ocrelizumab in 500 mL 0.9% 
sodium chloride infused over approximately 3.5 hours every 24 weeks (±14 days) for the 
remainder of the study duration (as in the main study) and the other group received 600 
mg ocrelizumab in 500 mL 0.9% sodium chloride infused over 2.0 hours followed by 100 
mL 0.9% sodium chloride given as a slow infusion over the remaining 1.5 hours, in order 
to mimic the standard-length infusion (3.5 hour) starting from week 24 for the remainder 
of the study duration. Please see Appendix 10 for further details. Patients already 
enrolled in the main study were offered to participate in the shorter infusion substudy 
and were randomized into the above 2 groups at the next main study visit if found 
eligible and after providing written informed consent. The protocol amendment version 
8.0 marked the completion of the shorter infusion substudy and patients will continue 
under the main study protocol.
Based on the results of the primary analysis of the shorter infusion substudy, patients 
will be allowed to switch from the conventional ocrelizumab infusion (3.5 hours) to the 
shorter ocrelizumab infusion (2.0 hours) at any visit after the Week 24 visit based on 
the schedules of infusion as per the protocol, after providing written informed consent 
and in agreement with their treating physician, provided they have not experienced any 
previous serious IRRs with ocrelizumab treatment. While on the shorter infusion, the 
patients can switch back to the conventional infusion, in agreement with their treating 
physician. If patients develop a serious IRR while on the shorter infusion, they will be 
switched to the conventional infusion and should not be restarted on the shorter infusion
at any following infusion visit.
All laboratory samples can be taken up to 2 weeks prior to the scheduled study visit. 
Local laboratory results for hematology, biochemistry and CD4 should be available prior 
to dosing as they are re-treatment criteria. Local laboratory results for CD8 and CD19 
may be available later, as they do not need to be verified prior to re-treatment. Samples 
for NfL, anti-drug antibodies (ADA), and ocrelizumab concentration are collected and 
sent to the central laboratory for analysis. Please see Section 4.5.8 for further details
After the end of treatment period visit of the last enrolled patient, approximately 24 weeks and 48 
weeks may be needed to allow the confirmation of the last event of the 24-week and 48-week CDP 
(CDP/CDI confirmation visit). For those patients presenting with an EDSS change at the end of 
the treatment period and who roll over to the LTE study (Study MN39158), the 24-week and 48-
week CDP confirmation visits will occur during the LTE study (Study MN39158). For patients 
who discontinue the study (e.g., move onto commercial ocrelizumab, or start treatment with 
another DMT), the EDSS CDP confirmatory assessments will not be performed.
Sub-studies will be conducted in selected countries according to local approvals and 
procedures. Please refer to Appendices 8, 9, and 10 for the sub-study protocols.


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UCriteria 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 
withheld indefinitely:

Life threatening (Common Terminology Criteria for Adverse Events [CTCAE] Grade 4) 
infusion-related event that occurred during a previous ocrelizumab infusion

Current active infection other than a fungal nailbed infection. The re-treatment should 
be delayed until the active infection is treated and patient fully recovered

CD4 cell count < 250/μL

Absolute neutrophil count (ANC) <1.0 × 103/μL

Elevated aspartate aminotransferase (AST)/ serum glutamic oxaloacetic 
transaminase (SGOT) or alanine aminotransferase (ALT) /serum glutamic pyruvic 
transaminase (SGPT) (3 the upper limit of normal [ULN]) in combination with 
either an elevated total bilirubin (2 ULN) or clinical jaundice

Hepatitis B screening tests prior to ocrelizumab administration
o
If total hepatitis B core antibody (HBcAb) was positive at screening, hepatitis 
B virus (HBV) deoxyribonucleic acid (DNA) measured by polymerase chain 
reaction (PCR) must be negative in order for a patient to be dosed with 
ocrelizumab. For patients with negative hepatitis B surface antigen (HBsAg) 
and positive total HBcAb, HBV DNA testing (by PCR) must be repeated every 
24 weeks and evaluated prior to ocrelizumab administration. If it becomes 
positive, treatment with ocrelizumab must be discontinued and the patient 
should enter the safety follow-up.

Any significant or uncontrolled medical condition or treatment-emergent, clinically 
significant laboratory abnormality

Ongoing pregnancy or breastfeeding (In case of unplanned pregnancy, treatment 
should be interrupted, however the patient will remain in the trial and will have the 
opportunity to re-start ocrelizumab treatment after birth and breastfeeding are over. 
The total duration of treatment period will be 192 weeks from the date of first dose of 
ocrelizumab, irrespective of how long the treatment was interrupted due to 
pregnancy. During pregnancy and breastfeeding, the patient will continue to come for 
the regular scheduled visits (whenever possible, adhering to the time of scheduled 
visits as per protocol) and will perform all assessments except MRI.
At the end of the study treatment the patients will be encouraged to be included in a 
separate LTE (MN39158) study, as applicable, to further evaluate the effectiveness and 
safety of ocrelizumab treatment. This LTE will also aim to evaluate the long-term outcomes 
with ocrelizumab treatment over the extended period of time in patients with MS.


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Figure 2 Overview of End of Treatment Period provides an overview of the end-of-treatment 
period. (Please see Section 3.1.4).
A structured telephone interview will be conducted by site personnel every 8 weeks between the 
study visits (starting after the site visit at 8 weeks) during the treatment period to identify and 
collect information on any changes in the patient’s health status that warrant an unscheduled 
visit (including new or worsening neurological symptoms) and possible events or infections.
Figure 2
Overview of End of Treatment Period
LTE = Long-term extension; MS = Multiple sclerosis
3.1.4
Safety Follow-up Period
Patients who discontinue treatment early for any reason and patients who complete the 192 
weeks Treatment Period and do not continue in a separate LTE study will be followed up for 48 
weeks after the last infusion of study drug. When patients begin an alternative treatment for 
MS (see section 4.4.1 “Prohibited Therapy”), they will be discontinued from the study.
Patients who discontinue study treatment and switch to commercially marketed 
ocrelizumab, either after completion of the 192 weeks Treatment Period or after early 
discontinuation of the 192 weeks Treatment Period, will not enter the Safety Follow-up 
Period.
A schedule of assessments for the Safety Follow-up Period is presented in Appendix55 2.
During the Safety Follow-up Period, patients will be formally assessed at clinical visits 
every 24 weeks.


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Related SAEs must be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed.
Unrelated SAEs must be collected and reported during the study through the end of the 
Safety Follow-Up Period, which is 48 weeks after the last infusion. Non-serious adverse 
events have to be reported until the end of Safety Follow-up Period. 
For patients withdrawing from treatment early, every effort should be made to complete 
the Safety Follow-up Period and all related assessments. 
3.1.5
Planned Total Sample Size
The main study was initially planned to enroll at least 600 patients. Please refer to the 
55 USection 6.1U55 for more details.
Approximately 550 additional patients were to be enrolled in the shorter infusion sub-
study. They would also be enrolled in the main study (see Appendix 10 for more 
details). 
Therefore, the main study would enroll a total of at least 1,100 patients. A total of 1,225 
patients (678 in the main study and 547 in the shorter infusion substudy) were enrolled 
in the study.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of the main study is defined as the last patient last visit in the Safety Follow-up 
period or last patient Week 192 visit, whichever occurs later.
The end of the study treatment period has been defined as the date on which the last 
patient receiving the full study treatment reached the 192-week visit. After the end of 
treatment period visit of the last enrolled patient, approximately 24 weeks and 48 weeks may be 
needed to allow the confirmation of the last event of the 24-week and 48-week CDP (CDP/CDI 
confirmation visit). For those patients presenting with an EDSS change at the end of the 
treatment period and who roll over to the LTE study LIBERTO (Study MN39158), the 24-week 
and 48-week CDP confirmation visits will occur during the LTE study (Study MN39158). For 
patients who discontinue the study (e.g., move onto commercial ocrelizumab, or start treatment 
with another DMT), the EDSS CDP confirmatory assessments will not be performed.
The total length of the main study, from screening of the first patient to the end of the 
study depends on the recruitment rate and is expected to be approximately 356 weeks 
(7 years). This includes an enrolment period of 116 weeks.
3.3
RATIONALE FOR STUDY DESIGN
The main study is a Phase IIIb, prospective, multicenter, open-label singe-arm study to 
assess the effectiveness and safety of ocrelizumab in patients in the early stage of 
RRMS. 


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As the efficacy and safety of ocrelizumab has already been demonstrated in pivotal 
double-blind, randomized controlled trials as described in Section 1.2, a single arm 
approach for this study, where the goal is to characterize the clinical profile of the drug in 
early patients, is considered to be appropriate. As the effect of existing standard of care 
treatments on the clinical course of early RRMS is already well established in the 
literature (Noyes and Weinstock-Guttman 2013; Rudick et al.2010), no direct 
comparators are required for this study. The main analyses will be in the form of 
descriptive statistics examining change from baseline to endpoint across the outcome 
parameters for the entire study sample, and for sub-groups of interest. A study duration 
of 4 years is considered to be sufficient to show a reliable and relevant effect of 
ocrelizumab on disability progression (EMA/CHMP/771815/2011, Rev. 2, 2015). Given 
the potentially long-term use of ocrelizumab in MS, this study of 4 years duration will 
provide additional safety data in a population with early stage of RRMS to be 
contextualized with the population studied in the pivotal phase III trials.
The effectiveness of ocrelizumab will be evaluated based on various clinical outcomes 
related to disease progression over 4 years. 
One of the key outcome measures is time to onset of confirmed CDP sustained for at 
least 24 weeks and 48 weeks with CDP defined as 1-point or greater worsening in EDSS 
from baseline. An increase of 1 point on the EDSS above baseline, subsequently
confirmed at repeat assessment either 3 or 6 months later (3 or 6 month confirmed 
progression) is the most commonly used measure in MS clinical trials (Gray and 
Butzkueven. 2008). In RRMS, the precise measurement of disability is complicated by 
the unpredictable occurrence of exacerbations with variable recovery. To ensure that 
worsening in EDSS score represents permanent physical disability rather than an 
exacerbation-related temporary fluctuation in neurological status, a worsening EDSS 
score has to be sustained for at least 6 months for a patient to be considered a 
treatment failure. Previous studies have shown that spontaneous recovery from 
sustained progression of 1.0 EDSS point of this duration is most unusual (Jacobs 1996). 
CDP is therefore a robust measure when performed over a 6-month interval, and 
reduction in the risk of 6-month CDP provides good evidence for the beneficial effects on 
disability of several high-efficacy treatments for RRMS (Wiendl et al. 2015).
EDSS is the most widely used and well-known scale to assess changes in disability in 
MS. Evaluation of change from baseline in EDSS score over the course of the study will 
provide an overall estimate of the dysfunction that was experienced by the patient during 
the study period. 
Other key end-points such as MRI variables (for example, lesion count, lesion volume, 
and brain volume) are commonly used in clinical trials to assess treatment efficacy and 
disease progression (Lavery et al. 2014). Based upon the Phase II data, and to allow the 
real evaluation of the treatment effect, MRI activity will be evaluated starting from week 8 
in this study. Time to onset of first relapse and proportion of patients who are relapse 


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free are also acceptable parameters to assess relapse-status in RRMS clinical trials 
(EMA/CHMP/771815/2011, Rev. 2, 2015). 
It is recognized that the EDSS does not adequately assess upper limb function and 
cognitive impairment and the use of specific methods could be useful. In this context, 
quantitative neurological performance tests, for example MSFC may be used as 
secondary measurements of disability. The MSFC score combines a measure of lower 
limb function (T25FWT), upper limb function (9HPT) and cognitive function (PASAT) and 
is useful to detect disability progression in MS trials, as it is sensitive to change over 
time. The scores for each test are normally distributed, and are highly responsive to 
change over 2 years, thus producing much greater statistical power to detect change in 
the context of clinical trials (Gray and Butzkueven. 2008).
Prevention of disability progression as measured by the different elements: CDP but also 
upper limb function (9HP) and lower limb function (T25FW) are from early on important 
for the patient to allow optimal functioning. In RRMS, beside the disability, also clinical 
and subclinical elements of disease activity (relapses, T1 Gd+ and new/enlarging T2 
lesions) remain of importance since these elements can contribute to the progression of 
the disability or the MS disease in general.
As the burden of cognitive impairment in MS is considerable, and is of crucial 
significance in employment outcomes and social disability (Gray and Butzkueven. 2008), 
the BICAMS, an international expert consensus recommended and validated battery of 
tests for mental processing speed and memory (Benedict et al., 2012) will be used as a 
secondary outcome measure to assess the changes from baseline in cognitive 
performances. 
MS is a chronic, disabling condition having a significant impact on patients quality of life 
(QoL) and therefore MSIS-29, a clinically useful and scientifically-sound patient-based 
outcome measure of the impact of MS in clinical trials (Hobart et al. 2001) will be used 
as a key exploratory outcome measure to assess the physical and psychological impact 
of MS from the patient’s perspective. 
During the controlled treatment periods of the Ocrelizumab Phase III studies 
approximately 1% (12/1311) of ocrelizumab-treated patients tested positive for 
treatment-emergent ADAs. Some of the inclusion criteria are different in this study 
compared to the pivotal studies. Moreover, commercial material is introduced in the 
phase IIIb studies for which no immunogenicity data are available. Therefore, ADAs will 
also be assessed in this study for two years. 
Rationale for measuring impact of ocrelizumab on response to SARS-CoV-2 vaccines
The results of the randomized, open-label Phase IIIb study (VELOCE), which assessed if 
ocrelizumab recipients with RMS raise adequate humoral responses to selected vaccines, indicate 
that patients with RMS who are peripherally B-cell depleted after treatment with ocrelizumab can 


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mount humoral responses, albeit attenuated, to tetanus toxoid, 23-valent pneumococcal 
polysaccharide, keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines. The 
immune response of other components of the immune system (e.g., T cell response), known to 
confer immunological protection in addition to antibodies, were not evaluated. 
Recently, vaccines against the SARS-CoV-2 virus have received authorizations for use from 
regulatory agencies. Vaccine efficacy data, and vaccine effectiveness from real world settings have 
shown that the available vaccines lead to a significant reduction in the number of COVID-19 
infections and the number of severe cases that require hospitalization or result in fatal outcomes. 
Available data from the vaccine trials demonstrate that these vaccines can induce an antibody 
response as well as T cell responses. While not fully understood, accruing evidence suggests that 
both antibodies and T cell-mediated immunity have a protective role against future SARS-CoV-2 
infection and severe clinical presentations. Currently, evidence on the SARS-CoV-2 vaccine 
response in persons taking immunomodulatory treatments is lacking, including in patients with 
MS treated with ocrelizumab.
Humoral immunity, including antibody titers, will be assessed by validated assays including the 
Elecsys SARS-CoV-2 Spike antibody test. SARS-CoV-2-specific T cell responses will be 
measured using a well-validated assay such as IFNg (interferon gamma) ELISpot (enzyme-linked 
immunospot). Immunophenotyping outcomes are to be assessed by flow cytometry. Other 
exploratory assays for humoral and cellular immune responses may be performed based upon 
emerging safety, efficacy, and immunogenicity data.
Responses will be measured within a few weeks post-immunization and up to 18 months after the 
vaccination to evaluate the impact of ocrelizumab on the vaccine immune response over time. 
3.3.1
Rationale for Ocrelizumab Dose and Schedule
The dose level of ocrelizumab administered in the main study is 600 mg. The first dose 
will be administered as two 300-mg IV infusions in 250 mL 0.9% sodium chloride each 
separated by 14 days in order to lower the amount of ocrelizumab administered upon 
first exposure. The remaining doses will be administered as single 600-mg infusion in 
500 mL 0.9% sodium chloride every 24 weeks (±14 days) to assess the tolerability of the 
intended administration regimen. 
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 RRMS.
3.3.2
Rationale for Patient Population
The main study will be conducted in treatment naïve early stage RRMS patients. 
As the primary objective of the study is to evaluate the effectiveness of ocrelizumab in 
early stage of RRMS, length of disease duration from first symptom of ≤ 3 years, and a 
low EDSS score of 0.0 to 3.5 are the key entry criteria to ensure inclusion of this early 
population (Jacobs et al. 1996; Coles et al. 2008). 


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4.
MATERIALS AND METHODS
4.1
PATIENTS
The main study was initially planned to enroll at least 600 patients with early stage 
RRMS who fulfil the eligibility criteria listed below. Approximately 550 additional 
patients were to be enrolled in the shorter infusion sub-study. They would also be 
enrolled in the main study (see Appendix 10 for more details). Therefore, the main 
study would enroll a total of at least 1,100 patients. A total of 1,225 patients (678 in the 
main study and 547 in the shorter infusion substudy) were enrolled in the study.
4.1.1
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 RRMS, as per the revised McDonald 2010 criteria 
(Polman et al. 2011)

Have a length of disease duration, from first documented clinical attack consistent 
with MS disease of ≤ 3 years

Within the last 12 months: 
One or more clinically reported relapse(s) 
OR
One or more signs of MRI activity

EDSS of 0.0 to 3.5 inclusive, at screening

For women of childbearing potential:  agreement to use an acceptable birth control 
method during the treatment period and for at least 6 months or longer after the last 
dose of ocrelizumab, as applicable in the ocrelizumab package leaflet.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). The definition of childbearing 
potential may be adapted for alignment with local guidelines or requirements.
The following are acceptable contraceptive methods (failure rate >1% as defined by 
the Clinical Trial Facilitation Group [CTFG] guidelines): (1) progestogen-only oral 
hormonal contraception, where inhibition of ovulation is not the primary mode of 
action, (2) male or female condom with or without spermicide, (3) cap, diaphragm, or 
sponge with spermicide, (4) combination of male condom with cap, diaphragm, or 
sponge with spermicide (double-barrier methods).
Birth control methods that are highly effective (i.e. failure rate <1% [CTFG]) may also be 
used but are not required, and include: (1) oral, intravaginal or transdermal combined 
hormonal contraception associated with inhibition of ovulation; (2) oral, injectable or 


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implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation; (3) intrauterine device; (4) intrauterine hormone-releasing system; (5) bilateral 
tubal occlusion; (6) vasectomised partner; (7) sexual abstinence.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

SPMS or history of primary progressive or progressive relapsing MS

Inability to complete an MRI (contraindications for MRI include but are not restricted 
to 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, claustrophobia, 
weight>140 kg 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 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, sarcoidosis)

History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression)
UExclusions Related to General Health

Pregnancy or lactation.

Patients intending to become pregnant during the study or within 6 months after the 
last dose of the study drug.

Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study.

History or currently active primary or secondary immunodeficiency.

Lack of peripheral venous access.


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
History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies.

Significant or uncontrolled somatic disease or any other significant disease that may 
preclude patient from participating in the study.

Congestive heart failure (New York Heart Association [NYHA] III or IV functional 
severity).

Known active bacterial, viral, fungal, mycobacterial infection or other infection, 
(excluding fungal infection of nail beds) or any major episode of infection requiring 
hospitalization or treatment with intravenous (IV) antibiotics within 4 weeks prior to 
screening or oral antibiotics 2 weeks prior to screening
Note: Active infections must be treated and effectively controlled before possible 
inclusion in the study

History of major opportunistic infections (i.e. cryptococcosis, Pneumocystis 
pneumonia, progressive multifocal leukoencephalopathy [PML])

History or known presence of recurrent or chronic infection (e.g., human 
immunodeficiency virus [HIV], syphilis, tuberculosis [TB])

History of malignancy, including solid tumors and hematological malignancies, 
except basal cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ 
carcinoma of the cervix of the uterus that have been previously completely excised 
with documented, clear margins.

History of alcohol or drug abuse within 24 weeks prior to baseline.

History or laboratory evidence of coagulation disorders.
UExclusions Related to Medications

Received any prior approved DMT with a label for MS, for example, interferons, GA, 
natalizumab, alemtuzumab, daclizumab, fingolimod, teriflunomide and 
dimethylfumarate.

Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the 
baseline visit.
In rare cases when patient requires vaccination with a live vaccine, the screening 
period may be extended but cannot exceed 8 weeks.

Treatment with any investigational agent within 24 weeks of screening (Visit 1) or 
five half-lives of the investigational drug (whichever is longer) or treatment with any 
experimental procedures for MS (e.g., treatment for chronic cerebrospinal venous 
insufficiency).

Contraindications to or intolerance of oral or IV corticosteroids, including 
methylprednisolone administered IV, according to the country label, including:
a) Psychosis not yet controlled by a treatment
b) Hypersensitivity to any of the constituents.

Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, 
atacicept, belimumab, or ofatumumab).


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
Systemic corticosteroid therapy within 4 weeks prior to screening.

Any previous treatment with immunosuppressants/ immunomodulators/ 
antineoplastic therapies (cyclophosphamide, azathioprine, mycophenolate mofetil, 
cyclosporine, methotrexate, cladribine, mitoxantrone, laquinimod, total body 
irradiation, or bone marrow transplantation).

Treatment with IV Ig within 12 weeks prior to baseline.

Treatment with investigational DMT

History of recurrent aspiration pneumonia requiring antibiotic therapy

Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stable 
dose for ≥ 30 days prior to screening. Wherever possible, patients should remain on 
stable doses throughout the 96-week treatment period
UExclusions Related to Laboratory Findings*

Positive serum β human chorionic gonadotropin (hCG) measured at screening.

Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, 
or positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA 
polymerase chain reaction [PCR]).

Lymphocyte count below LLN

CD4 count<250/μL.

AST/ SGOT or ALT /SGPT≥ 3.0 × ULN

Serum creatinine >1.4 mg/dL (> 124 μmol/L) for women or > 1.6 mg/dL (> 
141μmol/L) for men

Hemoglobin < 8.5 g/dL (< 5.15 mmol/L)

Platelet count <100,000/μL (<100 × 109/L)

Absolute neutrophil count <1.0 × 103/μL.
*
URe-testing before baseline: any abnormal screening laboratory value that is clinically 
relevant should be retested in order to rule out any progressive or uncontrolled 
underlying condition. The last value before randomization must meet study criteria. 
UPlease note: based on local Ethics Committees (EC) or National Competent Authority 
requirements, additional diagnostic testing may be required for selected patients or 
selected centers to exclude tuberculosis, Lyme disease, HTLV-1 associated myelopathy 
(HAM), acquire immunodeficiency syndrome (AIDS), hereditary disorders, connective 
tissue disorders, or sarcoidosis. Other specific diagnostic tests may be requested when 
deemed necessary by the Investigator.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
The main study is open-label 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. 


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for the main study is ocrelizumab.
4.3.1
Study Treatment Formulation and Packaging
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 106 mM trehalose 
dihydrate and 0.02% polysorbate 20. The drug product is provided as a single-use liquid 
formulation in a 15-cc, type I United States Pharmacopeia (USP), glass vial fitted with a 
20-mm, fluoro-resin, laminated stopper and an aluminum seal with a flip-off plastic cap. 
The vial contains 300 mg ocrelizumab. No preservative is used as each vial is designed 
for single use, thus the vials should be handled aseptically.
The ocrelizumab drug product in vials should be stored at 2-8 degrees Celsius and 
protected from light, should not be frozen and not be shaken.
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 0.2μm).
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, the total storage time of 
the infusion solution prior to administration should not exceed 24 hours at 2 to 8°C and 8 
hours at room temperature for a total of 32 hours. 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 IB 
and Drug Preparation Guidelines.
4.3.2
Study Treatment Dosage, Administration, and Compliance
4.3.2.1
Ocrelizumab
The first dose of ocrelizumab will be administered as two 300-mg infusions (600 mg 
total) in 250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15), 
followed by one 600-mg infusion in 500 mL 0.9% sodium chloride every subsequent 
doses (i.e., every 24 weeks ±14 days) for a maximum of 8 doses.


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It is anticipated that the patient will need to stay at the hospital or clinic for the infusion 
visits. Ocrelizumab infusions should be initiated and supervised by an experienced 
professional with access to appropriate medical support to manage severe reactions 
such as serious IRRs. Each ocrelizumab infusion should be given as a slow IV infusion 
over approximately 150 minutes (2.5 hours) for the 300 mg dose and for the 600 mg 
dose, it should be given over approximately 215 minutes (3.5 hours) for the conventional 
infusion and approximately 120 minutes (2.0 hours) for the shorter infusion. To reduce 
potential IRRs, all patients will receive prophylactic treatment with 100 mg intravenous
methylprednisolone, or equivalent, administered by slow IV infusion, to be completed 
approximately 30 minutes and not less than 25 minutes prior to each ocrelizumab 
infusion and antihistamine, via oral, intramuscular or IV route to be completed
approximately 30-60 minutes and not less than 25 minutes prior to each infusion of 
ocrelizumab (the antihistamine should be the first premedication to be administered). 
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be 
considered. Additional premedication is recommended, see Section 4.3.3.
Additional patients enrolled into the shorter infusion substudy and randomized to the 
shorter infusion group received 600 mg ocrelizumab in 500 mL 0.9% sodium chloride 
infused over 2.0 hours followed by 100 mL 0.9% sodium chloride given as a slow 
infusion over the remaining 1.5 hours, in order to mimic the standard-length infusion (3.5 
hour) starting from week 24 for the remainder of the study duration. The patients
received the same premedications as in the main study. Please see Appendix 10 for the 
details on infusion rate and time for the shorter infusion of ocrelizumab. The protocol 
amendment version 8.0 marked the completion of the shorter infusion substudy and 
patients will continue under the main study protocol.
Hypotension, as a symptom of IRR, may occur during ocrelizumab IV infusions. 
Therefore, withholding antihypertensive treatments should be considered for 12 hours 
prior to and throughout each 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. 
The patient will need to remain at the clinic at every visit for at least 1 hour after the 
completion of the infusion for observation. After completion of the infusion, the IV 
cannula should remain in situ for at least 1 hour to allow for administration of drugs 
intravenously, if necessary, in the event of a delayed reaction. If no adverse events 
occur during this period of time, the IV cannula may be removed and the patient may be 
discharged.


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See the Ocrelizumab IB and Drug Preparation Guidelines for detailed instructions on 
drug preparation, storage, and administration.
An overview of the ocrelizumab dosing is presented in Table 2 and the infusion rates for 
the conventional and the shorter infusions in Table 3.
Table 2Overview of Ocrelizumab Dosing
Group
1st Dose a,c
2nd 
Dose b,c
3rd 
Dose b,c
4th 
Dose b,c
5th 
Dose b,c
6th 
Dose b,c
7th 
Dose b,c
8th 
Dose b,c
(Weeks 1 24)
(Weeks 
24 48 ± 
14 days)
(Weeks 
48 72 ± 
14 days)
(Weeks 
72 96 ± 
14 days)
(Weeks 
96 120
± 14 
days)
(Weeks 
120 144
± 14 days)
(Weeks 
144 168
± 14 days)
(Weeks 
168 192
± 14 days)
Day 1 
Infusion
Day 15 
Infusion
Week 24 
Infusion
Week 48 
Infusion
Week 72 
Infusion
Week 96 
Infusion
Week 120 
Infusion
Week 144 
Infusion
Week 168 
Infusion
Ocrelizumab
300 mg IV
in 250 mL 
0.9%
sodium 
chloride
300 mg IV
in 250 mL 
0.9%
sodium 
chloride
600 mg IV
in 500 mL 
0.9%
sodium 
chloride
600 mg IV
in 500 mL 
0.9%
sodium 
chloride
600 mg IV
in 500 mL 
0.9%
sodium 
chloride
600 mg IV
in 500 mL 
0.9%
sodium 
chloride
600 mg IV
in 500 mL 
0.9%
sodium 
chloride
600 mg IV
in 500 mL 
0.9%
sodium 
chloride
600 mg IV
in 500 mL 
0.9%
sodium 
chloride
IVintravenous.
Note:  Before each infusion of ocrelizumab, 100 mg of methylprednisolone IV and an 
antihistaminic drug will be administered to reduce the potential for infusion-related reactions.  
Each dose has a duration of 24 weeks.  The open-label treatment period consists of 192 weeks 
of treatment; patients will receive a maximum of 8 doses. 
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.
Table 3Ocrelizumab infusion rates for Conventional and Shorter Infusions
in absence of IRRs 
Time (min)
Shorter infusion
Conventional infusion
Infusion 
rate (mL/hr)
Max dose 
per 
interval 
(mg)
Cumulative 
dose
(mg)
Infusion 
rate 
(mL/hr)
Max dose 
per 
interval 
(mg)
Cumulative 
dose
(mg)
0-15
100
30
30
40
23.18
23.18
16-30
200
60
90
31-60
250
150
240
85
49.27
72.45
61-90
300
180
420
130
75.36
147.81
91-120
300
180
600
169
98.05
245.86
121 – 215
/
/
/
200
354.14
600


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IRR infusion-related reaction
Note: Patients will be allowed to switch from the conventional ocrelizumab infusion (3.5 hours) to 
the shorter ocrelizumab infusion (2.0 hours) at any visit after the Week 24 visit, based on the 
schedules of infusion as per the protocol, after providing written informed consent and in 
agreement with their treating physician, provided they have not experienced any previous serious 
IRRs with ocrelizumab treatment. If patients develop a serious IRR while on the shorter infusion, 
they will be switched to the conventional infusion and should not be restarted on the shorter 
infusion at any following infusion visit.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF). AEs associated with an 
overdose or incorrect administration of study drug should be recorded on the AE eCRF.
4.3.3
Prophylactic Treatment
The following premedications must be administered prior to each infusion of ocrelizumab 
to reduce the frequency and severity of IRRs:

100 mg intravenous methylprednisolone (or an equivalent), administered by slow 
IV infusion, to be completed approximately 30 minutes and not less than 25 
minutes prior to each ocrelizumab infusion

Antihistamine, via oral, intramuscular or IV route to be completed approximately 
30-60 minutes and not less than 25 minutes prior to each ocrelizumab infusion 
(the antihistamine should be the first premedication to be administered)

The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be 
considered
Any overdose or incorrect administration of methylprednisolone and antihistaminic drug 
should be noted on the Pre-Infusion Prophylactic Treatment eCRF. Adverse events 
associated with an overdose or incorrect administration of methylprednisolone and 
antihistaminic drug should be recorded on the Adverse Event eCRF.
Patients administered a sedating antihistamine for the treatment or prevention of IRRs 
should be given appropriate warnings concerning drowsiness and potential impairment 
of ability to drive or operate machinery.
4.3.4
Investigational Medicinal Product Handling and Accountability
The IMP required for completion of the main study (ocrelizumab) will be provided by the 
Sponsor where required by local health authority regulations. The study site 
(i.e., investigator or other authorized personnel [e.g., pharmacist]) is responsible for 


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maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each patient, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that patients are provided with doses specified by the 
protocol.
The study site should follow all instructions included with each shipment of IMP. The 
study site will acknowledge receipt of IMP supplied by the Sponsor, using the interactive 
voice/Web response system (IxRS) to confirm the shipment condition and content. Any 
damaged shipments will be replaced. The investigator or designee must confirm that 
appropriate temperature conditions have been maintained during transit, either by time 
monitoring (shipment arrival date and time) or temperature monitoring, for IMP received and 
that any discrepancies have been reported and resolved before use of the IMP. All IMP 
must be stored in a secure, environmentally-controlled and monitored (manual or 
automated) area in accordance with the labeled storage conditions, with access limited 
to the investigator and authorized staff.
Only patients enrolled in the study may receive IMP, and only authorized staff may 
supply or administer IMP.
The IMP 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 destroying Sponsor-supplied IMP must 
be agreed to by the Sponsor. The site must obtain written authorization from the 
Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must be 
documented on the appropriate form.
Accurate records of all IMP received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log.
Refer to the Dose Preparation Guidelines and/or the ocrelizumab IB for information on 
IMP handling, including preparation and storage, and accountability. 
4.3.5
Continued Access to Ocrelizumab
Patients may be eligible to receive ocrelizumab as part of an extension study (MN39158) 
to evaluate long-term effectiveness and safety, as described in Section 3.1.3.
The Sponsor will offer continued access to Roche IMP (ocrelizumab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (ocrelizumab) after completing the study if 
all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being


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
There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Roche IMP (ocrelizumab) after completing the 
study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for RMS and PPMS

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
RMS and PPMS

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
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 in addition to protocol-mandated treatment within 6 weeks prior to the screening 
visit to the study completion/ discontinuation visit. All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Prohibited Therapy
No formal drug-drug interaction studies have been conducted with ocrelizumab, as no 
drug-drug interactions are expected via the Cytochromes P450, other metabolizing 
enzymes or transporters.
Ocrelizumab is a monotherapy and has not been studied in combination with other 
DMTs. As with other immunomodulatory therapies, exercise caution when initiating 
ocrelizumab after an immunosuppressive therapy, and when initiating another therapy 
after ocrelizumab, taking into consideration the potential for overlapping 
pharmacodynamic effects.
Immunosuppressants, lymphocyte-depleting agents, or lymphocyte-trafficking blockers 
should NOT be administered while patient is B-cell depleted.
Hypotension, as a symptom of IRR, may occur during ocrelizumab IV infusions. 
Therefore, withholding antihypertensive treatments should be considered for 12 hours 
prior to and throughout each ocrelizumab infusion. 


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See the Ocrelizumab IB for a more detailed safety profile. In addition, the Investigator 
should contact the Medical Monitor if questions arise regarding medications not listed 
above.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the main study is provided in 
Appendix 1. All activities must be performed and documented for each patient.
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 to confirm that patients meet 
all eligibility criteria and none of the exclusion criteria before enrolment. 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, Concomitant Medication, and Demographic 
Data
Patients’ demographics (age, gender, self-reported race, and educational level), and 
neurological examination will be collected. Medical History will include clinically 
significant diseases, surgeries, reproductive status, smoking history, and all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, and nutritional supplements) used by the patient within 6 weeks prior to the 
screening visit:
MS disease history: 
First MS symptom: date, symptoms, severity, MRI. 
Diagnosis of MSU: 
Date, disease status, (EDSS, relapses, MRI) and, when available, criteria on which the 
diagnosis is based.
Baseline disease statusU:
EDSS, Number of relapses in the previous year, MRI lesions
4.5.3
Physical Examinations
A complete physical examination should include an evaluation of head, eye, ear, nose, 
and throat (HEENT), cardiovascular, dermatological, musculoskeletal, respiratory, and 
gastrointestinal systems. The following assessments will also be conducted:  
neurological examination (see Section 4.5.5), relapse description, EDSS (see 
Section 4.5.6), and MRI (see Section 4.5.7). Changes from baseline abnormalities 
should be recorded in patient notes. New or worsened clinically significant abnormalities 
not related to MS should be recorded as adverse events on the Adverse Event eCRF. 
Height and weight will be measured at screening only. See Appendix 1 (Schedule of 
Assessments) for the timing of these assessments.


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4.5.4
Vital Signs
Vital signs will include measurements of heart rate, systolic and diastolic blood 
pressures.
Vital signs should be taken within 45 minutes prior to the premedication
methylprednisolone (or an equivalent) infusion. In addition, vital signs should be 
obtained prior to the ocrelizumab infusion, then every 15 minutes (5 minutes) for the 
first hour, followed by every 30 minutes (±10 minutes) until 1 hour after the end of the 
infusion. Vital signs will be reported in the eCRF only in case of an IRR. 
Vital sign measurements will be performed as outlined in the schedule of assessments 
(see Appendix 1). Record abnormalities observed before enrolment on the General 
Medical History and Baseline Conditions eCRF. At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF (as presented 
in Section 5.3.5.6).
4.5.5
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 
treatment period. See Appendix 1 (Schedule of Assessments) for the timing of these 
assessments.
A protocol-defined MS relapse is an occurrence of new or worsening neurological 
symptoms attributable to MS that meets the following criteria:

Symptoms must persist for >24 hours and should not be attributable to 
confounding clinical factors (e.g., fever, infection, injury, adverse reactions to 
medications)

Symptoms should be preceded by neurological stability for at least 30 days

Symptoms should be accompanied by new objective neurological worsening 
determined with a timely EDSS/ Functional Systems Score (FSS) assessment, 
consistent with an increase of at least: 

≥0.5 points on EDSS scale

or ≥2 points on one of the following FSS scales: pyramidal, ambulation, 
cerebellar, brainstem, sensory, or visual

or ≥1 point on two or more of the following FSS scales: 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).
All patients with new neurological symptoms suggestive of a relapse should have an 
EDSS/FSS assessment performed as soon as possible, ideally within 7 days of the 


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onset of symptoms. EDSS/FSS data is needed to allow the sponsor to confirm whether 
the reported clinical relapse meets the criteria for a protocol-defined relapse.
Please note: All MS relapses (i.e., regardless of whether they may meet criteria for a 
protocol-defined relapse which will be adjudicated by the Sponsor based on the above 
criteria) will be recorded on a pre-specified eCRF “MS relapse” form. MS relapses 
should not be reported as an Adverse Event, unless they are serious.
As infection is a potentially serious complication of B cell-depleting therapy, investigators 
will also screen patients for signs and symptoms of any CNS infections and specifically
PML by evaluating neurological deficits localized to the cerebral cortex, such as cortical 
symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual 
defects, hemiparesis, cerebellar symptoms/signs (e.g., gait abnormalities, limb 
incoordination). Patients with suspected PML should be withheld from ocrelizumab 
treatment until PML is ruled out by complete clinical evaluation and appropriate 
diagnostic testing. A patient with confirmed PML should be withdrawn from the study.  
PML should be reported as a serious adverse event (with all available information) with 
immediate notification of the Medical Monitor. Please refer to Appendix 5 for guidance 
for diagnosis of PML.
Cognitive status: The cognitive status of the patient will be evaluated at baseline, and 
further yearly for the full duration of the trial with the use of BICAMS components.
4.5.6
Assessment of Disability
Disability in MS will be measured by the EDSS and MSFC. See Appendix 1 (Schedule of 
Assessments) for the timing of these assessments.
The EDSS is based on a standard neurological examination, incorporating seven 
functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, 
and cerebral rated and scored as FSS. Each FSS is an ordinal clinical rating scale 
ranging from 0 to 5 or 6. These ratings are then used in conjunction with observations 
and information concerning ambulation and use of assistive devices to determine the 
EDSS score (i.e., ambulation score 0 to 12). When determining the EDSS step, the Visual and 
the Bowel and Bladder FSS will be converted to a lower score as per the Neurostatus instructions. 
The original unconverted score should be recorded in the respective eCRF page. The EDSS is a 
disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death) (see
Appendix 3).
Disability progression has been defined as an increase of ≥ 1.0 point from the baseline EDSS score 
that is not attributable to another etiology (e.g., fever, concurrent illness, or concomitant 
medication) when the baseline score is 5.5 or less, and ≥ 0.5 when the baseline score is above 5.5. 
For patients with an EDSS of 0, progression is defined as a change >=1.5 points Disability 
progression is considered confirmed when the increase in the EDSS is confirmed at a regularly 
scheduled visit at least 24 weeks after the initial documentation of neurological worsening.


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CDI is defined as an improvement of 1 point on the EDSS score confirmed at a regular scheduled 
visit at least 24 weeks after the initial documentation of neurological worsening (measured only 
patients with a baseline EDSS of ≥2.0).
Stable disability is defined as a difference in EDSS score of no greater than ± 0.5 at the end of 
each year compared with baseline scores, worsened disability as an increase in EDSS score of > 
0.5 at the end of each year compared with baseline, and improved disability as a reduction in 
EDSS score of > 0.5 at the end of each year compared with baseline.
MSFC is a score combining a measure of lower limb function (T25FWT), upper limb 
function (9HPT) and cognitive function (PASAT) used to detect disability progression in 
MS trials. 
4.5.7
Brain Magnetic Resonance Imaging
MRI will be used to monitor CNS lesions and potentially other pathophysiology, such as 
inflammation and neurodegeneration. Brain MRI scans will be obtained at study visits as 
shown in the Schedule of Assessments (see Appendix 1). 
MRI scans will be read and assessed by a centralized reading center for effectiveness 
endpoints. As soon as the scan is received by the central MRI reading center, it will be 
evaluated for quality, completeness and adherence to the protocol including 
effectiveness endpoints. Confirmation of acceptable MRI quality or a description of the 
quality problems, if detected, will be communicated to the site. If the MRI scan is 
incomplete or incorrectly performed, the study center and the patient might be asked to 
repeat it. After completion of the quality check, all scans will be analyzed according to 
the MRI protocol.
Investigators must comply with local country regulations for MRI repetition. The final 
decision for the repetition of the MRI scans lies with the Investigator.
Further details on scanning acquisition sequences, methods, handling, transmission of 
the scans, and certification of site MRI scanners are described in a separate MRI 
technical manual.
Assessments will include T1-weighted scans before and after injection of gadolinium 
contrast, and may also include, but may not be limited to:  FLAIR, proton density-
weighted, and T2-weighted scans. The MRI activity will be based upon the MRI scan 
taken on week 8 when the drug has reached its anti-inflammatory activity. 
The total brain volume and the different white and grey matter structures will be 
measured over the full duration of the study and follow-up period.
The brain MRI scan should be obtained within 14 days prior to the next ocrelizumab 
infusion and it should be reviewed by the local/treating investigator to exclude non-MS 


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pathology, including PML before the next infusion is administered. The MRI should be 
approved by the Medical Image Analysis Centre for efficacy evaluation before dosing 
with ocrelizumab.
If a patient receives corticosteroid for the treatment of a MS relapse, every effort should 
be made to obtain the scan prior to the first steroid dose, if the pre-steroid scan is within 
1 week of the scheduled visit. In patients already receiving corticosteroids for an MS 
relapse, there should be an interval of at least 3 weeks between the last dose of 
corticosteroid and the scan, to allow normalization of the blood brain barrier.
4.5.8
Laboratory, Biomarker, and Other Biological Samples
Laboratory samples can be taken up to 2 weeks prior to the scheduled study visit. Local 
laboratory results for hematology, biochemistry and CD4 should be available prior to 
dosing as they are re-treatment criteria. Local laboratory results for CD8 and CD19 may 
be available later, as they do not need to be verified prior to re-treatment. Samples for 
NfL, ADA, and ocrelizumab concentration are collected and sent to the central laboratory 
for analysis. Please see details below.
Pre-infusion laboratory samples should be drawn so that routine laboratory test results are 
available for review before the infusion, unless otherwise specified. 
Routine laboratory assessments (performed in local laboratory) will include the following:

Hematology (hemoglobin, hematocrit, platelet count, red blood cell [RBC] count, 
white blood cell [WBC] count, percent and absolute differential count [neutrophils, 
eosinophils, lymphocytes, monocytes, basophils]).

Serum chemistries (AST, ALT, gamma-glutamyl transpeptidase [GGT], total 
bilirubin, creatinine, random glucose, potassium, sodium)

Urine dipstick at site

Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a serum pregnancy test at screening. A urine pregnancy 
test should be performed prior to methylprednisolone infusion in subsequent doses. 
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
The follicle-stimulating hormone (FSH) test is only applicable to confirm 
postmenopausal status in female patients.

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

Lymphocytes subtypes

Whole-blood samples will be collected to determine the duration of B-cell 
depletion and recovery (CD19+) and T-cell counts (CD4+, CD8+)


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Additional laboratory samples will be collected:

Serum samples will be collected for determination of ocrelizumab concentrations and 
antibodies against ocrelizumab (ADA) for 2 years of treatment for each patient. Since 
ocrelizumab concentrations can affect the ADA assay, the concentration of 
ocrelizumab will be measured as well at all time points with ADA assessment to 
enable interpretation of the results. For details please refer to Schedule of 
Assessments (see Appendix 1). Sample should be collected before the 
methylprednisolone infusion. Following 2 years, samples should only be collected in 
any event of anaphylaxis, anaphylactoid reaction, or serious or severe 
hypersensitivity reaction as close as possible to the event and then at 4- and 16-
weeks post-dose.

A serum sample will be collected before the methylprednisolone infusion (if obtained 
on the days of ocrelizumab infusion), and analysis may include, but will not be limited to
NfL. This sample description covers retrospectively the serum collected for 
immunoglobulins up to protocol version 5.0.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Per local Institutional Review Board (IRB)/EC requirements, additional testing may be 
required for selected patients or selected centers to exclude tuberculosis, Lyme disease, 
HAM, AIDS, hereditary disorders, connective tissue disorders, or sarcoidosis.
4.5.9
Patient-Reported Outcomes
PRO data will be elicited from patients in the main study to better characterize patient 
quality of life. 
The MSIS-29 version 2 is the second version of 29-item questionnaire designed to 
measure the physical and psychological impact of MS from the patient’s perspective 
(Hobart et al. 2001). Each question is scored on the scale of 1-4. The physical (20 items) 
and psychological (9 items) scales are scored separately. Scores are transformed into a 
0-100 scale with higher scores indicating a greater degree of disability or impact of MS 
on the daily life of the patient. 
The SymptoMScreen is a composite score based upon a battery of seven-point Likert 
scales for 11 distinct domains commonly affected by MS: mobility, dexterity, vision, 
fatigue, cognition, bladder function, sensation, spasticity, body pain, depression and 
anxiety. Total score (0-66) and subscale scores are assessed over the study duration 
(Green et al. 2015). Higher scores indicate greater severity of symptoms.
The Employment Status WPAI is a questionnaire that assesses working status and the 
impact of MS on absenteeism, presentism and the ability to perform regular activities.
Please refer to Appendix 6 for a sample copy of the PROs. 


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The PRO instruments, translated as required in the local language, will be distributed by 
the investigator staff and completed in their entirety by the patient. To ensure instrument 
validity and that data standards meet health authority requirements, PRO questionnaires 
should be self-administered at the investigator site prior to the completion of other study 
assessments and the administration of study drug. Patients must complete these 
measures prior to the patient having any tests and prior to any discussion of the patient’s 
progress with their physician or any other healthcare personnel at the site. The 
recommended order of administration is first the SymptoMScreen, followed by MSIS-29 
and finally WPAI. PRO assessments will be performed as outlined in the schedule of 
assessments (see Appendix 1).
4.5.10
BICAMS
The BICAMS battery includes the following tests of mental processing speed and 
memory:

Symbol Digit Modalities Test (SDMT)

California Verbal Learning Test 2 (CVLT-II)

Brief Visuospatial Memory Test Revised (BVMT-R)
Please note that the BICAMS should be administered only after the patient has 
completed all the PRO assessments. The recommended order of administration is first 
the SDMT, followed by the CVLT-II and then the BVMT-R. The BICAMS will be scored 
centrally by a global reader and the results will be provided to the sites to be recorded in 
the eCRF. 
If the CVLT-II is not available in the subject’s official language; patients will not be 
participating in this portion of the BICAMS test. The other two BICAMS test: Symbol Digit 
Modalities Test (SDMT) and Brief Visuospatial Memory Test Revised (BVMT-R) will still 
be completed by these patients.
4.5.11
Telephone Interviews
The telephone interview will be conducted by site personnel familiar with the patient(s) 
every 8 weeks (±3 days) between the study visits (starting after the site visit at 8 weeks)
during the treatment period. The purpose of this semi-structured interview is to identify 
new or worsening neurological symptoms that warrant an unscheduled visit and collect 
information on possible events of infections. The site will record in the eCRF the 
telephone interview as “Done” or “Not Done” and documentation of the interview will be 
maintained in the patient’s study file. Please refer to Appendix 4 for detailed information 
on the telephone interview questions.
4.5.12
Patient Diary (optional)
In the main study, the patient visits will occur every 24 weeks and site staff will conduct a 
telephone interview every 8 weeks in between the visits at site. Due to this visit 
frequency, patient diaries have been proposed as an optional tool to collect and 


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document adverse events and concomitant medication during the periods between 
visits, which would be transferred in eCRF at the next patient visit. The decision to use 
the patient diary is left to the discretion of each investigator. The investigator must 
ensure that required IRB/EC approval was obtained before implementing the patient 
diary at his/her site. See the guidance document to investigators for use of patient diary 
for additional details.
4.5.13
Analysis of immune responses following SARS-CoV-2 vaccination
(Optional Procedure)
This optional procedure is applicable to only selected sites that allow the expedited processing of 
blood samples to central laboratories that are confirmed processing centers for this sample, as 
identified by study sponsor feasibility assessment. The Informed Consent Form will contain a 
separate section that addresses this optional procedure.  A separate, specific signature will be 
required to document patient's agreement to undergo the described optional procedure. 
For patients participating in the T and B cells impact substudy (Appendix 8) and the immune 
substudy (Appendix 9), blood collection for this optional procedure should not be performed at the 
visits with scheduled blood collection for the substudy assessments.
Samples for SARS-CoV-2 vaccine immunological assessments
●
Patients who receive the SARS-CoV-2 vaccine and who consent to provide the blood 
samples before the vaccination has occurred: the analyses of anti-SARS-CoV-2 antibody 
titers and T cell responses will be performed at maximum four time points: (1) at the 
study visit when the patient signs an optional informed consent form, prior to the 
administration of the vaccine, (2) at the next consecutive study visit(s) to a maximum of 
three visits following the last dose of vaccine. Please see Figure 3 for details.
●
Patients who receive the SARS-CoV-2 vaccine and who consent to provide the blood 
samples after the vaccination has occurred: the analyses of anti-SARS-CoV-2 antibody 
titers and T cell responses will be performed at the next consecutive study visit(s) to a 
maximum of three visits after patient provided consent and following the last dose of the 
vaccine. Please see Figure 3 for details.
●
A serum sample will be collected to evaluate the humoral immunity, including antibody 
titers. A whole blood sample will be collected and then processed centrally to allow for 
isolation of PBMCs and to measure SARS-CoV-2-specific T cell responses. Samples 
collected on the day of the ocrelizumab infusion must be collected prior to the IV 
methylprednisolone administration.
●
When available, previously collected serum samples and whole blood/PBMC samples may 
be used to measure SARS-CoV-2 antibodies and T cell responses prior to the vaccination, 
in consenting patients. 
●
In patients who complete the parent study (ENSEMBLE) and who roll over to the LTE 
study LIBERTO (study MN39158), the sample collection can be carried over and 
performed according to the LIBERTO study schedule of visits. Patients will need to 
provide new consent to the optional procedure in the LIBERTO study.


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●
The study sponsor will terminate the collection of blood samples for this optional research 
when it is considered that enough interpretable data has been collected.
For sampling procedures, storage conditions, and shipment instructions, see the laboratory 
manual.
Figure 3 Overview of Sample Collection for SARS-CoV-2 Vaccine 
Immunological Assessments for Optional Procedure
ICF = Informed consent form; SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2
4.6
OPTIONAL SAMPLES FOR RESEARCH BIOSAMPLE 
REPOSITORY
4.6.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
The whole blood sample for the RBR will be collected from patients who give specific 
consent to participate in this optional research. RBR specimens will be used to achieve 
the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression


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
To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug 
absorption and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.6.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body. 
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.6.2) will not be applicable at that site.
4.6.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to Ocrelizumab, MS or 
related diseases:

Blood sample collected at baseline for DNA (if the sample is not collected at 
baseline, it can be collected at any of the subsequent visits)

Remaining blood, serum, plasma, and any derivatives thereof (e.g., DNA, RNA, 
proteins, peptides) from other samples collected in the study.
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing (NGS), or other genomic analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches. Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies. 
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted. However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).


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4.6.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.6.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR. Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period. A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens. 
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent/Withdrawal eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.6.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason. However, if RBR specimens have been tested prior 
to withdrawal of consent, results from those tests will remain as part of the overall 
research data. If a patient wishes to withdraw consent to the testing of his or her 
specimens, the investigator must inform the Medical Monitor in writing of the patient's 


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wishes through use of the appropriate RBR Subject Withdrawal Form and, if the trial is 
ongoing, must enter the date of Informed Consent withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent/Withdrawal eCRF. The patient will be provided 
with instructions on how to withdraw consent after the trial is closed. A patient's 
withdrawal from Study MA30143 does not, by itself, constitute withdrawal of specimens 
from the RBR. Likewise, a patient's withdrawal from the RBR does not constitute 
withdrawal from Study MA30143.
4.6.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form. Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor. The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.7
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.7.1
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Pregnancy: patients becoming pregnant by chance during the study will be withheld 
from ocrelizumab treatment, but will remain in trial and will have the opportunity to 
re-start ocrelizumab treatment after the pregnancy/breastfeeding are over. During 
pregnancy and breastfeeding, these patients will continue to come for the regular 
scheduled visits (whenever possible, adhering to the time of scheduled visits as per 
protocol) and will perform all assessments except MRI. The total duration of 
treatment period will be 192 weeks from the date of first dose of ocrelizumab, 
irrespective of how long the treatment was interrupted due to pregnancy.

Patients who plan to become pregnant during the study will be withheld from 
ocrelizumab treatment and will follow the recommendations for contraception period 
after the last infusion with ocrelizumab for at least 6 months or longer in accordance 
with locally applicable ocrelizumab package leaflet. Upon discontinuation of study 
treatment, these patients will enter the safety follow-up period but will not restart the 
study treatment.

Life-threatening (NCI CTCAE Grade 4) IRR or serious hypersensitivity reaction

New onset or reactivation of hepatitis B infection 

PML

Any other serious adverse event, including laboratory values abnormalities, that 
present an unfavorable benefit-risk of treatment with ocrelizumab as deemed by the 
investigator.


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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patient discontinuing the study treatment prematurely will be further 
monitored in a safety follow-up (see Section 3.1.4).
Patients who discontinue study treatment prematurely will not be replaced.
Refer to the schedule of activities (see Appendix 1) for details on follow-up assessments to be 
performed for patients who permanently discontinue study treatment.
4.7.2
Patient Discontinuation from Study
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 patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent 

Study termination or site closure

Adverse event

Loss to follow-up

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Patient non-compliance, defined as failure to follow dosing instructions or to 
complete study visits
Every effort should be made to obtain a reason for patient discontinuation from the 
study. The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF. Patients who withdraw from the study will not be replaced.
4.7.3
Study Discontinuation
The Sponsor has the right to terminate the main 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 enrolment is unsatisfactory.
Whenever needed, the investigator should reassess and discuss with the patient the 
benefits and risks of continuing with ocrelizumab treatment, and should, together with 
the patient, explore also alternative treatment options.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 


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4.7.4
Site Discontinuation
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice (GCP)

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 has been recently approved for the treatment of adult patients with 
relapsing or primary progressive forms of MS in several countries and regions including 
Australia/New-Zealand, Europe, Middle East, South America and the USA and for the 
treatment of adult patients in relapsing form of MS in Canada. 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 the main 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) CTCAE v5.0.
Administration of ocrelizumab will be performed in a hospital, clinic environment or 
doctor’s office/practice under close supervision of the investigator or a medically 
qualified staff member with immediate availability of full resuscitation facilities. All 
adverse events and serious adverse events will be recorded during the study and at 24 
and 48 weeks (or until B-cell repletion) after the last dose of ocrelizumab as provided 
through this study. Safety assessments will include the incidence, nature, and severity of 
(serious) adverse events graded per the NCI CTCAE v5.0. Safety assessments will be 
conducted per the schedule of assessments in Appendix 1. 
The potential safety issues anticipated in the main study, as well as measures intended 
to avoid or minimize these issues, are outlined in the following sections.


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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
Infusion-Related Reactions 
All CD20+ depleting agents administered via the intravenous route, including 
ocrelizumab have been associated with acute IRRs. Following the approved 
administration regimen (which includes the use of premedication prior to treatment with 
ocrelizumab in order to reduce frequency and severity of IRRs) symptoms of IRRs may 
occur during any ocrelizumab infusion, but have been more frequently reported during 
the first infusion. Physicians should alert patients that IRRs can occur within 24 hours of 
the infusion. Across the RMS and PPMS trials, symptoms associated with IRRs 
included, but are not limited to pruritus, rash, urticaria, erythema, throat irritation, 
oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, 
pyrexia, fatigue, headache, dizziness, nausea, tachycardia and anaphylaxis. 
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. 
Further details on prevention and management of infusion-related reactions are 
described in Section 5.1.4 and in the current IB.
Infections 
Infection is an identified risk associated with ocrelizumab treatment, predominantly 
involving mild to moderate respiratory tract infections. Non-disseminated herpes virus-
associated infections, mostly mild to moderate, were also reported more frequently with 
ocrelizumab (approximately 5 to 6%, simplex and zoster) than with comparators 
(approximately 3%).


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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 IB.
No opportunistic infections were reported by any MS patient treated with ocrelizumab
during the controlled period of the pivotal trials. 
In interventional clinical 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 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” below.
Decrease in immunoglobulins
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins (Ig) over the 
controlled period of the studies, mainly driven by reduction in IgM. The proportion of 
patients with decrease in Igs below LLN increased over time and with successive 
dosing. Based on additional patient exposure, in cases of continuous decrease over 
time, a higher risk of serious infection cannot be ruled out.
Serious infections related to decrease in immunoglobulins (particularly in patients 
previously exposed to immunosuppressive/ immunomodulatory drugs or with pre-
existing hypogammaglobulinemia)
Based on additional patient exposure an association between decrease in 
immunoglobulins and serious infections with ocrelizumab treatment was observed and 
was most apparent for IgG. There was no difference in the pattern (type, type, latency, 
duration, outcome) of the serious infections reported in this subset of patients compared 
to the overall serious infections profile. In addition, risk factors for a subset of patients at 
higher risk of serious infections could not be identified.


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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 time-point 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 B cells was 72 weeks (range 27 − 175 weeks). 
Impaired Response to Vaccination
After treatment with ocrelizumab over 2 years in pivotal clinical trials, the proportion of 
patients with positive antibody titers against S. pneumoniae, mumps, rubella, varicella 
were generally similar to the proportions at baseline.
The results of the randomized, open-label phase IIIb study (BN29739) that assessed if 
ocrelizumab recipients with RMS raise adequate humoral responses to selected 
vaccines indicate that patients treated with ocrelizumab were able to mount humoral 
responses, albeit decreased, to tetanus toxoid, 23-valent pneumococcal polysaccharide, 
keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines. The results 
are summarized in the current version of the IB.
Physicians should review the immunization status of patients being considered for 
treatment with ocrelizumab. Patients who require vaccination should complete it at least 
6 weeks prior to initiation of ocrelizumab. For seasonal influenza vaccines it is still 
recommended to vaccinate patients on ocrelizumab. Vaccination with live-attenuated or 
live vaccines is not allowed during treatment and until B-cells have returned to normal 
levels.
Due to the potential depletion of B-cells in neonates and infants of mothers who have been 
exposed to ocrelizumab during pregnancy, it is recommended that vaccination with live or 
live-attenuated vaccines should be delayed until B-cell levels have recovered; therefore, 
measuring CD19-positive B-cell level, in neonates and infants, prior to vaccination is 
recommended.
It is recommended that all vaccinations other than live or live-attenuated should follow 
the local immunization schedule and measurement of vaccine-induced response titers 
should be considered to check whether individuals can mount a protective immune 
response because the efficacy of the vaccination may be decreased. Please see IB for 
further detail.
5.1.3.2
Potential Risks
Progressive multifocal leukoencephalopathy (PML)
PML has been reported in patients receiving ocrelizumab but only in patients where 
other contributory factors were present, such as prior immunosuppressive treatment (for 


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example, natalizumab or fingolimod). Physicians should be vigilant for early signs and 
symptoms of PML, which can include any new onset, or worsening of neurological signs 
or symptoms as these can be similar to an MS relapse. If PML is suspected, dosing with 
ocrelizumab must be withheld. Evaluation of PML, including MRI, confirmatory CSF 
testing for John Cunningham virus (JCV) DNA and repeat neurological assessments, 
should be considered. If PML is confirmed, ocrelizumab must be discontinued 
permanently. Please refer to Appendix 5 for guidance for diagnosis of PML. Please see 
the IB for more details.
Hypersensitivity reactions 
Hypersensitivity may be difficult to distinguish from IRRs in terms of symptoms. A 
hypersensitivity reaction may present during any infusion, although typically would not 
present during the first infusion. For subsequent infusions, more severe symptoms than 
previously experienced, or new severe symptoms, should prompt consideration of a 
potential hypersensitivity reaction. If a hypersensitivity reaction is suspected during 
infusion, the infusion must be stopped immediately and permanently. Patients with 
known IgE-mediated hypersensitivity to ocrelizumab must not be treated.
Malignancies including Breast Cancer
Patients should follow standard breast cancer screening guidelines.
Please see the IB for more details.
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, approximately 1% of the patients had Grade 3 or 4 neutropenia; 
and no temporal association with infections was identified. Based on additional patient 
exposure an association between neutropenia and serious infections with ocrelizumab 
treatment was not observed.
Additional information can be found in the current IB.
5.1.4
Management of Patients Who Experience Specific Adverse 
Events
Guidelines for management of specific adverse events are outlined in Table 4. Additional 
guidelines are provided in the subsections below.


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Table 4Guidelines 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 re-started 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.
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.
hrhour; 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 5.1.4. 
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition); see Section 5.3.5.9 and
Section 5.3.5.10 for more information


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
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are UnotU 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).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the Investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see
Section 5.4.2 for reporting instructions). Adverse events of special interest for this study 
include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see 55 USection 5.3.5.7U55).

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 UonlyU when a 
contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see 55 USection 5.2.1U55
for definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in 55 USection 5.4U55, 55 USection 5.5U55
and
55 USection 5.6U55.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see 55 USection 5.2.2U55 for seriousness criteria), severity (see 
55 USection 5.3.3U55), and causality (see 55 USection 5.3.4U55). 
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 
55 USection 5.4.2U55 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 48 weeks after 
the last dose of study drug. Instructions for reporting adverse events that occur after the 
adverse event reporting period are provided in Section 5.6.


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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 time points. Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 5 will be used for assessing severity for infusion 
related reactions and adverse events that are not specifically listed in the NCI CTCAE.
Table 5Adverse Event Severity Grading Scale for IRRs and Other Events 
Not Specifically Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
55 Uhttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm U55
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 55 USection 5.4.2U55 for reporting instructions), per the definition of serious 
adverse event in 55 USection 5.2.2U55.
d Grade 4 and 5 events must be reported as serious adverse events (see 55 USection 5.4.2U55 for 
reporting instructions), per the definition of serious adverse event in 55 USection 5.2.2U55.
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
6):


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
Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 6Causal 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
UAn adverse event will be considered related, unless it fulfils the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction") on the Adverse Event eCRF. If possible, avoid ambiguous 
terms such as "systemic reaction."  Associated signs and symptoms should be recorded 
on the dedicated Infusion-Related Reaction eCRF. If a patient experiences both a local 
and systemic reaction to a single administration of study treatment, each reaction should be 
recorded separately on the Adverse Event eCRF, with signs and symptoms also 


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recorded separately on the dedicated Infusion-Related Reaction eCRF. Please consider 
reporting a local IRR for any symptoms affecting only the skin, and localized to only one 
place. Any other IRR should be considered as systemic.
5.3.5.2
Diagnosis versus Signs and Symptoms
For all 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). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF. If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF
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 time points. 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. Details regarding any increases in severity will be captured on the Adverse Event 
Intensity or Grade Changes eCRF. If the event becomes serious, it should be reported to 


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the Sponsor immediately (i.e., no more than 24 hours after learning that the event 
became serious; see 55 USection 5.4.2U55 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 time points 
and subsequently recurs. Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating 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 55 USection 5.3.5.4U55 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


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
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (e.g., 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 55 USection 5.3.5.4U55 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 
55 USection 5.4.2U55).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
55 USection 5.3.1U55), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see 55 USection 5.4.2U55). 
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. 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 


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cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., “sudden cardiac death”). 
If the death is attributed solely to progression of RRMS, "RRMS progression" should be 
recorded on the Adverse Event eCRF. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
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 UonlyU 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
Deterioration that is judged by the investigator to have unexpectedly worsened in severity or 
frequency or changed in nature (i.e., deterioration beyond the expected pattern of progression of 
the underlying disease) should be recorded as an adverse event.  When recording an 
unanticipated worsening of MS on the Adverse Event eCRF, it is important to convey the 
concept that the condition has changed by including applicable descriptors (e.g., "accelerated 
worsening of multiple sclerosis).  Events that are clearly consistent with the expected 
pattern of progression of the underlying disease, or other MS related symptoms, should 
UnotU be recorded as adverse events. These data will be captured as effectiveness 
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., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in 55 USection 5.2.2U55), except as outlined 
below. 


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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

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 ‘’Surgeries and Procedures’’ eCRF.

Hospitalization following an MS relapse as long as the reason for hospitalization is to receive 
standard treatment with i.v. methylprednisolone (or with another equivalent corticosteroid)

Planned hospitalization required by the protocol (e.g., for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:

The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease

The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours.
5.3.5.12
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of the 
drug.
Special situations are not in themselves adverse events, but may result in adverse 
events. Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF. If the associated adverse event fulfils 
seriousness criteria or qualifies as an adverse event of special interest, the event should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see 55 USection 5.4.2U55).
For ocrelizumab, adverse events associated with special situations should be recorded 
as described below for each situation:


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
Accidental overdose:  Enter the adverse event term. Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term. Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term. 
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with ocrelizumab, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache. The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
Adverse events associated with an overdose of ocrelizumab in previous clinical studies 
include IRRs and infection.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor and safety 
analyses will not be performed using PRO data. Sites are not expected to review the 
PRO data for adverse events. 
Please note that the methods for collecting and analyzing PRO data are different from 
those for the ascertainment of observed or volunteered adverse events. Due to 
these differences, PRO data will not be reported as adverse events and no attempt will 
be made to resolve any noticeable discrepancies between PRO data and observed or 
volunteered adverse events.


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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 (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see 5Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, 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
Medical Monitors and Emergency Medical Contacts
Contact Information for All Sites
Emergency Medical Contact:
 (Primary)
Mobile Telephone No.:
Emergency Medical Contact:
(Secondary)
Mobile Telephone No.:
  
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week in case the above-listed contacts cannot be 
reached. The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls. Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to all investigators. 


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5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 48 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 Roche 
Safety Risk Management by the EDC system 
In the event that the EDC system is unavailable, the paper Clinical Trial 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 serious adverse events that occur after the end of the adverse 
event reporting period are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study. A 
paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators. Pregnancy should not be recorded on the 
Adverse Event eCRF. The investigator must withhold study drug for the duration of 
pregnancy and breastfeeding and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus. Monitoring of the patient should 
continue until conclusion of the pregnancy. Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 


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Adverse Event eCRF. In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. Information about child heath up to 1 year should be collected on the 
infant health questionnaire (see Appendix 7). 
Pregnancy: patients becoming pregnant by chance during the study will be withheld from 
ocrelizumab treatment but will remain in trial (patients will come at the clinic for the 
scheduled visits [wherever possible, adhering to the time of scheduled visits as per 
protocol] and will perform all assessments except MRI) and will have the opportunity to 
re-start ocrelizumab treatment after birth and breastfeeding are over. The total duration 
of treatment period will be 192 weeks from the date of first dose of ocrelizumab, 
irrespective of how long the treatment was interrupted due to pregnancy. 
Patients who plan to become pregnant during the study will be withheld from 
ocrelizumab treatment and will follow the recommendations for contraception period 
after the last infusion with ocrelizumab for at least 6 months or longer in accordance with 
locally applicable ocrelizumab package leaflet. Upon discontinuation of study treatment, 
these patients will enter the safety follow-up period but will not restart the study 
treatment.
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see 55 USection 5.4.2U55). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see 55 USection 5.4.2U55). 


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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 adverse event reporting period (defined in Section 5.3.1), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the patient’s 
medical record to facilitate source data verification.
All pregnancies reported during the study should be followed with a Pregnancy Outcome 
and Infant Health Information on First Year of life questionnaire provided by the Sponsor.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
48 weeks after the last dose of study drug), if the event is believed to be related to prior 
exposure to study drug. 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.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the reference safety information in the 
following document:

Ocrelizumab IB
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.
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The analysis of this open label, single arm study will be descriptive and primarily based 
on descriptive statistical methods. Unless otherwise specified, statistical tests will be 
exploratory in nature. Corresponding 95% CIs will be presented as appropriate. No 
correction for multiple testing will be applied.
Full details of all statistical aspects 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 and may include further exploratory analyses not explicitly described in 
this section, as well as analyses of data from the study phase beyond the main 192-
week study period, e.g., safety follow-up information.
Analysis populations
The primary effectiveness and safety analyses will be performed using the intent-to-treat 
(ITT) population. The per-protocol (PP) population will be used for supportive 
effectiveness analyses of selected effectiveness endpoints in order to evaluate the 
influence of major protocol violators on key effectiveness endpoints. 
ITT Population
All enrolled patients who received any dose of ocrelizumab will be included in the ITT 
population. Patients who prematurely withdrew from the study for any reason will still be 
included in the ITT population. 
PP Population
The PP population will include all ITT patients without protocol deviations deemed to 
affect the assessment of effectiveness. The list of criteria leading to exclusion from the 
PP population will be finalized prior to database closure and documented in the SAP. 


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Safety Population
The safety population will include all enrolled patients who received any dose or part of a 
dose of ocrelizumab. 
6.1
DETERMINATION OF SAMPLE SIZE
The main study is a single-arm effectiveness and safety study. There is no formal 
statistical hypothesis and all analyses will be descriptive. The results for the key 
endpoints will be presented in a descriptive analysis including the corresponding 95% 
the confidence intervals.
Sample size considerations for the main study are based on pooled data from two 
ocrelizumab phase III trials in RRMS (OPERA I and II). Based on extrapolations from 
these studies, we can conservatively expect 15% of patients (or less) to have a CDP 
event and approximately the same number of patients to be prematurely withdrawn and 
censored before week 192. 
In this case, for 1,100 patients, the precision (half-width of the 95% confidence interval) 
of the estimated CDP rate by study end is expected to be approximately 1.8%, i.e., the 
95% confidence interval of (13.2%, 16.8%). 
In OPERA the EDSS improvement at 2 years had a standard deviation of 0.74, based on 
240 patients from the ocrelizumab group, who were previously treatment-naïve with 
disease duration ≤3 years and EDSS ≤3.5. The standard deviation was rather stable 
over time and is assumed to remain stable after four years of treatment. A sample size 
of 1,100 patients is expected to provide a precision for the estimate of the EDSS change 
from baseline of about 0.037, assuming a standard deviation of 0.75. Assuming no 
EDSS change from baseline, the 95% confidence interval is expected to be ( -0.074, 
0.074).
The main study was initially planned to enroll at least 600 patients. Approximately 550 
additional patients were to be enrolled in the shorter infusion sub-study. They would also 
be enrolled in the main study (see Appendix 10 for more details). Therefore, the main 
study would enroll a total of at least 1,100 patients. A total of 1,225 patients (678 in the 
main study and 547 in the shorter infusion substudy) were enrolled in the study.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrolment, screening failures, ocrelizumab administration, and discontinuations from the 
study will be summarized using descriptive statistics (frequency tables for categorical 
endpoints and mean, median, range, standard, deviation [SD] and 25th-75th quartiles for 
the continuous endpoints). Patient disposition and the incidence of treatment 
discontinuation for different reasons will be tabulated. Major protocol violations, including 
violations of inclusion/exclusion criteria, will also be summarized.


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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Patients’ demographics (age, gender, and self-reported race), medical history and 
neurological examination will be summarized. The following will also be summarized: MS 
disease history (duration since first MS symptoms, duration of MS since diagnosis, 
relapses in the past year), baseline measures of MRI, EDSS and other important 
variables. 
6.4
EFFECTIVENESS ANALYSES
6.4.1
Effectiveness Endpoints
Effectiveness of ocrelizumab will be evaluated by means of a set of endpoints 
addressing different facets of MS. There is no primary endpoint defined in the main
study. These effectiveness endpoints include time to onset of confirmed CDP sustained 
for at least 24 and 48 weeks, change from baseline in EDSS score over time, relapse 
rates, MRI-based measures of disease activity and progression or degeneration, 
measures of cognition and PROs.
For a full list of effectiveness endpoints refer to 55 USection 255
After the Week 192 visit of the last enrolled patient, approximately 24 weeks and 48 weeks 
may be needed to allow the confirmation of the last event of the 24-week and 48 week-
CDP (CDP/CDI confirmation visit). The main study analysis will be performed after the 
last CDP and CDI confirmation visit. With respect to CDP confirmation visits, only EDSS 
data at all the visits occurring in the treatment period of the study and LTE study (for patients 
who roll over to study MN39158) will be used. Appropriate statistical methods to account for 
missing confirmation visits will be defined in the SAP.
The evaluation of the clinical effectiveness of ocrelizumab will be based upon the events 
and assessments in-between baseline and week 192.
For patients who do not have an event by week 192, the time-to-event endpoints will be 
censored at the time of last visit in the study. A descriptive analysis based on the 
Kaplan-Meier method will be performed for the time to CDP and other time-to-event 
endpoints, such as the time to first relapse or the time to first event of disease activity. 
Cox proportional hazards regression will be used to identify predictors for CDP and other 
time-to-event endpoints. Variables to be included in the regression model will be region, 
gender, baseline EDSS, and some other variables, as appropriate. Further details will be 
specified in the SAP.
The change from baseline in EDSS, as well as other continuous variables, will be 
primarily analyzed using descriptive statistics, the mean, corresponding 95% CI, 
standard deviation and other statistics will be presented. Furthermore, the change of 
EDSS from baseline to each visit will be analyzed by linear mixed models for repeated 
measures (MMRM) adjusting for covariates such as the respective baseline score, 
geographical region, and baseline EDSS.


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MRI activity will be evaluated from week 8 (baseline for MRI-based endpoints) to week 
192.
For binary endpoints, e.g., NEP, NEDA and NEPAD, the proportion of patients meeting 
the endpoint at Week 96, 144 and 192 will be calculated and the corresponding two-
sided Clopper-Pearson 95% CI will be presented. Logistic regression models will be 
used to identify prognostic factors. 
The annualized relapse rates will be analyzed using a Poisson regression model, 
adjusting for region and baseline EDSS. 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, 96, 144 and 192. A Poisson model will be used to estimate the rate of 
lesion occurrence. A quasi Poisson or negative binomial regression may be applied as a 
sensitivity analysis.
An analysis of individual components of the composite endpoint will also be performed.
6.4.2
Exploratory Endpoints
The exploratory effectiveness objective for the main study is to further assess the 
effectiveness of ocrelizumab 600 mg IV given every 24 weeks by monitoring endpoints 
as listed in Section 2.
The exploratory endpoints will be summarized descriptively and using methods similar to 
those used for the other effectiveness endpoints. Full details of the derivations and 
analyses of exploratory endpoints will be provided in the SAP.
6.5
SAFETY ANALYSES
6.5.1
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.
6.5.2
Safety Analyses
The safety analysis will be performed on Safety population. Safety will be assessed 
through summaries of adverse events (including rates/incidence rates and 
corresponding 95% CIs) and clinical laboratory abnormalities. 
All adverse events occurring on or after treatment on Day 1will be summarized by 
mapped term, appropriate thesaurus level and toxicity 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, 
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related adverse event 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. 
Ocrelizumab exposure will be summarized, including duration and dosage. 
Concomitant medications recorded during the study will be summarized by frequency 
tables. 
6.6
OTHER ANALYSIS
Other information, including, but not limited to, ADA, JCV, and biomarker endpoints will 
be analyzed. Exploratory immunology analyses of SARS-CoV-2 antibody titers and SARS-
CoV-2 T cell responses will be analyzed as appropriate and details will be specified in a 
separate Biomarker Analysis Plan.
6.7
SUBGROUP ANALYSIS
Some effectiveness analyses may be undertaken in specific patient subgroups, for 
example, female patients interrupting treatment due to pregnancy. Details of these 
subgroup analyses will be presented in the SAP.
6.8
HANDLING OF MISSING DATA
Patients not completing the study for reasons different from lack of effectiveness or 
death will be defined as not reaching the NEDA endpoint (“NEDA=no”). The same rule 
will be used for NEP and NEPAD. More details about the missing data handling will be 
specified in statistical analysis plan.
6.9
INTERIM ANALYSIS
No formal effectiveness interim analyses are planned. Exploratory analyses of selected 
endpoints (including CDP and safety analysis) will be performed during the course of the 
study, for example, after all patients have completed the first 48 weeks of the treatment 
phase and the necessary data are available. In addition, an interim analysis will be 
performed after completion of the core part of the shorter infusion substudy (see 
Appendix 10).
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
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 Sponsor will perform oversight of the data management of this study. The CRO will 
produce eCRF Specifications for the study based on Sponsor’s templates including 
quality checking to be performed on the data. Central imaging review data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. 
System backups for data stored at the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will be collected on paper questionnaires. The data from the PRO 
questionnaires as well as the BICAMS scoring data received from the central reader will 
be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records. Acknowledgement of receipt of 
the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 


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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 or paper PRO data, Informed Consent Forms, 
laboratory test results, medication inventory records, and images, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 


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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 (US) or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the European Union (EU) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC) and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent 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.
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the study, the 
patients or a legally authorized representative must re-consent by signing the most 
current version of the Consent Forms or the addendum, in accordance with applicable 
laws and IRB/EC policy. For any updated or revised Consent Forms, the case history or 
clinical records for each patient shall document the informed consent process and that 


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written informed consent was obtained using the updated/revised Consent Forms for 
continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996. If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC. Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor. Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
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 


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authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication (see 
Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study. These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.


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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. Prior 
to study initiation, the Sponsor identified potential risks associated with critical trial 
processes and data and implemented plans for evaluating and controlling these risks. 
Risk evaluation and control included the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation. Detection of deviations from 
quality tolerance limits will trigger an evaluation to determine if action is needed. Details 
on the establishment and monitoring of quality tolerance limits are provided in a Quality 
Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs. The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored by Roche, and will be managed by Roche and CROs. CROs 
will provide clinical operations management, data management, biostatistics, and 
medical monitoring. 
For the shorter infusion substudy, an Independent Data Monitoring Committee (iDMC) will 
be employed to monitor the incidence of IRR and perform additional unblinded safety 
analyses during the study as described in the iDMC charter. 
An IxRS will be used to assign patient numbers, monitor enrolment 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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9.6
DISSEMINATION 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. Study data may be shared with others who 
are not participating in this study (see Section 8.4 for details), and redacted Clinical 
Study Reports and other summary reports will be made available upon request. For 
more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report. In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation. This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.


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Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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a new patient-based outcome measure. Brain 2001;124(5):962-73.
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APPENDICES


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APPENDIX 1
Schedule of Assessments: Screening through the End of Treatment Period
Visit
Screening
Treatment Period a
Early study 
treatment 
discontinua
tion 
evaluation
Safety 
Follow-Up
48 weeks 
after the last 
infusion b
Refer to 
Appendix 2
1
2 
(Baseline)
3
4
5
6
7
8
9
10
11
12
Week
–4 to –1 
weeks
1
2
(±2 
days)
8
(±3 
days)
24
(±14 
days)
48
(±14 
days)
72
(±14 
days)
96
(±14 
days)
120
(±14 
days)
144
(±14 
days)
168
(±14 
days)
192
(±14 
days)
Informed 
consent c
X
Medical history 
and 
demographic 
data d
X
Review 
inclusion & 
exclusion 
criteria
X
X
Physical 
examination e
X
X
X
X
X
X
X
X
X
X
X
X
Height and 
weight
X
Vital signs f
X
X
X
X
X
X
X
X
X
X
X
X
PROs
X
X
X
X
X
X
X
Brain MRI g
X
X
X
X
X
X
X
X
Laboratory 
assessments


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Visit
Screenin
g
Treatment Period
Early 
study 
treatment 
discontinu
ation  
evaluation
Safety 
Follow-Up
48 weeks after 
the last 
infusion b
Refer to 
Appendix 2
1
2 
(Baseline
)
3
4
5
6
7
8
9
10
11
12
Week
–4 to –1 
weeks
1
2
(±2 
days)
8
(±3 
days)
24
(±14 
days)
48
(±14 
days)
72
(±14 
days)
96
(±14 
days)
120
(±14 
days)
144
(±14 
days)
168
(±14 
days)
192
(±14 
days)
Hematology, 
chemistry, urinalysis h
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test i
X
X
X
X
X
X
X
X
X
X
X
Hepatitis screening j
X
Hepatitis B virus DNA 
test j
X
Lymphocytes 
subtypes sample k
X
X
X
X
X
X
X
X
X
X
X
Serum for NfL l
X
X
X
X
X
X
Optional blood for 
DNA (RBR) m
X
ADA n
X
X
X
X
X
X
Ocrelizumab 
concentration n
X
X
X
X
X
X
Optional whole blood &
serum samples for 
SARS-CoV-2 vaccine 
immunological 
assessments o
Please see Figure 3 for details.
EDSS score p
X
X
X
X
X
X
X
X
X
X
X


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Visit
Screening
Treatment Period
Early study 
treatment 
discontinu
ation  
evaluation
Safety
Follow-Up
48 weeks 
after the last 
infusion b
Refer to 
Appendix 2
1
2 
(Baseline)
3
4
5
6
7
8
9
10
11
12
Week
–4 to –1 
weeks
1
2
(±2 
days)
8
(±3 
days)
24
(±14 
days)
48
(±14 
days)
72
(±14 
days)
96
(±14 
days)
120
(±14 
days)
144
(±14 
days)
168
(±14 
days)
192
(±14 
days)
MSFC
X
X
X
X
X
X
X
X
X
X
Neurological 
examination q
X
X
X
X
X
X
X
X
X
X
X
X
BICAMS 
assessment
X
X
X
X
X
       
Recording of 
potential relapses
X
X
X
X
X
X
X
X
X
X
X
Adverse event 
assessment r
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
treatment review
X
X
X
X
X
X
X
X
X
X
Methylprednisolone 
and 
antihistaminic drug 
premedication s
X
X
X
X
X
X
X
X
X
Ocrelizumab 
administration t
X
X
X
X
X
X
X
X
X
Telephone contact 
every 8 weeks u
u
(X)


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ADA = Anti-drug antibodies; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BICAMS= Brief International Cognitive 
Assessment for Multiple Sclerosis; CDI = Confirmed disability improvement; CDP = Confirmed disability progression; DMT = disease modifying treatment; eCRF electronic Case 
Report Form; EDSS Expanded Disability Status Scale; FSH follicle-stimulating hormone; GGT = gamma-glutamyl transpeptidase; HBcAb hepatitis B core antibody; 
HBsAg hepatitis B surface antigen; HBV hepatitis B virus; hCG = human chorionic gonadotropin; ICF = Informed consent form; IRR = Infusion-related reaction; 
IV intravenous; LTE = Long-term extension; MRI = magnetic resonance imaging; MS multiple sclerosis; MSFC = multiple sclerosis functional composite; NfL = 
neurofilament light chain; PCR polymerase chain reaction; PML progressive multifocal leukoencephalopathy; RBC = red blood cell; RBR = Research Biosample 
Repository; SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2; SoA = schedule of assessments; WBC = white blood cell. 
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case of an adverse event).
a The study visits during the treatment period may be spread over more than one day to complete all the assessments before study drug administration.
b
Patients who discontinue treatment early for any reason and patients who complete the 192-week Treatment Period and do not continue in a separate LTE study will be followed up for 48 
weeks after the last infusion of the study drug. When patients begin an alternative treatment for MS, they will be discontinued from the study. Patients who discontinue study 
treatment and switch to commercially marketed ocrelizumab, either after completion of the 192 weeks Treatment Period or after early discontinuation of the 192 weeks 
Treatment Period, will not enter the safety Follow-up Period.
c
Written informed consent will be obtained from all patients during screening in order to be eligible for the study.
d
Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, and all medications (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 6 weeks prior to the screening visit.  Demographic data will 
include age, sex, self-reported race/ethnicity, and educational level. 
e
A complete physical examination should be performed at the screening and baseline visits and at all dosing visits during treatment.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF. Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities not related to MS should be recorded as adverse events on the Adverse Event eCRF. 
f
Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures.  Vital signs should be taken within 45 minutes prior to the premedication 
methylprednisolone (or an equivalent). In addition, vital signs should be obtained prior to the ocrelizumab infusion, then every 15 minutes (± 5 minutes) for the first hour, 
followed by every 30 minutes (± 10 minutes) until 1 hour after the end of the infusion. Vital signs will be reported in the eCRF only in case of an IRR. Record 
abnormalities observed before enrolment on the General Medical History and Baseline Conditions eCRF. At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF. 
g
The MRI scans should be obtained within 14 days prior to next ocrelizumab infusion and should be reviewed by local/treating investigator for safety reasons before 
dosing with ocrelizumab. The MRI should be approved by the Medical Image Analysis Centre for efficacy evaluation before dosing with ocrelizumab.
h
Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute and differential, ANC, and quantitative platelet count.  Chemistry will include AST, ALT, GGT,
creatinine, total bilirubin, random glucose, potassium and sodium. Urine dipstick will be done at site locally.
i
Serum b-hCG must be performed at screening in women of childbearing potential.  Subsequently, urine β-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.  The FSH test is only applicable to confirm postmenopausal status in female patients.


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j
All patients must have negative HBsAg result screening tests prior to enrolment.  If 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. 
k
Lymphocytes subtypes samples should be collected prior to ocrelizumab infusion to screen for CD19+, T-cell counts (CD4+, CD8+), and other cell subsets at the local 
laboratory.
l        Serum sample to include but not be limited to measurement of NfL, will be collected prior to the IV methylprednisolone infusion (if obtained on the days of ocrelizumab 
infusion) at baseline and repeated every 48 weeks according to SoA, and will be analyzed at central laboratory.
m
Optional whole blood sample for RBR DNA is only collected from patients who sign the separate consent for storage and research use of their samples (RBR ICF). If the
sample is not collected at baseline, the sample can be collected at any visit. 
n
Serum samples are collected prior to the methylprednisolone infusion for 2 years of treatment for each patient. Following 2 years, samples should only be collected in 
any event of anaphylaxis, anaphylactoid reaction, or serious or severe hypersensitivity reaction as close as possible to the event and then at 4- and 16-weeks
post-dose.
o   Whole blood and serum samples collected on the day of the infusion must be collected prior to the IV methylprednisolone administered as premedication. Samples will be collected up to 18 
months following the last dose of vaccine.
p
Patients must have an EDSS score of 0.0 to 3.5 points, inclusive at screening to be eligible. After the end of treatment period visit of the last enrolled patient, approximately 24 
weeks and 48 weeks may be needed to allow the confirmation of the last event of the 24-week and 48-week CDP (CDP/CDI confirmation visit). For those patients presenting with an 
EDSS change at the end of the treatment period and who roll over to the LTE study (Study MN39158), the 24-week and 48-week CDP confirmation visits will occur during the LTE 
study (Study MN39158). For patients who discontinue the study (e.g., move onto commercial ocrelizumab, or start treatment with another DMT), the EDSS CDP confirmatory 
assessments will not be performed.
q
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 PML by evaluating neurological deficits localized to the cerebral cortex, such as 
cortical symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual defects, hemiparesis, cerebellar symptoms/signs (e.g., gait abnormalities, 
limb incoordination).  Patients with suspected PML should be withheld from ocrelizumab treatment until PML is ruled out by complete clinical evaluation and appropriate 
diagnostic testing.  A patient with confirmed PML should be withdrawn from the study.  
r
Adverse events will be reported throughout the study and until 48 weeks after the last dose of ocrelizumab as provided during the study period.  After this period, the 
investigator should report any serious adverse events that are believed to be related to prior study drug treatment (see Sections
55 U5.3.1U55 and 55 U5.6U55). At the end of treatment 
evaluation, reasons for study discontinuation will be captured via telephone call unless a site visit is requested by the investigator.  
s
All patients must receive prophylactic treatment with 100 mg methylprednisolone (or an equivalent), administered by slow IV infusion, to be completed approximately 30 
minutes and not less than 25 minutes prior to each ocrelizumab infusion and an antihistamine, via oral, intramuscular or IV route to be completed approximately 30-
60 minutes and not less than 25 minutes prior to before each infusion of ocrelizumab (the antihistamine should be the first premedication to be administered). The 
addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be considered.


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t    Ocrelizumab will be administered as two 300-mg IV infusions in 250 mL 0.9% sodium chloride each on Days 1 and 15 and one 600-mg infusion in 500 mL 0.9% sodium 
chloride every subsequent dose (i.e., every 24 weeks ±14 days) for a maximum of 168 weeks. It is anticipated that the patient will need to stay at the hospital or clinic for 
the infusion visits. Patients will be allowed to switch from the conventional ocrelizumab infusion ( 3.5 hours) to the shorter ocrelizumab infusion (2.0 hours) at any visit
after the Week 24 visit, based on the schedules of infusion as per the protocol, after providing written informed consent and in agreement with their treating physician, 
provided they have not experienced any previous serious IRRs with ocrelizumab treatment. While on the shorter infusion, the patients can switch back to the 
conventional infusion, in agreement with their treating physician. If patients develop a serious IRR while on the shorter infusion, they will be switched to the conventional 
infusion and should not be restarted on the shorter infusion at any following infusion visit.
u
A structured telephone interview will be conducted by site personnel every 8 weeks (± 3 days), starting after the site visit at 8 weeks to identify and collect information on 
any changes in the patient’s health status that warrant an unscheduled visit (including new or worsening neurological symptoms) and possible events or infections. No 
telephone contact is needed in weeks where patient is performing on-site visits (week 24, 48, 72, 96, etc.).
Note:  All lab samples can be taken up to 2 weeks prior to the scheduled study visit. Local laboratory results for hematology, biochemistry and CD4 should be available 
prior to dosing as they are re-treatment criteria. Local laboratory results for CD8 and CD19 may be available later, as they do not need to be verified prior to re-
treatment. Samples for NfL, ADA, and ocrelizumab concentration are collected and sent to the central laboratory for analysis.


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APPENDIX 2
Safety Follow-up Schedule of Assessments
Patients who discontinue treatment early for any reason and patients who complete the the 192 
weeks Treatment Period and do not continue in a separate long-term extension (LTE) study will 
be followed up for 48 weeks after the last infusion of the study drug. When patients begin an 
alternative treatment for multiple sclerosis (MS), they will be discontinued from the study.
Patients who discontinue study treatment and switch to commercially marketed 
ocrelizumab, either after completion of the 192 weeks Treatment Period or after early 
discontinuation of the 192 weeks Treatment Period, will not enter the safety Follow-up 
Period.
Safety Follow Up
Patients 
who 
complete 
the 
Treatment 
Period
Patients who discontinue treatment 
early
Assessment
Week 48 after 
the last infusion 
of study drug
(14 days)
Week 24 after the last 
infusion of study 
drug (14 days)
Week 48 after the 
last infusion of 
study drug (14 
days)
Routine safety laboratory 
tests a
X
X
X
Lymphocytes subtypes Pb
X
X
X
Vital signs
X
X
X
EDSS score c
X
X
X
Potential relapses recorded
X
X
X
Adverse events d
Pd
X
X
X
Concomitant medication
X
X
X
CDI = Confirmed disability improvement; CDP = Confirmed disability progression; EDSS Expanded Disability 
Status Scale; MS = Multiple sclerosis
a Routine safety lab: hematology, chemistry and urinalysis.
b Lymphocytes subtypes samples for CD19+, T-cell counts (CD4+, CD8+), and other cell subsets.
c After the end of treatment period visit of the last enrolled patient, approximately 24 weeks and 48 weeks may be needed 
to allow the confirmation of the last event of the 24-week and 48-week CDP (CDP/CDI confirmation visit).
d Related SAEs must be collected and reported regardless of the time elapsed from the last study drug 
administration, even if the study has been closed. Unrelated SAEs must be collected and reported during 
the study through the end of the Safety Follow-Up Period, which is 48 weeks after the last infusion. Non-
serious adverse events have to be reported until the end of Safety Follow-up Period (see Sections
55TU5.3.1U55T
and 55TU5.6U55T).


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APPENDIX 3
Expanded Disability Status Scale (EDSS)
EDSS steps
0
Normal neurological exam (all FS grade 0)
1.0
No disability, minimal signs in one FS (one FS grade 1)
1.5
No disability, minimal signs in more than one FS (more than one FS grade 1)
2.0
Minimal disability in one FS (one FS grade 2, others 0 or 1)
2.5
Minimal disability in two FS (two FS grade 2, others 0 or 1)
3.0
Fully ambulatory but with moderate disability in one FS (one FS grade 3, others 0 or 1) OR
Fully ambulatory but with mild disability in three or four FS (three / four FS grade 2, others 0 or 
1)
3.5 
Fully ambulatory but with moderate disability in one FS (one FS grade 3) and mild disability in 
one or two FS (one / two FS grade 2) and others 0 or 1; OR
Fully ambulatory with two FS grade 3 (others 0 or 1); OR
Fully ambulatory with five FS grade 2 (others 0 or 1)
4.0
Fully ambulatory for ≥500 meters without aid or rest; up and about some 12 hours a day 
characterised by relatively severe disability consisting of one FS grade 4 (others 0 or 1) or 
combinations of lesser grades exceeding limits of previous steps
4.5 
Ambulatory for 300 - 500 meters without aid or rest; up and about much of the day, 
characterised by relatively severe disability usually consisting of one FS grade 4 and combination 
of lesser grades exceeding limits of previous steps
5.0 
Ambulatory for 200 - 300 meters without aid or rest (usual FS equivalents include at least 
one FS grade 5, or combinations of lesser grades usually exceeding specifications for step 4.5)
5.5 
Ambulatory for 100 - 200 meters without aid or rest 
6.0 
Ambulatory for at least 100 meters with intermittent or constant unilateral assistance 
(cane or crutch) with or without rest OR
Ambulatory < 100 meters without help or assistance OR
Ambulatory ≥ 50 meters with unilateral assistance OR
Ambulatory ≥ 120 meters with bilateral assistance 
6.5 
Ambulatory for at least 20 meters with constant bilateral assistance (canes or crutches) 
without rest OR
Ambulatory for < 50 meters with unilateral assistance (cane or crutch) OR
Ambulatory 5 to 120 meters with constant bilateral assistance (canes or crutches)
7.0 
Unable to walk 5 meters even with aid, essentially restricted to wheelchair; wheels self 
and transfers alone; up and about in wheelchair some 12 hours a day
7.5 
Unable to take more than a few steps; restricted to wheelchair; may need some help in 
transferring and in wheeling self
8.0 
Essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most of 
day; retains many self-care functions; generally has effective use of arms
8.5
Essentially restricted to bed much of the day; has some effective use of arm(s); retains some 
self-care functions
9.0 
Helpless bed patient; can communicate and eat
9.5 
Totally helpless bed patient; unable to communicate effectively or eat/swallow
10 
Death due to MS
Standardised Neurological Examination and Assessment of Kurtzke’s Functional Systems and Expanded Disability Status Scale
Slightly modified from J.F. Kurtzke, Neurology 1983:33,1444-52
©2011 Ludwig Kappos, MD, Neurology, University Hospital Basel, 4031 Basel, Switzerland; Version 04/10.2


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Functional System Scores
1.
Visual FSS
0
normal 
1
disc pallor and / or small scotoma and / or visual acuity (corrected) of worse eye less than 20 / 20 
(1.0) but better than 20 / 30 (0.67)
2
worse eye with maximal visual acuity (corrected) of 20 / 30 to 20 / 59 (0.67 – 0.34)
3
worse eye with large scotoma and/or moderate decrease in fields and/or maximal visual acuity 
(corrected) of 20 / 60 to 20 / 99 (0.33 – 0.21)
4
worse eye with marked decrease of fields and/or maximal visual acuity (corrected) of 20 / 100 to 20 / 
200 (0.2 – 0.1); grade 3 plus maximal acuity of better eye of 20 / 60 (0.33) or less
5
worse eye with maximal visual acuity (corrected) less than 20 / 200 (0.1); grade 4 plus maximal 
acuity of better eye of 20 / 60 (0.33) or less
6
grade 5 plus maximal visual acuity of better eye of 20 / 60 (0.33) or less
2.
Brainstem FSS
0
normal 
1
signs only
2
moderate nystagmus and / or moderate EOM impairment and / or other mild disability
3
severe nystagmus and / or marked EOM impairment and / or moderate disability of other cranial 
nerves
4
marked dysarthria and / or other marked disability
5
inability to swallow or speak
3.
Pyramidal FSS
0
normal 
1
abnormal signs without disability
2
minimal disability: patient complains of motor-fatigability or reduced performance in strenuous 
motor tasks (motor performance grade 1) and/or BMRC grade 4 in one or two muscle groups
3
mild to moderate paraparesis or hemiparesis: BMRC grade 4 in >two muscle groups; and/or
BMRC grade 3 in one or two muscle groups (movements against gravity are possible); and/or
Severe monoparesis: BMRC grade 2 or less in one muscle group
4
marked paraparesis or hemiparesis: usually BMRC grade 2 in two limbs and/or
monoplegia: BMRC grade 0 or 1 in one limb; and/or
moderate tetraparesis: BMRC grade 3 in ≥ three limbs
5
paraplegia: BMRC grade 0 or 1 in all muscle groups of the lower limbs; and/or
marked tetraparesis: BMRC grade 2 or less in ≥ three limbs; and/or
hemiplegia
6
tetraplegia: BMRC grade 0 or 1 in all muscle groups of the upper and lower limbs


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4.
Cerebellar FSS
0
normal 
1
abnormal signs without disability
2
mild ataxia and/or moderate station ataxia (Romberg) and/or tandem walking not possible
3
moderate limb ataxia and/or moderate or severe gait/truncal ataxia
4
severe gait/truncal ataxia and severe ataxia in three or four limbs
5
unable to perform coordinated movements due to ataxia
X
pyramidal weakness (BMRC grade ≤3) or sensory deficits interfere with cerebellar testing
5.
Sensory FSS
0
normal 
1
mild vibration or figure-writing or temperature decrease only in 1 or 2 limbs
2
mild decrease in touch / pain / position sense or moderate decrease in vibration in 1 or 2 limbs
and/or
mild vibration or figure-writing or temperature decrease alone in more than 2 limbs
3
moderate decrease in touch / pain / position sense or marked reduction in vibration in 1 or 2 limbs
and/or
mild decrease in touch or pain or moderate decrease in all proprioceptive tests in > 2 limbs
4
marked decrease in touch or pain in 1 or 2 limbs
and/or 
moderate decrease in touch or pain and/or marked reduction of proprioception > 2 limbs
5
loss (essentially) of sensation in one or two limbs 
and/or
moderate decrease in touch or pain and/or marked reduction of proprioception for most of the body 
below the head
6
sensation essentially lost below the head
6.
Bowel/Bladder FSS
0
normal 
1
mild urinary hesitancy, urgency and/or constipation
2
moderate urinary hesitancy/retention and/or moderate urinary urgency/incontinence and/or
moderate bowel dysfunction
3
frequent urinary incontinence or intermittent self-catheterisation; needs enema or manual measures 
to evacuate bowels
4
in need of almost constant catheterization
5
loss of bladder or bowel function; external or indwelling catheter
6
loss of bowel and bladder function


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7.
Cerebral FSS
0
normal 
1
signs only in decrease in mentation; mild fatigue
2
mild decrease in mentation; moderate or severe fatigue
3
moderate decrease in mentation
4
marked decrease in mentation
6
dementia
8.
Ambulation score
0
unrestricted 
1
Fully ambulatory ≥ 500 meters without help or assistance but not unrestricted (pyramidal or cerebellar FS ≥ 2)
2
Ambulatory ≥ 300 meters, but < 500 meters, without help or assistance (EDSS 4.5 or 5.0, defined by FSS)
3
Ambulatory ≥ 200 meters, but < 300 meters, without help or assistance (EDSS 5.0)
4
Ambulatory ≥ 100 meters, but < 200 meters, without help or assistance (EDSS 5.5)
5
Ambulatory < 100 meters without help or assistance (EDSS 6.0)
6
Ambulatory ≥ 50 meters with unilateral assistance (EDSS 6.0)
7
Ambulatory ≥ 120 meters with bilateral assistance (EDSS 6.0)
8
Ambulatory < 50 meters with unilateral assistance (EDSS 6.5)
9
Ambulatory ≥ 5 meters, but < 120 meters with bilateral assistance, (EDSS 6.5)
10
Uses wheelchair without help; unable to walk 5 meters even with aid, essentially restricted to wheelchair; 
wheels self and transfers alone; up and about in wheelchair some 12 hours a day (EDSS 7.0)
11
Uses wheelchair with help; unable to take more than a few steps; restricted to wheelchair; may need some help 
in transferring and in wheeling self (EDSS 7.5)
12
essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most of day; retains many 
self-care functions; generally has effective use of arms (EDSS 8.0)
Standardised Neurological Examination and Assessment of Kurtzke’s Functional Systems and Expanded Disability Status Scale
Slightly modified from J.F. Kurtzke, Neurology 1983:33,1444-52
©2011 Ludwig Kappos, MD, Neurology, University Hospital Basel, 4031 Basel, Switzerland; Version 04/10.2


Ocrelizumab—F. Hoffmann-La Roche Ltd
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APPENDIX 4
Telephone Interviews 
The purpose of this interview is to identify and collect information on any changes in the 
patient’s health status that warrant an unscheduled visit (including new or worsening 
neurological symptoms). Telephone interviews should be performed by study personnel 
every 8 weeks between clinic visits (see also Section 4.5.11)
Please ask the following questions and record patient’s answers during the
Telephone Interview:
Questions 
             No   Yes
1. Since your last visit or telephone interview, have you had any new
or worsening medical problems related to multiple sclerosis (such as sudden 
changes in your thinking, alterations in your behavior, visual disturbances,
extremity weakness, limb coordination problems, or gait
abnormalities) that have persisted over more than one day?
2. Since your last visit or telephone interview, have you had any signs
of an infection?
3. Since your last visit or telephone interview, have you had any other new or 
worsening medical problems or conditions (including pregnancy)?
4. Since your last visit or telephone interview, have you taken any
new medicines (including medicines to treat cancer or MS, or any other new 
medicines
that weaken your immune system, or steroid medicines other than for the 
treatment of a recent relapse)?
If the patient answered YES to any question, contact the Treating Investigator and 
review
patient’s answers. The Investigator can determine if an unscheduled visit is required.
Record any pertinent comments made by the patient during the interview:
______________________________________________________________________
__
______________________________________________________________________
__
______________________________________________________________________
__
NAME: ______________________________ Date: 
______________________________
Name of person completing the telephone interview


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


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APPENDIX 5
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 John Cunningham 
virus (JCV) DNA using a validated sensitive assay should be undertaken. A 
diagnosis of PML can potentially be made by evaluating clinical and MRI findings 
plus the identification of JCV in the CSF. 

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 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 5
Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
(cont.) 
Table 2
MRI Lesion Characteristics Typical of PML and MS
Feature
MS (relapse)
PML
Location of 
new lesions
Mostly focal; affect entire brain and 
spinal cord, in white and possibly 
gray matter
Diffuse lesions, mainly subcortical and 
rarely periventricular, located almost 
exclusively in white matter, although 
occasional extension to gray matter has 
been seen; posterior fossa frequently 
involved (cerebellum)
Borders
Sharp edges; mostly round or finger-
like in shape (especially 
periventricular lesions), confluent 
with other lesions; U-fibers may be 
involved
Ill-defined edges; irregular in shape; 
confined to white matter, sparing gray 
matter; pushing against the cerebral 
cortex; U-fibers destroyed 
Mode of 
extension
Initially focal, lesions enlarge within 
days or weeks and later decrease in 
size within months
Lesions are diffuse and asymmetric, 
extending homogeneously; no 
confluence with other lesions; confined 
to white-matter tracks, sparing the 
cortex; continuous progression
Mass effect
Acute lesions show some mass 
effect
No mass effect even in large lesions 
(but lesion slightly abuts cerebral cortex)
On T2-
weighted 
sequence
Acute lesions: hyperintense 
center, isointense ring, discrete 
hyperintensity outside the ring 
structure
Subacute and chronic lesions: 
hyperintense, with no ring 
structure
Diffuse hyperintensity, slightly increased 
intensity of newly involved areas 
compared with old areas, little irregular 
signal intensity of lesions 
On T1-
weighted 
sequence
Acute lesions: densely hypointense 
(large lesions) or isointense (small 
lesions); increasing signal intensity 
over time in 80%; decreasing signal 
intensity (axonal loss) in about 20%
Slightly hypointense at onset, with signal 
intensity decreasing over time and along 
the affected area; no reversion of signal 
intensity 
On FLAIR 
sequence
Hyperintense, sharply delineated
Hyperintensity more obvious, true 
extension of abnormality more clearly 
visible than in T2-weighted images
With 
enhancement
Acute lesions: dense 
homogeneous enhancement, 
sharp edges
Subacute lesions: ring 
enhancement
Chronic lesions: no enhancement
Usually no enhancement even in large 
lesions; in patients with HIV, some 
peripheral enhancement is possible, 
especially under therapy 
Atrophy
Focal atrophy possible, due to focal 
white matter degeneration; no 
progression 
No focal atrophy 
Adapted from Yousry TA et al. 2006


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APPENDIX 6
Patient Reported Outcomes


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Work Productivity and Activity Impairment Questionnaire: 
Multiple Sclerosis V2.0 (WPAI:MS)
The following questions ask about the effect of your multiple sclerosis on your ability to work and 
perform normal daily activities. Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? 
______NO
______YES
If NO, tick “NO” and skip to question 6.
The next questions refer to the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of problems 
Uassociated with your multiple sclerosisU? Include hours you missed on sick days, times you 
went in late, left early, etc., because of your multiple sclerosis. Do not include time you 
missed to participate in this study.
______HOURS
3.
During the past seven days, how many hours did you miss from work because of any other 
reason, such as annual leave, holidays, time off to participate in this study?
______HOURS
4.
During the past seven days, how many hours did you actually work?
______HOURS (If “0”, skip to question 6)


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5. During the past seven days, how much did your multiple sclerosis affect your productivity 
Uwhile you were workingU? 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 
usual. If multiple sclerosis affected your work only a little, choose a low number. Choose a 
high number if multiple sclerosis affected your work a great deal. 
Consider only how much multiple sclerosis affected 
productivity Uwhile you were workingU.
Multiple sclerosis
had no effect on 
my work
Multiple sclerosis
completely prevented 
me from working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6. During the past seven days, how much did your multiple sclerosis affect your ability to 
perform your normal daily activities, other than work at a job? 
By normal activities, we mean the usual activities you perform, such as working around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were limited in 
the amount or kind of activities you could perform and times you accomplished less than you 
would like. If multiple sclerosis affected your activities only a little, choose a low number. 
Choose a high number if multiple sclerosis affected your activities a great deal. 
Consider only how much multiple sclerosis affected your ability
to do your normal daily activities, other than work at a job.
Multiple sclerosis
had no effect on 
my daily activities
Multiple sclerosis
completely prevented 
me from doing my 
daily activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993; 4(5): 353-65.


Ocrelizumab—F. Hoffmann-La Roche Ltd
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Ocrelizumab—F. Hoffmann-La Roche Ltd
125/Protocol MA30143, Version 10.0
APPENDIX 7
Pregnancy Outcome and Infant Health Information on First Year 
of Life
Pregnancy Outcome and Infant Health Information on First Year of Life
If twin or multi-gestational pregnancy, this questionnaire has to be filled out separately for each baby born 
in the multi-gestational pregnancy.
Please check all that apply and provide detailed information on complications in infant on last page.
Table 1: Parent’s (or person with parental responsibility in law) consent to data collection
Has parent’s (or person’s with parental 
responsibility in law) data authorisation 
form been signed?
☐Yes
☐No
Date signed
_________________
Other – comment
________________
Date consent withdrawn:
(if applicable)
Table 2: Information on birth
Mode of birth
☐Vaginal delivery
       Forceps / vacuum: 
     - Yes ☐
     - No ☐
☐Cesarean section (CS)
     - scheduled CS ☐
     - emergency CS ☐
Reason for assisted delivery/Cesarean 
section_______________________________________
Gestational age at birth
-----------------------weeks
      - since conception ☐
      - since LMP ☐
Induced labour
     - Yes ☐
     - No ☐
Table 3: Growth alteration, congenital anomalies and functional deficits
Date of Assessment
Growth alteration
     - Yes ☐
     - No  ☐
☐Small for gestational age  (SGA)
☐Low birth weight
☐Short birth length
If Growth alteration present::
Specify weight:______: 
Specify length:_______
Contributing factors: 
Congenital anomalies
     - Yes ☐
     - No  ☐
☐Major structural malformation 
A defect that has either cosmetic or 
functional significance to the child
Specify: _____________
____________________
____________________
Contributing factors: 
________________
________________
☐Minor structural malformation 
A defect that occurs infrequently but 
has neither cosmetic nor functional 
Specify: _____________
____________________
Contributing factors: 
________________


Ocrelizumab—F. Hoffmann-La Roche Ltd
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significance to the child
____________________
________________
☐Deformation 
A defect attributable to deformation of a 
structure, which had previously formed 
normally (usually due to mechanical 
force)
Specify: _____________
____________________
____________________
Contributing factors: 
________________
________________
☐Disruption 
A defect due to destruction of a 
structure, which has previously formed 
normally (may be of vascular, 
infectious, or mechanical origin)
Specify: _____________
____________________
____________________
Contributing factors: 
________________
________________
Functional deficit (except 
for infections, which should 
be described in separate table 
below)
     - Yes ☐
     - No ☐
☐Functional deficit
Specify: _____________
____________________
____________________
Contributing factors: 
________________
________________
Infant status at the time of latest follow-up (at birth, 3 months, 6 months, 12 months)
Table 4: Status of infant
Date of Assessment
Contributing factors / 
Comments
Status of infant
☐Normal
☐Abnormal, specify abnormality: __________________________
☐Neonatal/infant death, specify cause and date of death:      
     ___________________________________________________
_________________
_________________
Nursing status
☐Exclusive breastfeeding
☐Mixed feeding (partial breastfeeding along with infant formula and/or 
baby food), specify date since when: _____________
☐Fully weaned, specify date since when: ______________
_________________
_________________
_________________
Infections in neonate and infant during first year of life
Any infection detected at birth?
☐Yes 
☐No 
☐Unknown


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If available, please provide CD19 count (B cell values) at birth (regardless of 
infection)?
☐normal
☐abnormal
☐unknown
If abnormal, specify test result: _______________
If abnormal, date of test: ___________
If infection detected at birth then Tables 5 and 6 should to be filled out and additional detailed information 
may be provided on last page. 
If no infection detected at birth, however an infection developed later during the first year of live, please 
move directly to Table 7.
If no infection detected at birth, and if also no infection developed during the first 12 months then move 
directly to Table 8.
Table 5: Information on infection in neonate at birth
Specify the event term:
Event number
Location of infection present in neonate at birth?
Site of infection (specify): __________________________
Outcome of infection?
Duration of infection?
☐Resolved
☐Improving
☐Fatal
☐Persisting
☐Unknown
Duration:___________
Intensity of infection (Grade 1-5 NCI 
CTCAE)?
Seriousness of 
infection?
Treatment with anti-
infective?
Pathogen causing infection 
known?
Severity: ☐Mild (Grade 1)
               ☐Moderate (Grade 2)
               ☐Severe (Grade 3)
               ☐Life-threatening (Grade 4)
               ☐Death (Grade 5)
Serious: 
☐Yes
☐No
☐Yes, specify: 
    ___________
☐No 
☐Unknown
☐Yes (specify): 
     ________________
☐No 
☐Unknown
Relevant laboratory test results (in newborn infant):
CD19 count
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: _______________
If abnormal, date of test: 
___________
IgG levels
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: _______________
If abnormal, date of test: 
___________
White blood cell count 
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: _______________
If abnormal, date of test: 
___________


Ocrelizumab—F. Hoffmann-La Roche Ltd
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Neutrophil count
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: _______________
If abnormal, date of test: 
___________
Lymphocyte count
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: _______________
If abnormal, date of test: 
___________
Other, specify:
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: _______________
If abnormal, date of test: 
___________
Table 6: Maternal risk factors for neonatal infection (during most recent pregnancy, if infant 
developed neonatal infection at birth)
Maternal risk factors for neonatal 
infection
Date of 
diagnosis
If diagnosed, was pregnant mother 
treated with anti-infective prior to 
delivery?
☐Maternal intrapartum colonisation or 
infection with group B streptococcus (GBS)
☐Maternal listeriosis
☐Premature rupture of membranes (PROM)
☐Meconium in amniotic fluid (meconium-
     stained liquid)
☐Active genital herpes infection
☐CMV
☐HPV (papilloma virus)
☐Other, specify
______________
______________
______________
______________
______________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
Relevant laboratory test results in pregnant mother: 
CD19 count
☐normal
☐abnormal
☐unknown
If abnormal, specify 
test result: 
_______________
If abnormal, date of 
test: ___________
IgG levels
☐normal
☐abnormal
☐unknown
If abnormal, specify 
test result: 
_______________
If abnormal, date of 
test: ___________
White blood cell count 
☐normal
☐abnormal
☐unknown
If abnormal, specify 
test result: 
_______________
If abnormal, date of 
test: ___________


Ocrelizumab—F. Hoffmann-La Roche Ltd
129/Protocol MA30143, Version 10.0
Neutrophil count
☐normal
☐abnormal
☐unknown
If abnormal, specify 
test result: 
_______________
If abnormal, date of 
test: ___________
Lymphocyte count
☐normal
☐abnormal
☐unknown
If abnormal, specify 
test result: 
_______________
If abnormal, date of 
test: ___________
Other, specify:
(e.g. any specific antibodies and their titers)
☐normal
☐abnormal
☐unknown
If abnormal, specify 
test result: 
_______________
If abnormal, date of 
test: ___________
Any infection detected during first year of infant’s life? 
☐Yes 
☐No 
☐Unknown
If infection detected during first year of infant’s life, then Table 7 should to be filled out and additional 
detailed information may be provided on last page. If no infection developed during first 12 months of life, 
then please move directly to Table 8.
Table 7: Information on infection detected during first year of infant’s life
Specify the event term:
Event number
(automatically 
populated by 
the system?)
Location of infection?
Infant’s age on 
day of onset of 
infection?
Outcome of infection?
Duration of infection?
Site of infection (specify): ____________
_________________________________
Age:_________
☐Resolved
☐Improving
☐Fatal
☐Persisting
☐Unknown
Duration:___________
Intensity of infection (Grade 1-5 NCI 
CTCAE)?
Seriousness of 
infection?
Treatment with anti-
infective?
Pathogen causing 
infection known?
Severity: ☐Mild (Grade 1)
               ☐Moderate (Grade 2)
               ☐Severe (Grade 3)
               ☐Life-threatening (Grade 4)
               ☐Death (Grade 5)
Serious: 
☐Yes
☐No
☐Yes, specify: 
    ___________
☐No 
☐Unknown
☐Yes (specify): 
     ________________
☐No 
☐Unknown
Relevant laboratory test results (in infant):


Ocrelizumab—F. Hoffmann-La Roche Ltd
130/Protocol MA30143, Version 10.0
CD19 count
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: 
_______________
If abnormal, date of test: 
___________
IgG levels
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: 
_______________
If abnormal, date of test: 
___________
White blood cell count 
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: 
_______________
If abnormal, date of test: 
___________
Neutrophil count
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: 
_______________
If abnormal, date of test: 
___________
Lymphocyte count
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: 
_______________
If abnormal, date of test: 
___________
Other, specify:
☐normal
☐abnormal
☐unknown
If abnormal, specify test 
result: 
_______________
If abnormal, date of test: 
___________
Table 8: Vaccinations administered to infant at birth and during first year of age
Vaccinations administered at 
birth and during first year of 
age
Date 
administered
Infant’s age on day 
of vaccination
Comments (abnormal outcome, 
reason for postponing vaccination, 
etc)
☐Hepatitis B
☐Rotavirus
☐Diphtheria, tetanus, and 
pertussis
☐Haemophilus influenzae type b
☐Pneumococcal


Ocrelizumab—F. Hoffmann-La Roche Ltd
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☐Poliovirus
     ☐Attenuated oral Polio 
vaccine
     ☐Inactivated Polio vaccine
☐Meningococcal group B 
bacteria
☐Tuberculosis (Bacille Calmette
     Guérin, BCG) bacteria
☐Other vaccination, specify: 
_______
Table 9: Fetal/neonatal abnormalities in previous pregnancies
Fetal/neonatal abnormalities (in previous pregnancies)
Please, provide specifics including contributing 
factors
None ☐
Yes ☐
Unknown ☐
Infection; if yes, specify
Death in utero; if yes, specify reason
Birth defects; if yes, specify
Family history of birth defects; if yes, specify
Small for gestational age at birth (or Intrauterine growth 
retardation)
Premature delivery (before 37 weeks)
Other; specify
Detailed information on health-related findings in infant during first year of life 
Please enter text in the free text box below:


Ocrelizumab—F. Hoffmann-La Roche Ltd
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APPENDIX 8
T and B Cells Impact Substudy Protocol
T AND B CELLS IMPACT SUBSTUDY PROTOCOL
TITLE:
A SUBSTUDY TO EVALUATE THE INDIRECT 
IMPACT OF OCRELIZUMAB ON THE T AND B CELL 
IMMUNE 
SYSTEM 
IN 
RELAPSING-REMITTING 
MULTIPLE SCLEROSIS PATIENTS 
ASSOCIATED WITH MA30143 CORE STUDY:
AN OPEN-LABEL, SINGLE-ARM STUDY TO 
EVALUATE THE EFFECTIVENESS AND SAFETY OF
OCRELIZUMAB IN PATIENTS WITH EARLY STAGE
RELAPSING REMITTING MULTIPLE SCLEROSIS 
PROTOCOL NUMBER:
MA30143 T and B cells Impact Substudy for France
VERSION NUMBER:
6.0 (for France)
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab, RO4964913
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below


Ocrelizumab—F. Hoffmann-La Roche Ltd
133/Protocol MA30143, Version 10.0
T and B Cells Impact Substudy PROTOCOL ACCEPTANCE FORM
TITLE:
A SUBSTUDY TO EVALUATE THE INDIRECT IMPACT OF 
OCRELIZUMAB ON THE T AND B CELL IMMUNE SYSTEM IN 
RELAPSING-REMITTING MULTIPLE SCLEROSIS PATIENTS 
ASSOCIATED WITH MA30143 CORE STUDY:  
AN OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE THE 
EFFECTIVENESS AND SAFETY OF OCRELIZUMAB IN 
PATIENTS WITH EARLY STAGE RELAPSING REMITTING 
MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
MA30143 T and B cells Impact Substudy for France
VERSION NUMBER:
6.0 (for France)
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab, RO4964913
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Co-Investigator’s Name (print)
Co-Investigator’s Signature
Date
Please retain the signed original of this form for your study files. Please return a copy as instructed 
by your study monitor.


Ocrelizumab—F. Hoffmann-La Roche Ltd
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UT AND B CELLS IMPACT SUBSTUDY UPROTOCOL SYNOPSIS
TITLE:
A SUBSTUDY TO EVALUATE THE INDIRECT IMPACT OF 
OCRELIZUMAB ON THE T AND B CELL IMMUNE SYSTEM 
IN RELAPSING-REMITTING MULTIPLE SCLEROSIS 
PATIENTS 
ASSOCIATED WITH MA30143 CORE STUDY:  
AN OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE 
THE EFFECTIVENESS AND SAFETY OF OCRELIZUMAB IN 
PATIENTS WITH EARLY STAGE RELAPSING REMITTING 
MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
MA30143 T and B cells Impact Substudy for France
VERSION NUMBER:
6.0 (for France)
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab, RO4964913
PHASE:
IIIb
INDICATION:
Relapsing-Remitting multiple sclerosis
SPONSOR:
F. Hoffmann-La Roche Ltd
UObjectives and Endpoints
B cell depletion by ocrelizumab has recently demonstrated efficacy in the treatment of RMS and 
PPMS. The aim of this substudy is to decipher the impact of B cell depletion by ocrelizumab on T 
cells and B cells subsets and functions before and after treatment with ocrelizumab. This substudy 
will obtain blood from patients enrolled in the main study MA30143 to assess:
T cell subsets, functionalities such as cytokine production and migration capacities but also 
repertoire and transcriptome, and B cells subsets, functionalities such as cytokine production, 
differentiation capacities as well as B cell repertoire and genes expression before and after 
treatment with ocrelizumab. Moreover, biomarkers related to efficacy outcomes in this study 
population might emerge from this substudy. 


Ocrelizumab—F. Hoffmann-La Roche Ltd
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Objectives
Corresponding endpoints
First objective: 
Part 1:
To evaluate the 
indirect impact 
of ocrelizumab-
dependent B 
cell depletion 
on T cell 
subsets and 
functions in 
naïve RRMS 
patients
The following analyses will be performed at baseline, 24 weeks, 48 weeks and 
at the end of the study at 192 weeks or earlier in case of withdrawal from the 
study.  These analyses will also be performed in case of extra visit due to relapse 
if applicable. 
Analysis of general immune cells frequencies in blood including B cells, T cells, 
dendritic cells, monocytes and NK cells subsets. Markers will include, but are 
not limited to CD4, CD8, CD19, CD11c, CD56, CD14, and CD16. 
Analysis of CD4+ and CD8+ T cells subset frequencies including naïve, central 
memory, effector memory or TEMRA subsets at baseline, 24, 48 and 192 
weeks of ocrelizumab treatment. 
Analysis of CD4+ and CD8+ T cells phenotype including regulatory and 
effector (Tc1, Tc17, Th1, Th17) subsets. Markers used include, but are not 
limited to CD3, CD4, CD8, CD161, CD45RC, CD127, IL18Ra, CXCR6, 
EOMES, PLZF1, perforin, GZB, CCR5, CCR6, CD25, CCR2, MCAM, DNAM, 
CD39, LFA1, PSGL1, VLA4, IFN-γ, IL-17, IL-22, Foxp3, Rorγt, or Tbet. 
Analysis of T cells activation of sorted blood CD4+ and CD8+ T cells in vitro 
by measurement of cytokine production. Cytokines, including, but not limited 
to GM-CSF, IFN- γ, IL-17, IL-22, IL-13, will be assessed by flow cytometry 
stainings in CD4+ or CD8+ T cells after 5 days of total PBMCs (Peripheral 
Blood Mononuclear Cells) stimulation with anti-CD3 and anti-CD28. 
Quantitative measurements of a large panel of cytokines and chemokines in 
culture supernatant will be performed using luminex technology. 
Analysis of transmigration capacities of CD4+ and CD8+ T cells across an 
experimental model of Blood-Brain-Barrier in resting or inflammatory 
conditions.
Analysis of T cell repertoire in sorted CD4+ and CD8+ T cells using high 
throughput sequencing (Illumina Miseq). This analysis will be performed on the 
first 20 patients’ samples and will not be performed at 24 weeks. 
Analysis of RNA sequencing in sorted CD4+ and CD8+ T cells using Illumina 
assays. This analysis will be performed on the first 20 patients samples and 
will not be performed at 24 weeks.
Indirect impact of ocrelizumab-dependent B cell depletion on T cell subsets and 
functions in naïve RRMS patients will be measured by change from baseline for 
each marker and for each time point.


Ocrelizumab—F. Hoffmann-La Roche Ltd
136/Protocol MA30143, Version 10.0
Objectives
Corresponding endpoints
Part 2: 
To decipher the 
indirect impact
of ocrelizumab 
on B cell 
repopulation
Two periods can be defined: 
-
B cell depletion period on ocrelizumab
-
B cell repletion off ocrelizumab. 
During B cell depletion period (weeks 24, 48 and 192, or study withdrawal visit), 
analyses will be performed only in partially repleted patients (below the lower 
limit of normal) with sufficient amount of B cells applicable for each analysis as 
described below. 
During B cell repletion period off ocrelizumab, analyses will be performed in 
partially repleted patients with sufficient amount of B cells and in repleted 
patients i.e. in patients having peripheral B cell level at or above the lower limit 
of normal. 
These analyses will also be performed in case of extra visit due to relapse in 
patients with sufficient amount of B cells. 
Analysis of the proportions of the different B cell subsets in peripheral blood. 
Different markers will be used to distinguish switched/unswitched memory, 
mature naïve, transitional B cells, plasmablasts and plasmocytes (CD19, 
CD20, CD27, IgD, CD38, CD24, CD138). Activated markers will also be 
determined (CD95, MHC-II, CD80, CD86). 

1.104 B cells per sample would trigger this analysis.
Analysis of the different B cell subsets will also be realized after some short 
(48h) stimulation protocols. We will evaluate the frequencies of regulatory and 
effector B cells after stimulation using flow cytometry. Cytokines such as IL-
10, GZM B, TGF b and IL-35 (for regulatory cells) but also TNFa, GM-CSF, LT 
and IL-6 (for effector B cells) will be measured. Quantitative measurements of 
a large panel of cytokines and chemokines in culture supernatant will be 
performed using luminex technology. 

This part will only be performed if there are enough B cells i.e. at least 
5.105 to 1.106 per sample.
Analysis of the differentiation abilities of B cells using a differentiation protocol 
lasting 6 days, already published (Chesneau et al, 2015). 

This part will only be performed if there are enough B cells in the 
peripheral blood i.e. at least 3.106 per sample.
Analysis of B cell repertoire in sorted B cells by immunosequencing (Adaptive 
biotechnologies) to assess immune reconstitution to establish correlations with 
clinical outcome. 

1.103 B cells per sample would trigger this analysis.
Analysis in reconstituted B cells of the expression of a panel of 96 genes 
(including surface markers, transcription factors, and cytokines) at the single 
cell level using parallel qPCR reactions (microfluidic technologies). 

5.103 B per sample cells would trigger this analysis. 
Thresholds mentioned for B cells analysis may be adjusted according to 
investigators decision and sampling procedures. In any cases, all analyses will 
describe the initial cell frequencies in study samples. 
Indirect impact of ocrelizumab-dependent B cell depletion on B cell subsets and 
functions in naïve RRMS patients will be measured by change from baseline for 
each marker and for each time point.


Ocrelizumab—F. Hoffmann-La Roche Ltd
137/Protocol MA30143, Version 10.0
Objectives
Corresponding endpoints
Second objective:
To assess the 
potential 
relationship 
between 
immunological 
biomarkers 
levels and 
clinical and/or 
subclinical 
change 
assessed by 
neurological 
markers in naïve 
RRMS patients 
treated with 
ocrelizumab. 
Relationship between any B cells subset, CD4+ or CD8+ T cell subset or 
immunological marker at baseline, 24, 48, 192  weeks or earlier in case of 
withdrawal from the study of ocrelizumab treatment or during relapses and 
core study efficacy and safety objectives of MA30143 core study (endpoints). 
For instance, neurological markers that will be correlated with interesting 
immunological markers identified in the first part, will include, but will not be 
limited to: 
-
Total number of T1 Gd-enhancing lesions as detected by brain MRI 
over time
-
Total number of new and/or enlarging T2 lesions as detected by brain 
MRI over time
-
Change in T1 volume over time
-
Change in brain volume (including white and grey matter fractions) as 
detected by brain MRI over time
-
Time to first relapse 
-
Change from baseline in EDSS score over the course of the study
Relationship between any biomarkers with any other biomarker. 
UStudy Design
Description of Study
This substudy is a longitudinal, multi-center, substudy of the Phase IIIb ocrelizumab trial MA30143. 
This substudy will evaluate the indirect impact of ocrelizumab-dependent B cell depletion on T and 
B cell subsets and functions in naïve RRMS patients, during B cell depletion and during B cell 
repletion period off ocrelizumab.
This substudy will help to assess the potential relationship between immunological biomarkers 
levels and clinical and/or subclinical change assessed by neurological markers in naïve RRMS 
patients treated with ocrelizumab.
Patients who provide consent to participate in this substudy and fulfill eligibility criteria will provide 
additional blood samples at baseline, 24 weeks, 48 weeks, end of treatment period (192 weeks or 
earlier in case of study withdrawal), every 24 weeks for 48 weeks after last infusion of ocrelizumab 
and in case of unscheduled visit due to relapse, as indicated in the schedule of assessments. 
Blood samples can be collected 2 weeks (± 4 days) prior to ocrelizumab infusion, in addition to 
laboratory samples required in the main study. 
12 tubes of 8mL each will be drawn at each time points. Samples will be prepared and frozen at 
investigational centers and sent to Nantes CHU for in vitro analyses.
Number of Patients
The number of patients enrolled in this MA30143 substudy is 50 patients. Patients enrolled in 
study MA30143 and recruited in specific centers in France will be offered to participate in this 
substudy. 
Participating centers are restricted to French investigator centers with PBMC (peripheral blood 
mononuclear cell) technical and storage capacity.
The number of patients that will withdraw from the study is estimated to be 10 (20% withdrawal rate 
over 192 weeks). As a consequence, approximately 10 patients would enter the follow-up period 
for B cell repletion. Patients will provide blood samples every 24 weeks for 48 weeks after last 
ocrelizumab infusion. 


Ocrelizumab—F. Hoffmann-La Roche Ltd
138/Protocol MA30143, Version 10.0
UTarget Population
UInclusion Criteria
Patients must meet the following criteria to be eligible for substudy entry:

Enrolled in the Phase IIIb study MA30143

Signed Informed Consent Form for the MA30143-T and B cell Substudy France

Able to comply with the substudy protocol, in the investigator’s judgment.
UExclusion Criteria
There is no exclusion criteria beyond those listed in the main protocol of the MA30143 study. 
End and length of the substudy
The end of the substudy is defined as the last patient visit. in the Safety Follow-up period or last patient 
Week 192 visit, whichever occurs later.
The maximum length of the study, from screening of the first patient to the end of the substudy, is 
expected to be approximately 316 weeks (6.5 years). This includes an enrolment period of 
approximately 76 weeks.
UInvestigational Medicinal Products
No IMP is specifically distributed for this substudy. In core MA30143 protocol, the first dose of 
ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) in 250 mL 0.9% sodium 
chloride each separated by 14 days (i.e., Days 1 and 15), followed by one 600-mg IV infusion in 
500 mL 0.9% sodium chloride every subsequent doses (i.e., every 24 weeks ±14 days) for a 
maximum of 8 doses.
UStatistical Methods
Due to the small sample size, the substudy data analysis will be descriptive only. 
If relevant, calculated confidence intervals will be displayed with a 95% level.
Indirect impact of ocrelizumab-dependent B cell depletion on T cell and B cell subsets and functions 
in naïve RRMS patients will be measured by the change from baseline for each marker and for 
each time point.
Relationship between biomarkers will be evaluated using correlation coefficient at each endpoint 
(linear and non-linear correlation will be searched).
Relationship between any B cells or T cell subsets (or any immunological marker at any time point) 
and core study efficacy and safety objectives will be performed using a regression model to 
evaluate biomarkers predictive factors of efficacy or safety objectives.
Full details of the derivations and analyses of exploratory endpoints will be detailed in the 
corresponding substudy Statistical Analysis Plan.


Ocrelizumab—F. Hoffmann-La Roche Ltd
139/Protocol MA30143, Version 10.0
USubstudy Design
USchedule of Assessments
Visit
Scree
ning
Treatment Period
Safety 
Follow-up 
period 
Unscheduled 
Visits
1
2 
(Base-
line)
5
6
12
Early study 
treatment 
disconti-
nuation visit
relapse 
1
relapse 
2
Week
-4 to -
1 wks
1
24 
(±14 
days)
48 
(±14 
days)
192
(±14 
days)
Visits Every 
24 weeks (+/-
14 days) (for 
48 weeks after 
last dose)
Substudy 
Inform 
Consent
X
Blood 
Collection 
for 
Substudy
X
X
X
X
X
(if applicable)
X
(if applicable)
X
(if 
applicab
le)
X
(if 
applicabl
e)


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ULIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ARR
Annualized Relapse Rate
BRC
Biological Resource Center
CD
Cluster of Differentiation
CDP
Confirmed Disability Progression
CHU
Centre Hospitalier Universitaire (University Hospital)
CI
Confidence Interval
CNS
Central Nervous System
CPT
Cell Preparation Tube
CSF
Cerebro-Spinal Fluid
EAE
Experimental Autoimmune Encephalomyelitis 
EDSS
Expanded Disability Status Scale
FC
Flow Cytometry
FSS
Functional Systems Score 
HC
Healthy Control
HR
Hazard ratio
IB
Investigator's Brochure
Ig
Immunoglobulin
MRI
Magnetic Resonance Imaging
MS
Multiple Sclerosis
NK
Natural Killer
OCBs
Oligoclonal Bands
OFSEP
French Observatory for Multiple Sclerosis
PBMCs
Peripheral Blood Mononuclear Cells
PPMS
Primary Progressive Multiple Sclerosis
PRMS
Progressive Relapsing Multiple Sclerosis
RRMS
Relapsing-Remitting Multiple Sclerosis
SAP
Statistical Analysis Plan
SPMS
Secondary Progressive Multiple Sclerosis
TEMRA
CD45RA+ effector memory T cells


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T AND B CELLS IMPACT SUBSTUDY PROTOCOL
BACKGROUND
Background on Multiple Sclerosis and ocrelizumab
Multiple sclerosis (MS) is a chronic, demyelinating and degenerative disease of the central nervous 
system (CNS) whose epidemiology, subtypes and symptoms are described in the main protocol 
(MA30143). 
Multiple Sclerosis is characterized by active demyelinating areas called lesions or plaques, CNS 
lesions in MS typically present immune cell infiltration and inflammation which are absent in normal 
brain tissue. Macrophages dominate the infiltrate, followed by CD8+ T cells, whereas lower 
numbers of CD4+ T cells, B cells and plasma cells can also be found. Resident cells also contribute 
to the disease pathophysiology and microglial cells and astrocytes are activated in the CNS 
(Dendrou, Fugger, and Friese 2015). Although the T cell composition of infiltrates does not differ 
as the disease develops, the relative proportion of B cells and plasma cells increases (Frischer et 
al. 2009). 
Humoral immunity has been implicated in MS for decades, as evidenced by inclusion of 
Cerebrospinal Fluid (CSF) oligoclonal bands (OCBs) and increased Immunoglobulin G (IgG) index 
in diagnostic criteria for MS (Polman et al. 2011; Siden 1979). 
Until very recently, the prevailing view of MS pathophysiology held that the CNS inflammation seen 
in MS is principally mediated by proinflammatory T cells.
However, rapidly expanding evidence suggests that B cells may contribute to MS pathogenesis 
much more fundamentally than was previously believed, potentially through either antibody 
dependent or independent mechanisms (Meinl, Krumbholz, and Hohlfeld 2006; Franciotta et al. 
2008; McFarland 2008). B lymphocytes have been detected within MS lesions and in the CSF of 
patients with MS.
B cells are thought to play an important role in the pathogenesis of multiple sclerosis by:
• Presenting auto-antigens and co-stimulatory signals to activate T cells (Constant 1999; Crawford 
et al. 2006; Harp et al. 2010)
• Secreting pro-inflammatory cytokines at greater relative proportions than protective cytokines 
(Bar-Or et al. 2010; Barr et al. 2012; Duddy et al. 2007; Li, Rezk, Healy, et al. 2015; Li, Rezk, 
Miyazaki, et al. 2015)
• Producing auto-antibodies which may cause tissue damage and activate macrophages (Genain 
et al. 1999; Storch et al. 1998)
• Creating meningeal lymphoid follicle-like structures, linked to microglia activation, local 
inflammation and neuronal loss in the nearby cortex (Magliozzi et al. 2010; Serafini et al. 2004)
As a consequence, B cell targeting represents an interesting therapeutic approach in MS. 
Ocrelizumab is a recombinant human monoclonal antibody that selectively targets and eliminates 
CD20+ B cells. In two phase III clinical trials in RMS, ocrelizumab has demonstrated superior 
efficacy over subcutaneous IFNβ-1a. Please refer to main protocol and Investigator Brochure for 
information regarding efficacy and safety of ocrelizumab in RMS patients.  


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Rationale for the substudy
Recent clinical trials in MS have shown the high efficacy of anti-CD20 mAbs in relapsing-remitting 
MS patients on inflammatory parameters. The efficacy of the treatment is seen as soon as 12 
weeks after treatment onset (Hauser et al. 2008) and does not modify the presence of oligoclonal 
bands in the CSF (Cross et al. 2006), indicating that the efficacy is not due to a direct effect on 
antibody production. B cells account for less than 5% of immune infiltrate in the CSF (Cepok et al. 
2005) and are found in MS patient’s lesions in lower numbers than T cells (10 times lower) or 
macrophages/microglial cells (Frischer et al. 2009). Therefore, it is hypothesized that the effect of 
anti-CD20 may be linked to antibody-independent effects of B cells via cytokine secretion by B cells 
or antigen presentation to T cells possibly in periphery.
It has been demonstrated that B cell depletion by anti-CD20 mAb influence T cells. For example, it 
has been shown that the use of anti-CD20 mAb modifies the amount of T cells in the CSF of patients 
(Cross et al. 2006; Piccio et al. 2010) and hypothetically in MS lesions. This hypothesis is supported 
by the reduction of T cell infiltration in the Experimental Autoimmune Encephalomyelitis (EAE) rat
model of MS when the animals are treated with anti-CD20 mAb (Anthony et al. 2014). However, if 
B cell depletion by ocrelizumab does not seem to influence T cells numbers it is hypothesized that 
ocrelizumab-induced B cell depletion might exert its beneficial effect in MS by influencing T cells 
subsets, phenotype and/or functions. It is not known whether the indirect T cell effect of ocrelizumab 
could be more pronounced on CD4 or CD8 T cells and in which subtypes of these T cells. It is also 
unknown whether ocrelizumab-induced B cell depletion modifies T cell repertoire or transcriptome, 
and impacts their functional ability to secrete specific cytokines (IL17, IFNg) or to migrate through 
the blood brain barrier. 
T cells subsets (CD4+
and CD8+
T cells) are thought to play a central role in MS 
immunopathophysiology. CD4+ T cells, and in particular Th1 and Th17 inflammatory subsets have 
been well studied in EAE mouse models (Fletcher et al. 2010) and both Th1 and Th17 cells are 
able to transfer EAE in mice although pathologies induced differ in terms of histopathological 
features and immune profile, suggesting complementary roles (Kroenke et al. 2008). Th1 and Th17 
cells role in human pathology has been similarly suggested (Fletcher et al. 2010). For instance, IL-
17 producing cells (including Th17 cells, but also glial cells and CD8+ T cells) were identified in 
active rather than inactive areas of MS lesions (Tzartos et al. 2008) and increased Th17 cells in 
blood of MS patients are associated with disease activity (Durelli et al. 2009).  Moreover, IFNγ+ IL-
17+ double positive T cells are enriched in MS brain tissue, suggesting a pathogenic role for those 
cells (Kebir et al. 2009).  On the contrary, many studies have suggested that Tregs 
immunosuppressive functions are impaired in MS patients (Fletcher et al. 2010; Dendrou, Fugger, 
and Friese 2015). 
CD8+ T cells seem to be particularly implicated in the disease process (Friese and Fugger 2009; 
Goverman 2009). They appear to be more numerous in MS patients brain lesions than other T cell 
subtypes and CD8+ T cell infiltrates within CNS lesions were frequently oligoclonally expanded, 
(Babbe et al. 2000; Junker et al. 2007; Montes et al. 2009; Skulina et al. 2004). Interestingly, the 
same clones were found in different lesion sites and even in the normal appearing white matter 
(Junker et al. 2007; Montes et al. 2009; Salou, Garcia, et al. 2015; Salou, Nicol, et al. 2015), 


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suggesting that few antigens may drive T cell response in the central nervous system (CNS). 
Looking at blood and CSF in MS patients, peripheral T cell repertoire was regularly skewed as 
compared to healthy controls (HC) repertoire (Gestri et al. 2001; Laplaud et al. 2004; Matsumoto 
et al. 2003; Muraro et al. 2002). Altogether, these arguments suggest a direct involvement of CD8+
T cells in the pathophysiological process of the disease. However, the precise role of these cells, 
i.e. the reasons for their entry into the CNS, and their antigen specificity remains to be determined. 
B cells are quickly depleted after anti-CD20 therapies (within 14 days after ocrelizumab treatment, 
see IB). Studies using Rituximab have shown that repleting B cells after the end of treatment exhibit 
a naïve phenotype (CD27- B cells) (Duddy et al. 2007; Palanichamy et al. 2014) and are less 
inflammatory than before depletion. For instance, after reconstitution, B cells secrete less 
inflammatory cytokines such as IL-6 or GM-CSF and more anti-inflammatory cytokines (IL-10) after 
in vitro stimulation than before depletion by rituximab (Barr et al. 2012; Duddy et al. 2007; Li, Rezk, 
Miyazaki, et al. 2015).
Therefore, the purpose of this substudy is to analyze B and T cells subsets during and after 
ocrelizumab-induced B cell depletion in order to better understand ocrelizumab mechanism of 
action.
Benefits / risk assessment
The results of this substudy are expected to help to better understand the mechanism of action of 
ocrelizumab in naïve RRMS patients. The substudy will particularly analyze the direct effects of 
ocrelizumab on B cells subsets and functions before and after repletion and its indirect effects on 
CD4+ and CD8+ T cells subsets and functions.
This substudy does not induce any major additional risk to the main study as it does not add any 
visit or procedure to the main study. Extra blood samples will be collected in addition to the blood 
laboratory samples planned in the main study. 
Objectives and Endpoints
The objectives of this substudy are to evaluate the impact of ocrelizumab-dependent B cell 
depletion on T and B cell subsets and functions in naïve RRMS patients, during B cell depletion 
and repletion. 
This substudy will help to assess the potential relationship between immunological biomarkers 
levels and clinical and/or subclinical change assessed by neurological markers in naïve RRMS 
patients treated with ocrelizumab.
T and B cells will be analyzed both before, during (on partially repleted patients for B cell analysis) 
and after (on partially repleted and repleted patients for B cell analysis) treatment with ocrelizumab. 
Specific objectives and corresponding endpoints for the substudy are outlined below.


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Objectives
Corresponding endpoints
First objective: 
Part 1: 
To evaluate 
the indirect 
impact of 
ocrelizumab-
dependent B 
cell depletion 
on T cell 
subsets and 
functions in 
naïve RRMS 
patients
The following analyses will be performed at baseline, 24 weeks, 48 weeks and 
at the end of the study at 192 weeks or earlier in case of withdrawal from the 
study.  These analyses will also be performed in case of extra visit due to 
relapse if applicable. 
Analysis of general immune cells frequencies in blood including B cells, T 
cells, dendritic cells, monocytes and NK cells subsets. Markers will include, 
but are not limited to CD4, CD8, CD19, CD11c, CD56, CD14, and CD16. 
Analysis of CD4+ and CD8+ T cells subset frequencies including naïve, 
central memory, effector memory or TEMRA subsets. 
Analysis of CD4+ and CD8+ T cells phenotype including regulatory and 
effector (Tc1, Tc17, Th1, Th17) subsets. Markers used include, but are not 
limited to CD3, CD4, CD8, CD161, CD45RC, CD127, IL18Ra, CXCR6, 
EOMES, PLZF1, perforin, GZB, CCR5, CCR6, CD25, CCR2, MCAM, DNAM, 
CD39, LFA1, PSGL1, VLA4, IFN-γ, IL-17, IL-22, Foxp3, Rorγt, or Tbet. 
Analysis of T cells activation of sorted blood CD4+ and CD8+ T cells in vitro 
by measuring cytokine production. Cytokines, including, but not limited to 
GM-CSF, IFN- γ, IL-17, IL-22, IL-13, will be assessed by flow cytometry 
stainings in CD4+ or CD8+ T cells after 5 days of total PBMCs (Peripheral 
Blood Mononuclear Cells) stimulation with anti-CD3 and anti-CD28. 
Quantitative measurements of a large panel of cytokines and chemokines in 
culture supernatant will be performed using luminex technology. Cytokines 
and chemokines analyzed will include  GM-CSF, IL-1β, IL-5, IL-4, IL-2, TNF-
α, IL-6, RANTES, MIG, VEGF, HGF, EGF, IL-8, IL-17, MIP-1α, IL-10, G-
CSF, MCP-1, IL-7, IL-15, IFN-α, IL-2R, IP-10, MIP-1β, Eotaxin, IL-1RA, IL-
12 (p40⁄p70) IL-13, FGF-Basic, IFN-γ.
Analysis of transmigration capacities of CD4+ and CD8+ T cells across an 
experimental model of Blood-Brain-Barrier in resting or inflammatory 
conditions.
Analysis of T cell repertoire in sorted CD4+ and CD8+ T cells using high 
throughput sequencing (Illumina Miseq). This analysis will be performed on 
the first 20 patients’ samples and will not be performed at 24 weeks. 
Analysis of RNA sequencing in sorted CD4+ and CD8+ T cells using Illumina 
assays. This analysis will be performed on the first 20 patients’ samples and 
will not be performed at 24 weeks.
Indirect impact of ocrelizumab-dependent B cell depletion on T cell subsets 
and functions in naïve RRMS patients will be measured by change from 
baseline for each marker and for each time point. 


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Part 2: 
   To decipher 
the indirect 
impact of 
ocrelizumab 
on B cell 
repopulation
Two periods can be defined: 
-
B cell depletion period on ocrelizumab
-
B cell repletion off ocrelizumab. 
During B cell depletion period (weeks 24, 48 and 192, or study withdrawal visit), 
analyses will be performed only in partially repleted patients with sufficient 
amount of B cells applicable for each analysis as described below. 
During B cell repletion period off ocrelizumab, analyses will be performed in 
partially repleted patients with sufficient amount of B cells and in repleted 
patients i.e. in patients having peripheral B cell level at or above the lower limit 
of normal. 
These analyses will also be performed in case of extra visit due to relapse in 
patients with sufficient amount of B cells. 
Analysis of the proportions of the different B cell subsets in peripheral blood. 
Different markers will be used to distinguish switched/unswitched memory, 
mature naïve, transitional B cells, plasmablasts and plasmocytes (CD19, 
CD20, CD27, IgD, CD38, CD24, CD138). Activated markers will also be 
determined (CD95, MHC-II, CD80, CD86). 

1.104 B cells per sample would trigger this analysis.
Analysis of the different B cell subsets will also be realized after some short 
(48h) stimulation protocols. We will evaluate the frequencies of regulatory 
and effector B cells after stimulation using flow cytometry. Cytokines such as 
IL-10, GZM B, TGF b and IL-35 (for regulatory cells) but also TNFa, GM-
CSF, LT and IL-6 (for effector B cells) will be measured. Quantitative 
measurements of a large panel of cytokines and chemokines in culture 
supernatant will be performed using luminex technology. 

This part will only be performed if there is enough B cells i.e. at least 
5.105 to 1.106 per sample.
Analysis of the differentiation abilities of B cells using a differentiation 
protocol lasting 6 days, already published (Chesneau et al, 2015). 

This part will only be performed if there is enough B cells in the 
peripheral blood i.e. at least 3.106 per sample.
Analysis of B cell repertoire in sorted B cells by immunosequencing (Adaptive 
biotechnologies) to assess immune reconstitution to establish correlations 
with clinical outcome. 

1.103 B cells per sample would trigger this analysis.
Analysis in reconstituted B cells of the expression of a panel of 96 genes 
(including surface markers, transcription factors, and cytokines) at the single 
cell level using parallel qPCR reactions (microfluidic technologies). 

5.103 B per sample cells would trigger this analysis. 
Thresholds mentioned for B cells analysis may be adjusted according to 
investigators decision and sampling procedures. In any cases, all analyses will 
describe the initial cell frequencies in study samples. 
Indirect impact of ocrelizumab-dependent B cell depletion on B cell subsets 
and functions in naïve RRMS patients will be measured by change from 
baseline for each marker and for each time point.


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Objectives
Corresponding endpoints
Second objective: 
To assess the 
potential 
relationship 
between 
immunological 
biomarkers 
levels and 
clinical and/or 
subclinical 
change 
assessed by 
neurological 
markers in 
naïve RRMS 
patients 
treated with 
ocrelizumab. 
Relationship between any B cells subset, CD4+ or CD8+ T cell subset or 
immunological marker at baseline, 24, 48, 192  weeks or earlier in case of 
withdrawal from the study of ocrelizumab treatment or during relapses and 
core study efficacy and safety objectives of MA30143 core study (endpoints). 
For instance, neurological markers that will be correlated with interesting 
immunological markers identified in the first part, will include, but will not be 
limited to: 
-
Total number of T1 Gd-enhancing lesions as detected by brain MRI 
over time
-
Total number of new and/or enlarging T2 lesions as detected by brain 
MRI over time
-
Change in T1 volume over time
-
Change in brain volume (including white and grey matter fractions) as 
detected by brain MRI over time
-
Time to first relapse 
-
Change from baseline in EDSS score over the course of the study
Relationship between any biomarkers with any other biomarker. 
STUDY DESIGN
Description of the substudy
This substudy is a longitudinal, multi-center, substudy of the Phase IIIb ocrelizumab trial MA30143.
This substudy will evaluate the indirect impact of ocrelizumab-dependent B cell depletion on T and 
B cell subsets and functions in naïve RRMS patients, during B cell depletion and during B cell 
repletion period off ocrelizumab. This substudy will help to assess the potential relationship 
between immunological biomarkers levels and clinical and/or subclinical change assessed by 
neurological markers in naïve RRMS patients treated with ocrelizumab.
Patients who provide consent to participate in this substudy and fulfill eligibility criteria will provide 
additional 12x8 mL blood samples at baseline, 24 weeks, 48 weeks, end of treatment period (192 
weeks or earlier in case of study withdrawal), and every 24 weeks for 48 weeks after last ocrelizumab 
infusion and in case of unscheduled visit due to relapse, as indicated in the schedule of 
assessments. 
Blood samples can be collected 2 weeks (± 4 days) prior ocrelizumab infusion, in addition to 
laboratory samples required in the main study. 
About 50 patients from specific centers in France enrolled in MA30143 study will be offered to 
participate in this substudy. 


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The number of patients that will withdraw from the study is estimated to be 10 (20% withdrawal rate 
over 192 weeks). As a consequence, approximatively 10 patients would enter the follow-up period 
for B cell repletion. Patients will provide blood samples every 24 weeks for 48 weeks after the last 
ocrelizumab infusion. 
Overview of study design
Figure 1 presents an overview of the substudy procedures.  A schedule of assessments is provided 
in 55 UAppendix 1U55.
Figure 1 Overview of Study design
Procedure in case of visit for relapse
In case of unscheduled visit due to a core protocol defined relapse between the weeks 24 and 192 
of the study, additional blood sample will be collected (12 x 8mL). This additional blood collection 
will not occur more than two times for a patient. Extra blood samples will not be collected in case 
of relapse within the first 24 weeks or during the follow-up. 
End and length of substudy
The end of the substudy is defined as the last patient visit in the Safety Follow-up period or last patient 
Week 192 visit, whichever occurs later.
The maximum length of the study, from first patient screening to the end of the substudy, is 
expected to be approximatively 316 weeks (6.5 years). This includes an enrolment period of 
approximately 76 weeks. 


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Centers
The substudy will take place in France, in centers associated with an investigator centers with 
PBMC technical and storage capacity which can prepare samples for storage, using a similar 
standardized protocol in all the centers (see 55 UAppendix 2U55). Frozen samples will be shipped to the 
CHU of Nantes where they will be analyzed. 
MATERIALS AND METHODS 
Patients
Patients with early stage RRMS who fulfill eligibility criteria for the Phase IIIb study (MA30143) and 
the eligibility criteria outlined in the following inclusion and exclusion sections of this substudy can 
be enrolled into the substudy. Approximately 50 patients are planned to be enrolled in the substudy. 
Inclusion Criteria
Patients must meet the following criteria to be eligible for substudy entry: 

Enrolled in the Phase IIIb study MA30143

Signed Informed Consent Form for the MA30143-T and B cell Substudy

Able to comply with the substudy protocol, in the investigator’s judgment.
Exclusion Criteria
There is no exclusion criteria beyond those listed in the main protocol of the MA30143 study. 
Substudy assessments 
Procedure for enrolment of eligible patients
All patients eligible for the main study are also eligible to enter in the substudy, if desired. 
Patients must sign and date the most current Institutional Review Board/Institutional Ethics 
Committee’s (IRB/IEC) approved written informed consent form for the main study in which they 
are participating (MA30143) and a separate informed consent form for the substudy before any 
substudy-specific assessments or procedures are performed. 
Sample Collection and visits assessments
Visits for this substudy will occur at the same time as visits for the main study (see 55 UAppendix 1U55).
Patients who have enrolled in the main study and enrolled in this optional research substudy will 
have additional substudy blood specimens collected at each time point as outlined in the schedule 
of assessments (55 UAppendix 1U55).
Twelve samples of 8 mL of whole blood (96 mL) will be collected in CPT tubes. Samples will be 
processed and frozen in the investigator centers with PBMC technical and storage capacity and 
stored before shipment to the CHU of Nantes where experiments will be performed. 
Each center is responsible for collection, preparation, freezing, storage and shipment of samples 
to Nantes CHU every 6 months.


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Leftovers of processed specimens, which will consist of frozen cells, will be retained for a maximum 
of 5 years after the end of the trial (for confirmation of results). CHU of Nantes will destroy those 
samples once the study report of the substudy has been finalized. 
Patient, Study and site discontinuation
Patient discontinuation
Patients have the right to voluntarily withdraw from the substudy at any time for any reason. 
Patient’s withdrawal from the substudy does not constitute a withdrawal from the main trial. Patients 
withdrawal from main study and/or substudy does not, by itself constitute withdrawal of specimens 
already collected for the substudy. Consent for further research to be performed on collected 
specimens as part of the substudy may be withdrawn at any time and collected samples destroyed, 
by contacting the sponsor, which will ask the CHU of Nantes to destroy the samples.
No replacement for patients who withdraw from the substudy is planned. 
Study and Site Discontinuation
The Sponsor has the right to terminate the main study or to close a site at any time. Reasons for 
termination are listed in the main study protocol (MA30143). The Sponsor will notify the 
investigators if the Sponsor decides to discontinue the study. Consequently, the substudy could be 
stopped.
The Sponsor has also the right to terminate this substudy at any time. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the substudy.  
ASSESSMENT OF SAFETY 
Safety assessment
Adverse events related to the substudy procedure will be collected throughout the substudy 
according the same procedure of the main study protocol, as outlined in the main study protocol 
(MA30193). 
Blood draw may have procedural adverse events such as minor discomfort, lightheadedness, or 
bruising at the draw site. If any AE occurs in regards to the procedure for this substudy sample, it 
should be reported according to the main study protocol instructions in Sections 55 U5.3U55 and 55 U5.4U55. 
Safety instructions and guidance
Safety measures regarding the study medication are not part of this substudy, and are detailed in 
the main protocol (MA30143). 
Reporting of Adverse Events
If an adverse event specifically related to the substudy procedure occurs, it will be recorded in the 
e-CRF and documented in the study report. 
Reporting of Serious Adverse Events
Refer to 55 USection 5.4.2U55 of main protocol. 


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Emergency Medical Contacts
Refer to Section 5.4.1 of main protocol. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Due to the small sample size, the substudy data analysis will be descriptive only. 
The number of patients expected to participate in this optional substudy is 50. 
Estimation for a proportion of 50%, with a study size of 50, the precision of the estimation is 13.9%.
If relevant, calculated confidence intervals will be displayed with a 95% level.
All variables will be summarized in statistical tables including the following descriptive statistics:

The quantitative variables will be described using the number of non-missing values, 
the number of missing values, the mean, the standard deviation, the median, the first 
and the third quartiles, the minimum and the maximum. 

The qualitative variables will be described using the number of non-missing values, 
the number of missing values, the frequency and the percentage per modality.
Full details of the derivations and analyses of exploratory endpoints will be detailed in the 
corresponding substudy Statistical Analysis Plan (SAP). The SAP will be written by the Sponsor in 
accordance with the investigator coordinator of this substudy. 
These data are intended to be hypothesis-generating, and are not expected to achieve statistical 
significance. Data generated as part of this substudy will be described in a separate clinical study 
report. 
Evaluation of the impact of ocrelizumab-dependent B cell depletion on T and B cell subsets and 
functions in naïve RRMS patients, during B cell depletion and during B cell repletion period off 
ocrelizumab at the end of the treatment will be measured by the change from baseline for each 
marker and for each time point. 
Assessment of the potential relationship between immunological biomarkers levels and clinical 
and/or subclinical change assessed by neurological markers will be measured using: 

Correlations between immunological markers and clinical outcome tested using linear 
and non-linear correlation coefficient. 

Relationship between any B cell subset, CD4+ or CD8+ T cell subsets (or any 
immunological marker at any time point) and core study efficacy objectives performed 
using a regression model to evaluate biomarkers predictive factors of efficacy or 
safety objectives. 
Any additional exploratory analysis might be conducted and will be discussed with the investigator 
coordinator of this substudy before being described in the SAP 


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DATA COLLECTION AND MANAGEMENT 
Data collection and management  
The overall procedures for quality assurance of clinical study data are described in the Sponsor’s 
(or designee’s) Standard Operational Procedures. 
A contract research organization (CRO) will be responsible for data management of this substudy, 
including quality checking of the data.  Data entered manually will be collected via EDC through 
use of eCRFs (e.g. informed consent, withdrawal of consent, sample collection dates). Investigators 
will be responsible for data entry into the EDC system.  In the event of discrepant data, the CRO 
will request data clarification from the site, which the site will resolve electronically in the EDC 
system. 
The sponsor will perform oversight of the data management of this study, including approval of the 
CRO’s data management plans and specifications. Sponsor’s standard procedures will be used to 
handle and process the electronic transfer of these data (including the non eCRF data). The clean 
database will be transferred to the Sponsor for analysis of the correlations with the clinical or 
subclinical efficacy and safety profile of the patients included in the substudy.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  System 
backups for data stored at the Sponsor and records retention for the study data will be consistent 
with the Sponsor’s standard procedures.
Substudy data will be recorded via the instrument used for data acquisition (flow cytometer, luminex 
technology, sequencing etc.) and for most experiments will be processed by CHU of Nantes to 
generate key data. These non eCRF data will be handled using the Sponsors standard procedures 
to handle and process these data.  
Source data documentation
The Investigators shall supply the Sponsor on request with any required background data from the 
substudy documentation or clinic records. This is particularly important when errors in data 
transcription are suspected. In case of special problems and/or governmental queries or requests 
for audit inspections, it is also necessary to have access to the complete study records, provided 
that patient confidentiality is protected. 
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.
Retention of records
Records and documents pertaining to the conduct of this substudy, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the Principal 


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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. 
ETHICAL CONSIDERATIONS
Compliance with Laws and Regulations
This study will be conducted in full conformance with the International Conference on 
Harmonization (ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration 
of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for Expedited 
Reporting).  Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. Food and Drug Administration regulations and applicable local, 
state, and federal laws.  Studies conducted in the European Union (E.U.) or European Economic 
Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
Informed Consent
All patients must sign the informed consent form for the main study (MA30193) prior to screening. 
Additionally, all patients enrolled in this substudy must sign a separate informed consent form for 
collection of sample(s) prior to any substudy specific assessments.
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent Forms 
such as a Caregiver Assent Form) will be provided to each site.  If applicable, it will be provided in 
a certified translation of the local language.  The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor's sample Informed Consent Forms or any alternate 
consent forms proposed by the site (collectively, the "Consent Forms") before IRB/EC submission.  
The investigator or authorized designee will explain to each patient the objectives, methods, and 
potential risks associated with substudy procedures.  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 
informed consent form will be required to document a patient's agreement to participate in substudy 
procedures.  
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.  
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.


Ocrelizumab—F. Hoffmann-La Roche Ltd
153/Protocol MA30143, Version 10.0
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.
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 Sponsor 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 sponsor 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.  Sponsor is also responsible for promptly informing the IRB/EC of any 
protocol amendments (see 55 USection 9.7U55).
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. 
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 or the patient’s legally authorized 
representative, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of the analyses, data derived from exploratory 
biomarker specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in accordance 
with the effective Roche policy on study data publication (see
55 USection 9.6U55).
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.
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).


Ocrelizumab—F. Hoffmann-La Roche Ltd
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STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION
Study Documentation and record keeping
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.  
Site Inspections
Site visits will be conducted by the Sponsor or an authorized representative for inspection of study 
data.  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.
Administrative Structure
This trial will be sponsored by Roche, and will be managed by Roche and CROs.  CROs will provide 
clinical operations management, data management, biostatistics, and medical monitoring. 
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 substudy 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 results. 
If interim analysis of core study is done, correlation with substudy in a separate statistical report 
might be envisioned.  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.


Ocrelizumab—F. Hoffmann-La Roche Ltd
155/Protocol MA30143, Version 10.0
Protocol amendments 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally required) before 
implementation of any changes, except for changes necessary to eliminate an immediate hazard 
to patients or changes that involve logistical or administrative aspects only (e.g., change in Medical 
Monitor or contact information).


Ocrelizumab—F. Hoffmann-La Roche Ltd
156/Protocol MA30143, Version 10.0
Appendices to Appendix 8
Appendix 1: Schedule of assessments
Visit
Scre
ening
Treatment Period
Safety Follow-up period 
Unscheduled Visits
1
2 
(Baselin
e)
5
6
12
Early study 
treatment 
discontinuatio
n visit
relapse 1
relapse 2
Week
-4 to -
1 
weeks
1
24 
(±14 
days)
48 
(±14 
days)
192
(±14 
days)
Visits Every 24 weeks (+/-
14 days) (for 48 weeks
after last dose)
Substudy 
Inform Consent
X
Blood 
Collection for 
Substudy
X
X
X
X
X
(if applicable)
X
(if applicable)
X
(if applicable)
X
(if applicable)


Ocrelizumab—F. Hoffmann-La Roche Ltd
157/Protocol MA30143, Version 10.0
Appendix 2: guidance for treatment of CPT tubes in OFSEP CRB  
to be followed by investigator centers with PBMC technical and storage capacity 


Ocrelizumab—F. Hoffmann-La Roche Ltd
158/Protocol MA30143, Version 10.0
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Ocrelizumab—F. Hoffmann-La Roche Ltd
161/Protocol MA30143, Version 10.0
APPENDIX 9
Immune Substudy Protocol
IMMUNE SUBSTUDY PROTOCOL
TITLE:
A 
SUBSTUDY 
TO 
RESEARCH 
IMMUNOLOGICAL 
PARAMETERS AND SIGNATURES ASSOCIATED WITH 
OCRELIZUMAB 
TREATMENT 
IN 
EARLY 
STAGE 
RELAPSING REMITTING MULTIPLE SCLEROSIS
ASSOCIATED WITH MA30143 CORE STUDY:  AN OPEN-
LABEL, SINGLE-ARM STUDY TO EVALUATE THE 
EFFECTIVENESS AND SAFETY OF OCRELIZUMAB IN 
PATIENTS WITH EARLY STAGE RELAPSING REMITTING 
MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
MA30143 Immune Substudy
VERSION NUMBER:
6.0
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
SPONSOR:
F. HOFFMANN-LA ROCHE LTD
Grenzacherstrasse 124,
4070 Basel, Switzerland
DATE FINAL:
See electronic date stamp below


Ocrelizumab—F. Hoffmann-La Roche Ltd
162/Protocol MA30143, Version 10.0
IMMUNE SUBSTUDY PROTOCOL ACCEPTANCE FORM
TITLE:
A 
SUBSTUDY 
TO 
RESEARCH 
IMMUNOLOGICAL 
PARAMETERS AND SIGNATURES ASSOCIATED WITH 
OCRELIZUMAB 
TREATMENT 
IN 
EARLY 
STAGE 
RELAPSING-REMITTING MULTIPLE SCLEROSIS  
ASSOCIATED WITH MA30143 CORE STUDY: AN OPEN-
LABEL, SINGLE-ARM STUDY TO EVALUATE THE 
EFFECTIVENESS AND SAFETY OF OCRELIZUMAB IN 
PATIENTS WITH EARLY STAGE RELAPSING REMITTING 
MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
MA30143 Immune Substudy
VERSION NUMBER:
6.0
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab, RO4964913
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Co-Investigator’s Name (print)
Co-Investigator’s Signature
Date
Please retain the signed original of this form for your study files. Please return a copy as instructed 
by your study monitor.


Ocrelizumab—F. Hoffmann-La Roche Ltd
163/Protocol MA30143, Version 10.0
IMMUNE SUBSTUDY PROTOCOL SYNOPSIS
TITLE:
A SUBSTUDY TO RESEARCH IMMUNOLOGICAL PARAMETERS 
AND 
SIGNATURES 
ASSOCIATED 
WITH 
OCRELIZUMAB 
TREATMENT IN EARLY STAGE RELAPSING REMITTING MULTIPLE 
SCLEROSIS
ASSOCIATED WITH MA30143 CORE STUDY: 
AN OPEN-LABEL, 
SINGLE-ARM STUDY TO EVALUATE THE EFFECTIVENESS AND 
SAFETY OF OCRELIZUMAB IN PATIENTS WITH EARLY STAGE 
RELAPSING REMITTING MULTIPLE SCLEROSIS
PROTOCOL NUMBER: MA30143 Immune Substudy 
VERSION NUMBER:
6.0
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab, RO4964913
PHASE:
IIIb
INDICATION:
Relapsing-Remitting multiple sclerosis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objective
To explore immunological changes associated with ocrelizumab treatment 
in a treatment naïve, early stage MS population. This substudy will help to 
assess the potential relationship between immunological biomarker levels 
and clinical and/or subclinical changes assessed by neurological markers 
in naïve RRMS patients treated with ocrelizumab.
Study 
design
This study is designed as a substudy to the MA30143 prospective, 
multicenter, open-label and single-arm effectiveness and safety study on 
ocrelizumab in patients with early stage RRMS. Patients giving their 
consent to participate in this substudy will be asked to provide 6 x 9 mL 
EDTA blood and 1 x 9 mL serum samples (total blood volume of 63 mL) at 
baseline, week 24, week 48, week 96, week 192/or early treatment 
discontinuation visit and at 48 weeks after the last infusion of ocrelizumab
Additional samples (6 x 9 mL EDTA blood and 1 x 9 mL serum samples 
[total blood volume of 63 mL]) will be collected, wherever possible, in 
cases of relapse, de novo vaccination or severe infection. Blood and 
serum samples will be collected, processed and stored at indicated time 
points aligning with the MA30143 study. Clinical and radiological 
parameters will be derived from the MA30143 trial and correlated with the 
immunological parameters measured in the substudy.


Ocrelizumab—F. Hoffmann-La Roche Ltd
164/Protocol MA30143, Version 10.0
Study 
duration
ULength of Substudy
The total length of the substudy is aligned with the main study. Total length 
of the parent study, from screening of the first patient to the end of the 
study, is expected to be approximately 356 weeks (7 years). This includes 
an enrolment period of 116 weeks.
UEnd of Substudy
The substudy end is defined as the last patient last visit in the Safety Follow-
up period or last patient Week 192 visit, whichever occurs later.
Study 
population
UInclusion Criteria
Patients must meet the inclusion criteria stated in the MA30143 parent 
study protocol. In addition, following criteria have to be met for substudy 
entry:

Signed informed consent form for the substudy

Able to comply with the substudy protocol, in the investigator’s 
judgment
UExclusion Criteria
There are no exclusion criteria beyond those listed in the parent MA30143 
study protocol.
UNumber of Patients
This substudy will enroll approximately 80 patients. 
Sites
Approximately 40 sites in Germany and other selected countries will be 
participating in this substudy.
Study 
Endpoints
UBasic Analysis (all evaluable Patients): 
Frequencies of circulating immune cell subsets (B cells, T cells, NK cells, 
antigen presenting cells), measured relative to baseline (pre-infusion) at
week 24, week 48, week 96, week 192/or early treatment discontinuation visit and 
at 48 weeks after the last infusion of ocrelizumab.
UExtended Analysis (first 30 enrolled Patients): Phenotypic and 
functional characterization
B cell and T cell expression of activation and lineage markers. Expression 
of phenotypic and activation markers on innate immune cells.
T cell cytokine production.
B and T cell proliferation, cytokine production and genetic immune 
receptor diversity.
UExploratory Associations: 
Associations of immunological parameters with clinical, MRI, and safety 
parameters.
For a comprehensive overview of assessed parameters see Tables 55155, 55255
and 55355 in 55 USection 2U55.


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Statistical 
Methods
Each lymphocyte subset parameter will be summarized using descriptive 
statistics for patients at each scheduled time as well as change from 
baseline. Such summaries may include further summaries by patient 
subgroups. For each lymphocyte subset parameter, the change in 
lymphocyte subset parameter value for ocrelizumab treated relapsing-
remitting multiple sclerosis (RRMS) patients after week 24, week 48, week 96, 
week 192 from baseline will be analyzed using a linear mixed model. 
Confidence intervals will be interpreted in an exploratory manner.
UDetermination of Sample Size 
No formal sample size determination was performed. The proposed 
numbers of patients are considered appropriate for this exploratory study 
and is consistent with other similarly conducted studies in the field (TERY-
DYNAMIC Study Clinical trials.gov NCT01863888, Neurology April 5, 2016 
vol. 86 no. 16 Suppl- P5.282)
UInterim Analyses
Exploratory analyses of selected endpoints will be performed during the 
course of the study.


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UIMMUNE SUBSTUDY PROTOCOL
U1 RATIONALE AND BENEFIT-RISK ASSESSMENT
1.1 RATIONALE
It is widely accepted that the clinical course of MS consists of two major phases; an early, 
focal inflammatory phase and a later, progressive phase characterized by 
neurodegeneration and CNS confined disseminated inflammation [55 U1-5U55] Current DMTs 
work effectively in modifying the early inflammatory phase and prevent long term neuronal 
damage and disability progression. Two pivotal phase III trials in RRMS have shown that 
ocrelizumab is more efficacious in reducing the risk of disability progression than 
subcutaneous IFNβ-1a [55655]. However, the study population in these two pivotal trials did 
not specifically include early RRMS patients naïve to previous disease modifying therapy. 
This gap is closed by the prospective open label, single arm MA30143 study. Endpoints 
of the main study include clinical, MRI and safety parameters but no immunological 
parameters. It is of particular value to explore immunological consequences of 
ocrelizumab in early, treatment naïve patients for two major reasons. First, immunological 
dysregulation is evident in the periphery and plays a role in disease pathophysiology 
particularly in early RRMS [55 U5, 7U55]. Second, the immune system has not been modified 
before in these patients by other immunemodulatory treatments that could bias the natural 
immunological changes induced by ocrelizumab treatment. 
1.2 BENEFIT-RISK ASSESSMENT
The results of this substudy are expected to yield a deeper understanding of ocrelizumab’s 
immunological mechanisms. Given the high potential to provide important cues to 
individual treatment response and risk-benefit ratio, a minimal added risk due to additional 
blood samplings occurring the substudy is regarded justified by the sponsor. 
U2. OBJECTIVES AND ENDPOINTS
The MA30143 (ENSEMBLE) immune substudy will investigate immunological changes 
associated with Ocrelizumab treatment in a treatment naïve, early stage RRMS population. 
During the OPERA trials the quantitative evolution of major lymphocyte subsets and NK 
cells over the study treatment was investigated and correlated with severe infections 
CTCAE grade III and IV, and herpes and opportunistic infections. The MA30143 immune 
substudy intends to gain additional insights by observing a broader panel of immune cell 
types and their functional properties under ocrelizumab treatment. In-depth 
characterization will be achieved by multicolor flow cytometry, in vitro cell culture and deep 
sequencing. This multiparametric exploration of the immune system is powerful to reflect 
its overall functional state which will be measured before, during and post ocrelizumab 
therapy as well as upon B cell repletion. Individual immune parameters will be correlated 
with clinical and/or subclinical changes assessed by neurological markers in the main 
study MA30143. 






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Table 3 Correlations with Parameters from the Main Study
Data from the main study as outlined below will be used for correlations with 
various immune parameters (to be determined in the substudy statistical analysis 
plan)
Clinical

Time to onset of confirmed disability progression (CDP) sustained for at least 24 
weeks and 48 weeks 

Proportion of patients who have confirmed disability improvement (CDI), CDP or 
stable disability (i.e. neither CDI nor CDP) assessed annually for at least 24 weeks 
and 48 weeks 

Change from baseline in Expanded Disability Status Scale (EDSS) score over the
course of the study

Time to first MA30143 protocol-defined event of disease activity

Time to first relapse 

Annualized relapse rate 

Proportion of patient relapse free by week 48, 96, 144 and 192

Proportion of patients with no evidence of protocol-defined disease activity (NEDA) 
over week 96, week 144 and week 192 and per epoch 

Proportion of patients with no evidence of progression (NEP) 

Proportion of patients with no evidence of progression sustained for at least 24 weeks 
and no active disease (NEPAD

Change from baseline of Multiple Sclerosis Functional Composite (MSFC) and its 
composites (T25FW, 9HP, and Paced Auditory Serial Addition Test [PASAT]) over 
time
MRI

Total number of T1 Gd-enhancing lesions as detected by brain MRI over time

Total number of new and/or enlarging T2 lesion as detected by brain MRI over time

Total number of fluid-attenuated inversion-recovery (FLAIR) lesion counts as detected 
by brain MRI over time

Percentage change in brain volume as detected by brain MRI over time
Safety
serious infections CTCAE grade III or IV
herpes
opportunistic infections


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U3 SUBSTUDY DESIGN
3.1 DESCRIPTION OF THE SUBSTUDY
This study is designed as a substudy to the MA30143 prospective, multicenter, open-label 
and single-arm effectiveness and safety study on ocrelizumab in patients with early stage 
RRMS. By an in-depth investigation of repopulation dynamics and qualitative changes this 
substudy aims to understand the consequences of B cell depletion for immune regulatory 
networks in early stages of MS. The study will utilize the deep immune profiling platform 
with standardized biosample acquisition, storage, processing and analysis established at 
the Münster University Hospital, department of Neurology. 
Approximately 80 patients, who fulfil eligibility criteria, will be included in this substudy. 
These will be recruited from approximately 40 sites in Germany and other selected 
countries. Blood and serum samples will be collected, processed and stored during the 
192 week treatment period and the 48 week follow-period of the MA30143 trial (overall 
storage of samples for up to 5 years after end of study). Clinical and radiological 
parameters will be derived from the MA30143 trial and correlated with the immunological 
findings of the substudy. This shall provide cues to immune signatures of immune cell 
depletion and repopulation associated with parameters of treatment response (clinical and 
radiological) or safety issues. The Sponsor expects a deeper understanding of 
ocrelizumab’s immunological effects to potentially improve patient selection and guidance 
and therefore the individual benefit-risk ratio.
Patients giving their consent to participate in this substudy will be asked to provide 6 x 9 
mL EDTA blood and 1 x 9 ml serum samples (total blood volume of 63 ml) at baseline, 
week 24, week 48, week 96, week 192/or early treatment discontinuation visit and at 48 weeks after 
the last infusion of ocrelizumab. Additional samples (6 x 9 mL EDTA blood and 1 x 9 mL 
serum samples [total blood volume of 63 mL]) will be collected, wherever possible, in cases 
of relapse, de novo vaccination or severe infection. Samples will be collected at the 
individual centers. After performing a differential blood count on site, samples will be 
immediately shipped to Münster University Hospital, where all samples will be further 
processed and analyzed.


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3.2 OVERVIEW OF STUDY DESIGN
Figure 1 - Overview of the Study Procedures
*For dropouts, a measurement 48 weeks after the last infusion of ocrelizumab will be performed to assess immune status 
during repletion. 
Table 4 – Visit Scheme
Visit # (Main Study)
Screening
Treatment Period
Safety Follow-
up
Unscheduled 
Visit
1
2
5
6
8
12
Ad-hoc
Ad-hoc
Visit # (Substudy)
1
2
3
4
5
6
Ad-hoc
Ad-hoc
Week
-4 to -1
1
24
48
96
192
48 weeks after 
last infusion of 
ocrelizumab
Informed consent
X
Mandatory blood 
samplesa
X
X
X
X
X
X
Informed consent 
for additional blood 
samples
X
Additional blood 
samples in cases of 
X


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relapse, de novo 
vaccination or 
severe infectionb
a 6 x 9 mL EDTA blood and 1 x 9 mL serum samples (total blood volume of 63 mL) at baseline, week 24, week 
48, week 96, week 192/or early treatment discontinuation visit and at 48 weeks after the last infusion of ocrelizumab.
b 6 x 9 mL EDTA blood and 1 x 9 mL serum samples (total blood volume of 63 mL).
3.3 SCREENING, TREATMENT PERIOD, FOLLOW UP PERIOD
Screening is performed according to procedures defined in the main study protocol. 
Patients need to enter the substudy before receiving the first dose of ocrelizumab. 
Treatment period, criteria for re-treatment and follow up period are defined in the main 
study protocol. Patients who prematurely withdraw or finish treatment period will 
additionally be assessed 48 weeks after the last infusion of ocrelizumab.
3.4 PLANNED TOTAL SAMPLE SIZE
This substudy will enroll approximately 80 patients. Please refer to the 
55 USection 6.1U55 for 
more details.
3.5 END OF SUBSTUDY AND LENGTH OF SUBSTUDY
Patients will remain enrolled in the substudy as long as in the main study MA30143, if 
consent is not prematurely withdrawn. Timelines are aligned to the main study. The end 
of the study treatment period is defined in the main study protocol. The substudy end is 
defined as the last patient last visit in the Safety Follow-up period or last patient Week 192 visit, 
whichever occurs later.
Total length of the parent study, from screening of the first patient to the end of the 
study, is expected to be approximately 356 weeks (7 years). This includes an enrolment 
period of 116 weeks.
3.6 CENTERS
Sites selected for the main study and located in Germany and other selected countries will 
be eligible to participate in this substudy. Approximately 40 sites are envisaged to 
participate in the substudy.
U4 MATERIALS AND METHODSU
4.1 PATIENTS
Patients with early stage RRMS who fulfill eligibility criteria for the Phase IIIb study 
(MA30143) and the eligibility criteria outlined in the following inclusion and exclusion 
sections of this substudy can be enrolled into the substudy. Up to 80 patients will be 
enrolled in the substudy. 


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4.1.1 Inclusion Criteria
Patients must meet the following criteria to be eligible for substudy entry:

Enrolled in the Phase IIIb study MA30143

Signed Informed Consent Form for the MA30143 Immune Substudy

Able to comply with the substudy protocol, in the investigator’s judgment.
U4.1.2 Exclusion Criteria
There are no exclusion criteria beyond those listed in the main protocol of the MA30143 
study. 
4.2 SUBSTUDY ASSESSMENTS 
U4.2.1 Procedure for enrolment of eligible patients
All patients eligible for the main study are also eligible to enter the substudy, if desired.
Patients must sign and date the most current Institutional Review Board/Institutional Ethics 
Committee’s (IRB/IEC) approved written informed consent form for the main study in 
which they are participating (MA30143) and a separate informed consent form for the 
substudy before any substudy-specific assessments or procedures are performed.
U4.2.2 Sample Collection and visits assessments
Visits for this substudy will take place as a part of the main study visits.
Patients who have enrolled in the main study and enrolled in this optional research 
substudy will have additional substudy blood specimens collected at each timepoint as 
outlined in the schedule of assessments. Seven samples of 9 mL blood will be collected 
(63 mL). Additional samples (6 x 9 mL EDTA blood and 1 x 9 mL serum samples [total 
blood volume of 63 mL]) will be collected, wherever possible, in cases of relapse, de novo 
vaccination or severe infection. Samples will be collected, processed at participating sites 
and immediately shipped to the Münster University Hospital (UKM) where experiments will 
be performed. Leftovers of processed specimens, which will consist of frozen cells, will be 
retained for a maximum of 5 years (for confirmation of results, if appropriate). Those 
samples will be destroyed once the study report of the substudy has been finalized. 
4.3 PATIENT, STUDY, AND SITE DISCONTINUATION 
U4.3.1 Patient Discontinuation
Patients have the right to voluntarily withdraw from the substudy at any time for any reason. 
Patient’s withdrawal from the substudy does not constitute a withdrawal from the main 
study. Patients withdrawal from main study and/or substudy does not, by itself constitute 
withdrawal of specimens already collected for the substudy. Consent to this immune 
substudy may be withdrawn at any time and collected samples destroyed, by contacting 


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the sponsor, which will ask the investigator to destroy the samples. No replacement for 
patients who withdraw from the substudy is planned.
U4.3.2 Study and Site Discontinuation
The Sponsor has the right to terminate the substudy at any time. The same clauses apply 
for the substudy as stated in the parent study protocol, 
55 USection 4.7.3U55. Substudy 
discontinuation does not affect parent study continuation. 
U5 ASSESSMENT OF SAFETY 
5.1 SAFETY ASSESSEMENT
Adverse events related to the substudy procedure will be collected throughout the 
substudy and reported as per main study. Other adverse events related to disease, 
medication, or other main study procedures should be reported as outlined in the Safety 
Assessment and/or Safety Instructions and Guidance sections of the main study protocol 
(MA30143). 
Blood draw may have procedural adverse events such as minor discomfort, 
lightheadedness, or bruising at the draw site, or in very rare cases, infection. If any AE 
occurs in regards to the procedure for this substudy sample, it should be reported 
according to the substudy protocol instructions in the guidance in Section 5.2 below. 
5.2 SAFETY INSTRUCTIONS AND GUIDANCE
Safety measures regarding the study medication of the Phase III trials are not part of this 
substudy, and are detailed in the respective main protocols (MA30143).
U5.2.1 Reporting of Adverse Events
If an adverse event specifically related to the substudy procedure occurs, it will be 
recorded in the e-CRF and documented in the study report and/or substudy report.
U5.2.2 Reporting of Serious Adverse Events
If a serious adverse event specifically related to the substudy procedure occurs, the event 
should be immediately reported to the Sponsor, it will be recorded in the e-CRF and 
documented in the study report and/or substudy report.)
U5.2.3 Emergency Medical Contacts
Refer to Section 5.4.1 of main protocol. 
U6 STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1 DETERMINATION OF SAMPLE SIZE 
The number of patients expected to participate in this substudy is up to 80. No formal 
sample size determination was performed. The proposed number of patients is considered 
appropriate for this exploratory study and is consistent with other similarly conducted 


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studies in the field (TERY-DYNAMIC Study Clinical trials.gov NCT01863888, Neurology 
April 5, 2016 vol. 86 no. 16 Suppl- P5.282).
6.2 OUTLINE OF ANALYSES
The results of this substudy are intended to be hypothesis-generating. Data generated as 
part of this substudy will be presented in a clinical study report separate from that of the 
parent study. 
This is an outline of the main analyses planned for this substudy. More details will be 
provided in the substudy Statistical Analysis Plan (SAP), which may include additional 
exploratory analyses not explicitly mentioned in this section. 
Analysis populations: the main analysis of this substudy will include all evaluable 
patients part of the ITT population of the parent study eligible for this substudy.
The analysis will be primarily descriptive. Where appropriate, 95% confidence intervals for 
point estimates will be calculated and interpreted in an exploratory manner.
Correlations between immunological markers and clinical outcome will be assessed. T cell 
repertoire analyses will be performed on samples of the first 30 enrolled patients. 
Relationship between any CD4+ or CD8+ T cell markers (or any immunological marker at 
baseline, 24 weeks or 48 weeks of ocrelizumab treatment) and core study efficacy and 
safety endpoints will be assessed using a regression model to evaluate biomarkers as 
predictive factors of efficacy or safety endpoints.
6.3 INTERIM ANALYSIS
Exploratory analyses of selected endpoints will be performed during the course of the 
study, for example, after all patients have completed the first 48 weeks of the treatment 
phase and the necessary data are available. As no confirmatory statistical tests will be 
conducted, no formal control to the type-I error rate is needed.
U7 DATA COLLECTION AND MANAGEMENT 
The overall procedures for quality assurance of clinical study data are described in the 
Sponsor’s (or designee’s) Standard Operational Procedures. 
The central laboratory for the substudy (Münster University Hospital) will be responsible 
for data management of this substudy, including quality checking of the data. In event of 
discrepant data, the Muenster University Hospital will request data clarifications from the 
site which will be revolved via their capture system. 
The sponsor will perform oversight of the data management of this study, including 
approval of the data management plans and specifications at Münster University Hospital. 
Sponsor’s standard procedures will be used to handle and process the electronic transfer 


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of these data. The clean data will be transferred to the Sponsor for analysis of the 
correlations with the clinical or subclinical efficacy and safety profile of the patients 
included in the substudy. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail 
(for eCRF data – e.g. informed consent, withdrawal of consent, sample collection dates). 
System backups for data stored at the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
Substudy data will be recorded via the instrument used for data acquisition and for most 
experiments will be processed by Münster University Hospital to generate key data. These 
non eCRF data will be handled using the Sponsors standard procedures to handle and 
process these data. 
Source data documentation
The Investigators shall supply the Sponsor on request with any required background data 
from the substudy documentation or clinic records. This is particularly important when 
errors in data transcription are suspected. In case of special problems and/or 
governmental queries or requests for audit inspections, it is also necessary to have access 
to the complete study records, provided that patient confidentiality is protected. 
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. 
Retention of records
Records and documents pertaining to the conduct of this substudy, 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. 
Use of data from the main study


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If patients remain enrolled in the main study beyond the end of the substudy, data 
collected from the main study may continue to be used for analysis with data generated 
in the substudy.
UREFERENCES
1.
Bar-Or, A., The immunology of multiple sclerosis. Semin Neurol, 2008. 28(1): p. 
29-45.
2.
Leray, E., et al., Evidence for a two-stage disability progression in multiple 
sclerosis. Brain, 2010. 133(Pt 7): p. 1900-13.
3.
Mahad, D.H., B.D. Trapp, and H. Lassmann, Pathological mechanisms in 
progressive multiple sclerosis. Lancet Neurol, 2015. 14(2): p. 183-93.
4.
Nicol, B., et al., The autoimmune concept of multiple sclerosis. Presse Med, 
2015. 44(4 Pt 2): p. e103-12.
5.
Vaknin-Dembinsky, A. and H.L. Weiner, Relationship of immunologic 
abnormalities and disease stage in multiple sclerosis: implications for therapy. J 
Neurol Sci, 2007. 259(1-2): p. 90-4.
6.
Hauser, S.L., et al., Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple 
Sclerosis. N Engl J Med, 2017. 376(3): p. 221-234.
7.
Fredrikson, S., Studies on activation variables in multiple sclerosis. Acta Neurol 
Scand Suppl, 1988. 115: p. 1-103.


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APPENDIX 10
Ocrelizumab Shorter Infusion Substudy Protocol
TITLE:
A SUBSTUDY TO EVALUATE THE SAFETY OF A 
SHORTER INFUSION OF OCRELIZUMAB IN PATIENTS 
WITH EARLY STAGE RELAPSING REMITTING 
MULTIPLE SCLEROSIS 
ASSOCIATED WITH MA30143 CORE STUDY
PROTOCOL NUMBER:
MA30143 shorter infusion substudy
VERSION NUMBER:
4.0
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab, RO4964913
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below


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OCRELIZUMAB SHORTER INFUSION SUBSTUDY PROTOCOL ACCEPTANCE 
FORM
TITLE:
A SUBSTUDY TO EVALUATE THE SAFETY OF A 
SHORTER INFUSION OF OCRELIZUMAB IN PATIENTS 
WITH EARLY STAGE RELAPSING REMITTING 
MULTIPLE SCLEROSIS 
ASSOCIATED WITH MA30143 CORE STUDY
PROTOCOL NUMBER:
MA30143 shorter infusion substudy
VERSION NUMBER:
4.0
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab, RO4964913
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current substudy protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Co-Investigator’s Name (print)
Co-Investigator’s Signature
Date
Please retain the signed original of this form for your study files. Please return a copy as instructed 
by your study monitor.




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Substudy Design
This is a prospective, multicenter, randomized, double-blind, controlled, parallel arm substudy 
evaluating the safety of a shorter duration infusion of ocrelizumab in a subgroup of patients with 
early stage RMS enrolled in the main MA30143 study. We expect approximately 700 patients to 
be enrolled in this substudy: expected approximately 150 patients currently participating in the 
main study, and approximately 550 newly enrolled patients, who will receive the randomized 
infusion at the second dose. Based on the current recruitment status of the main study, all 
patients are expected to have received Dose 2, hence new patients are needed to be recruited in 
order to assess the IRR rate of the shorter infusion at Dose 2. The primary endpoint is the 
proportion of patients with IRR related to the first infusion after randomization into the substudy.
Ocrelizumab dose and schedule remains unchanged in this substudy.
After providing written informed consent, patients will enter a screening period (up to 4-weeks) to 
be evaluated for eligibility. The patients currently enrolled in the main study can participate in the 
substudy if they are eligible and provide the written informed consent. 
For the additional patients, the first dose of ocrelizumab will be administered as an initial dose of 
two 300-mg infusions (600 mg total) in 250 mL 0.9% sodium chloride each separated by 14 days 
(i.e., Days 1 and 15) as per the main study protocol. At week 24 visit, patients eligible to take part 
in this substudy will be randomized into the following 2 groups in a 1:1 ratio stratified by region 
(United States [US], Canada, Australia versus Rest of the World [ROW]).

One Group: patients will receive 600 mg ocrelizumab in 500 mL 0.9% sodium chloride 
infused over approximately 3.5 hours every 24 weeks for the remainder of the study 
duration (as in the main MA30143 study)

Other Group: patients will receive a shorter duration infusion of 600 mg ocrelizumab in 
500 mL 0.9% sodium chloride infused over 2.0 hours followed by 100 mL 0.9% sodium 
chloride given as a slow infusion over the remaining 1.5 hours, in order to mimic the 
standard-length infusion (3.5 hour) every 24 weeks for the remainder of the study 
duration. 
Patients already enrolled in the main study will be randomized into the above 2 groups at the next 
main study visit. The randomization will be stratified by dose at which the patient is randomized 
and region. 
An interim analysis (IA) will be performed when approximately 400 patients will be randomized and 
dosed.
In this substudy the actual infusion rate for each group is blinded. An independent Data 
Monitoring Committee (iDMC) will examine unblinded safety data at regular intervals until the 
primary analysis is performed, as described in the iDMC charter.
The interim analysis became the primary analysis based on the recommendations of the Sponsor 
internal data review board (DRB), and these data have been submitted to the Health Authorities. 
As per the iDMC charter, the iDMC is no longer operating; the last independent data review 
meeting was held on 6th November 2019 and the close-out meeting was held on 22nd January 
2020. 
In accordance with the statistical analysis plan (SAP), the Roche internal study management 
team was unblinded to patients included in the primary analysis but remained blinded to patients 
not included in the primary analysis until all patients have reached their primary endpoint (IRRs at 
the first randomized dose) and data have been cleaned (on 14 February 2020). After the 
unblinding of this substudy, patients will continue under the main study protocol.


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Number of Patients
Approximately 700 patients are expected to participate in this substudy overall:
-
approximately 550 additional patients will be recruited in the main MA30143 study
-
approximately 150 patients are expected to be represented by patients currently 
participating in the main study who consent to be included in this sub-study. 
Target Population
Patients with early stage RRMS who fulfil eligibility criteria for the main study (MA30143) and the 
eligibility criteria outlined below can be enrolled into the substudy. 
Inclusion Criteria
Patients must meet the following criteria to be eligible for substudy entry: 

Enrolled in the Phase IIIb study MA30143 (main study)

Signed Informed Consent Form for this substudy

Ability to comply with the substudy protocol, in the investigator’s judgment.
Exclusion Criteria

Any previous serious IRR experienced with ocrelizumab treatment.
End of Substudy
The protocol amendment (version 8.0) marks the completion of the shorter infusion substudy and 
patients will continue under the main study protocol.
Length of Substudy
The total length of the substudy will be dependent on the time of approval of the substudy in each
country/site. 
Investigational Medicinal Products
Test Product (Investigational Drug)
For the additional patients, the first dose of ocrelizumab will be administered as two 300-mg IV 
infusions (600 mg total) in 250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 
and 15). At week 24 visit, patients will be randomized into 2 groups (patients already enrolled in 
the main study will be randomized into these 2 groups at the next main study visit), One Group 
will receive 600 mg ocrelizumab in 500 mL 0.9% sodium chloride infused over approximately 3.5 
hours every 24 weeks for the remainder of the study duration and the other Group will receive 
600 mg ocrelizumab in 500 mL 0.9% sodium chloride infused over 2.0 hours followed by 100 mL 
0.9% sodium chloride given as a slow infusion over the remaining 1.5 hours, in order to mimic the 
standard-length infusion (3.5 hour) every 24 weeks for the remainder of the study duration.
UNon-Investigational Medicinal Products
Pre-medicate with 100 mg of methylprednisolone (or an equivalent), administered by slow IV 
infusion, to be completed approximately 30 minutes prior to each ocrelizumab infusion and an 
antihistaminic drug (e.g., diphenhydramine) approximately 60 minutes before each infusion of 
ocrelizumab to reduce the frequency and severity of IRRs.  The addition of an antipyretic (e.g., 
acetaminophen/ paracetamol) may also be considered.
Statistical Methods
Primary Analysis
The primary analysis will be based on the intent-to-treat (ITT) population. The proportion of 
patients with IRRs in the two randomized groups will be presented together with 95% confidence 


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interval (CI). Supportive analyses based on per-protocol (PP) and safety population will be 
performed. The difference between the proportions in two arms will be presented with its 95% 
CI. A stratified analysis will also be performed, and the details will be specified in the SAP.
Determination of Sample Size
Regarding currently enrolled patients, we assume that approximately 40 and 110 will receive the 
randomized treatment at Dose 3 or at Dose 4 or at subsequent dose, respectively. In addition, 
since no currently enrolled patients will receive shorter infusion at Dose 2, we plan to include 
approximately 550 new patients, of which approximately 500 are expected to receive the 
randomized treatment at Dose 2 and be evaluable for the primary analysis. In total, approximately 
650 patients are expected to be randomized into two groups and be evaluable for the primary 
analysis.
The different IRR rates at Dose 2, 3 or 4 or at subsequent dose are considered in the calculation 
of the pooled IRR rate. In the Opera studies (WA21092 and WA21093), 13.7%, 9.6% and 7.8% of 
patients had at least one IRR at Dose 2, 3 and 4, respectively, which leads to an expected pooled 
IRR rate of approximately 12.4% excluding Dose 1 for this study. Therefore, we assume an 
observed IRR rate in the conventional infusion group of 12.4% excluding Dose 1. 
Based on the assumption that the IRR rate in control group is 12.4%, a sample size of 650
patients will provide sufficient precision around the IRR rates for this substudy.


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ULIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
CI
Confidence interval
CTCAE
Common Terminology Criteria for Adverse Events
eCRF
Electronic case report form
DRB
Data Review Board
IA
Interim Analysis
iDCC
Independent Data Coordinating Center
iDMC
Independent Data Monitoring Committee
IMP
Investigational medicinal product
IRR
Infusion-related reaction
ITT
Intent-to-treat
IxRS
Interactive voice/Web response system
MS 
Multiple sclerosis
PP
Per protocol
RMS
Relapsing multiple sclerosis
ROW
Rest of the world
RRMS
Relapsing remitting multiple sclerosis
SAP
Statistical analysis plan
SD
Standard deviation
US
United States


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1. BACKGROUND
1.1 RATIONALE FOR THE SUBSTUDY
Ocrelizumab is administered by intravenous infusion as a 600 mg dose every 6 months. 
The first ocrelizumab dose of 600 mg is always administered as a divided dose (2 x 300 
mg infusions administered 14 days apart) to help reduce the incidence of infusion-
related reactions (IRRs) which is highest upon the first infusion of ocrelizumab. The 
incidence and severity of IRRs is also higher upon the first infusion of all other B-cell 
depleting agents. The subsequent doses of ocrelizumab are administered as a single
600 mg infusion, with a minimum interval of 5 months to be maintained between each 
dose of ocrelizumab. 
IRRs are among the most frequent adverse events associated with ocrelizumab 
treatment. During the Phase III relapsing multiple sclerosis (RMS) controlled treatment 
period, the incidence of IRRs in patients receiving ocrelizumab was highest during the 
first infusion (Dose 1, Infusion 1; 27.5% of RMS OPERA I and II [WA21092 and 
WA21093] patients pooled), and with subsequent dosing IRRs occurred with decreasing 
incidence. After the first dose, the incidence (RMS OPERA I and II pooled: 4.7% to 
13.7% of patients), severity (Grade 1 or 2; RMS OPERA I and II pooled: 92.6% of 
patients) and symptoms (in >= 10% of RMS patients with IRRs: pruritus, rash, throat 
irritation and flushing) of IRRs were similar in both studies.
A preliminary analysis was performed on an ad-hoc data cut (06-April-2018) in the main 
study (ENSEMBLE) including 675 patients who had received the first infusion of dose 1 
and 172 who had received dose 2 at week 24. The proportions of patients with IRRs 
were 28.7% and 12.2% at dose 1 and dose 2, respectively, which were similar to the 
rates of 27.5% and 13.5% observed in OPERA I and II pooled.
To reduce the frequency and severity of IRR, patients are pre-medicated with 100 mg IV 
methylprednisolone (or an equivalent) approximately 30 minutes prior to each 
ocrelizumab infusion, and with an antihistamine (e.g. diphenhydramine) approximately 
60 minutes before each infusion. In RMS patients, during the Phase III controlled 
treatment period, IRRs were also well managed by slowing or interrupting infusions. In 
78% of the IRR events, symptomatic therapy for the management of IRR symptoms was 
needed in addition to the slowing down or interruption of the infusion to manage the 
IRRs. For 22% of the IRR events, no additional intervention was necessary and infusion 
adjustments were the only intervention which led to a resolution of the IRR. Therefore, 
IRRs were not considered as a treatment limiting factor. 
The aim of this substudy investigation is to determine differences in IRR rate with 
acceleration of the ocrelizumab infusion. Infusions with a faster infusion rate can 
increase the rate of IRRs, and therefore the safety of a faster infusion with ocrelizumab 
will be assessed in this study. Results of a previous study of rituximab in patients with 
rheumatoid arthritis (RATE-RA study) showed that there was no increase in the rate or 


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severity of IRRs with a shorter (over 2.0 hours) infusion of rituximab as compared to the 
conventional (over 4.25 hours) infusion (Pritchard et al. 2014), based on historical 
control numbers. 
Currently, single infusions of 600 mg ocrelizumab are initiated at a rate of 40 mL/hour. In 
the absence of IRRs, the rate is increased in 40 mL/hour increments every 30 minutes to 
a maximum of 200 mL/hour with a total estimated infusion time of approximately 3.5 
hours. With this conventional infusion, the total observation time for the patient, including 
the administration of premedication is at least 5.5 hours (this can be prolonged in case 
infusion is slowed down): 0.5 - 1 hour for premedication and set-up of the infusion; 3.5-
hour infusion of ocrelizumab; 1-hour post infusion observation. 
A shorter 2-hour infusion would allow for an overall reduction of the ocrelizumab 
administration to about 3.5 to 4 hours in total (including premedication – 0.5 to 1 hour, 
drug infusion – 2 hours and observation time – 1 hour) [Please refer to Table 1 for a 
comparison of the infusion rate and time for the conventional and shorter infusion of 
ocrelizumab]. The proposed shortening of the infusion time, if assessed in this substudy 
to be as safe as the conventional infusion, would significantly reduce both the patient 
burden (i.e. less time taken for treatment administration and faster return to daily 
activities) and the burden of patient management for the nursing staff (e.g. such as to 
allow centers the possibility of offering morning/afternoon appointments or the 
scheduling of two patients in a day rather than one). 
Table 1 Comparison of the infusion rate and time for conventional and 
shorter infusion of 600 mg of ocrelizumab 
Infusion type
Infusion rate 
mL/hr
Time required for infusion
Time for 
premedication 
and set-up
Infusion 
time
Time for 
post-
infusion 
observation
Total time
Conventional 
infusion
Group 
Initiated at 
40mL/hour 
and 
increased to 
maximum of 
200mL/hour
0.5 to 1 hour
3.5 hours
1 hour
5.5 hours
Shorter 
infusion
Group 
Initiated at 
100mL/hour 
and 
increased to 
maximum of 
300mL/hour
0.5 to 1 hour
2.0 hours 
1 hour
4 hours
Of note: The exact ocrelizumab administration rate for each group is blinded in this study. 
Please refer to Table 3 for further details on the shorter infusion rates of ocrelizumab




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patients with early stage RRMS enrolled in the main MA30143 study. Ocrelizumab dose 
and schedule remains unchanged in this substudy.
Approximately 150 patients currently participating in the main study are expected to be 
enrolled and approximately 550 additional patients will be enrolled in the main study 
specifically for the purpose of this substudy. Based on the current recruitment status of 
the main study, all patients are expected to have received Dose 2, hence new patients 
are needed to be recruited in order to assess the IRR rate of the shorter infusion at Dose 
2. 
After providing written informed consent, patients will enter a screening period (up to 4-
weeks) to be evaluated for eligibility. The patients currently enrolled in the main study 
can participate in the substudy if they are eligible and provide the written informed 
consent. 
For the additional patients, the first dose of ocrelizumab will be administered as an initial 
dose of two 300-mg infusions (600 mg total) in 250 mL 0.9% sodium chloride each 
separated by 14 days (i.e., Days 1 and 15) in all the patients as per the main study 
protocol. At week 24, patients eligible to take part in this substudy will be randomized 
into the following 2 groups: 

One Group: patients will receive 600 mg ocrelizumab in 500 mL 0.9% sodium 
chloride infused over approximately 3.5 hours every 24 weeks for the remainder 
of the study duration (as in the main MA30143 study)

Other Group: patients will receive a shorter infusion of 600 mg ocrelizumab in 
500 mL 0.9% sodium chloride infused over 2.0 hours, followed by 100 mL 0.9% 
sodium chloride given as a slow infusion over the remaining 1.5 hours, in order to 
mimic the standard-length infusion (3.5 hour), every 24 weeks for the remainder 
of the study duration. 
Patients already enrolled in the main study will be randomized into the above 2 groups at 
the next main study visit. 
Randomization into the two treatment groups will be in a 1:1 ratio. For the additional 
patients, randomization will be stratified by region (United States [US], Canada, Australia 
versus Rest of the World [ROW]). For patients, already enrolled in the main study, 
randomization will be stratified by dose at which the patient is randomized and region.
The actual infusion rate for each group is blinded – for details on blinding, please refer to 
Section 4.2 of this substudy protocol.
Patients will be assessed for safety every 24 weeks as described in the Schedule of 
Assessments presented in Appendix 1 of the main study protocol.


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Please see the main protocol Section 3.1.3 for the criteria for re-treatment with 
ocrelizumab.
Please see the main protocol Section 3.1.4 for the details on the follow-up period.
An interim analysis (IA) will be performed when approximately 400 patients will be 
randomized and dosed (see Section 6.6 of this substudy protocol). An independent Data 
Monitoring Committee (iDMC) will examine unblinded safety data at regular intervals 
until the primary analysis is performed, as described in the iDMC charter.
The interim analysis became the primary analysis based on the recommendations of the 
Sponsor internal Data Review Board (DRB), and these data have been submitted to the 
Health Authorities. As per the iDMC charter, the iDMC is no longer operating; the last 
independent data review meeting was held on 6th November 2019 and the close-out 
meeting was held on 22nd January 2020. In accordance with the statistical analysis plan 
(SAP), the Roche internal study management team was unblinded to patients included in 
the primary analysis but remained blinded to patients not included in the primary 
analysis until all patients have reached their primary endpoint (IRRs at the first 
randomized dose) and data have been cleaned (on 14 February 2020). After the 
unblinding of this substudy, patients will continue under the main study protocol.
3.1.1 Overview of study design
Figure 1 presents an overview of the substudy procedures. 


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Figure 1
Overview of Substudy design
IRR = Infusion-related reaction
3.1.2 Planned Total Sample Size 
Approximately 700 patients are expected to participate in this substudy overall. 
- approximately 550 additional patients will be recruited into the main MA30143 
study
- approximately 150 patients are expected to be represented by patients currently 
participating in the main study who consent to be included in this substudy. 
See Section 6.1 for further details.
3.2 END AND LENGTH OF SUBSTUDY
The protocol amendment (version 8.0) marks the completion of the shorter infusion 
substudy and patients will continue under the main study protocol.
The total length of the substudy will be dependent on the time of approval of the substudy 
in each country/site.


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3.3 RATIONALE FOR THE SUBSTUDY DESIGN
Please see Section 1.1 (rationale of the substudy) 
3.3.1 Rationale for ocrelizumab dose and schedule
Ocrelizumab dose and schedule remains unchanged in this substudy; please see 
Section 3.3.1 of the main study protocol for the rationale for ocrelizumab dose and 
schedule. The rationale for accelerating the infusion rate in this substudy is discussed in 
Section 1.1.
4. MATERIALS AND METHODS 
4.1 PATIENTS
Patients with early stage RRMS who fulfil eligibility criteria for the Phase IIIb study 
(MA30143) and the eligibility criteria outlined in the following inclusion and exclusion 
sections of this substudy can be enrolled into the substudy. 
4.1.1 Inclusion Criteria
Patients must meet the following criteria to be eligible for substudy entry: 

Enrolled in the Phase IIIb study MA30143 (main study)

Signed Informed Consent Form for this substudy

Ability to comply with the substudy protocol, in the investigator’s judgment.
4.1.2 Exclusion Criteria

Any previous serious IRRs experienced with ocrelizumab treatment 
4.2 METHODS OF TREATMENT ASSIGNMENT AND BLINDING
Patients will be randomized in 2 groups in a 1:1 ratio. For the additional patients, 
randomization will be stratified by region (US, Canada, Australia versus ROW). For 
patients, already enrolled in the main study, randomization will be stratified by dose at 
which the patient is randomized and region. An interactive voice/web response system 
(IxRS) provider will conduct randomization and hold the treatment assignment code. 
Blinding of the infusion rates and actual duration of the infusion will be achieved by the 
following measures:


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
The substudy group assignment (randomization) codes will only be visible to the 
pharmacy personnel preparing the drug infusions and to the unblinded personnel 
operating the infusion pump (called infusion nurse thereafter).

Infusions will be pre-loaded and placed into standardized infusion cover bags 
and placed on an infusion rack, and the actual infusion administration pump will 
be covered and operated by the unblinded infusion nurse. 

The actual infusion rates and associated activities related to infusion 
administration will be blinded to the site study team (including the study 
coordinator and the treating investigator), patient and the Sponsor. 

The standard-length infusion will be administered as described above and in the 
main study protocol. The shorter infusion will be administered within 2 hours (520 
mL infusion volume at the rates as presented in Table 3), followed immediately 
by administration of a separate 100mL normal saline (0.9 % NaCl) bag without 
any additional component over the remaining 1.5h with an approximate infusion 
rate of 60mL/hr. For patients randomized to the standard-length infusion, the 
infusion nurse will mimic a switch infusion at approximately 2 hours (timing to be 
adapted depending on the infusion rate adaptation during the first 2 hours). The 
infusion nurse will check and adjust the infusion rates periodically as needed 
both for maintaining the correct rates of the infusion and for maintaining of 
blinding/masking of the two infusion groups (See Figure 2a and b). Adjustments 
needed for managing IRRs are allowed at any time and should follow the 
guidance from the main study protocol. Please refer to Section 4.3.2 Dosage, 
Administration and Compliance for further details on the infusion preparation and 
administration 

The infusion nurse (unblinded) or the clinical nurse (blinded) will collect patient’s 
vital signs at the time of premedication onwards (see Section 4.5.4 of the main 
study protocol). Vital signs will be reported in the electronic case report form 
(eCRF). Blinded treating investigator will evaluate and confirm all IRRs occurring 
during or within 24 h post-infusion. 

The unblinded information related to the infusion will be entered into the IxRS by 
the unblinded site staff member. The unblinded site staff members have to keep 
any data related to the infusion (group allocation, infusion duration and content, 
etc.) confidential:
- they must not further communicate these data, neither verbally nor in writing–
they will maintain the corresponding files in a locked, access restricted location 

Additional operational measures will be undertaken at local level to ensure the 
appropriate level of blinding of the personnel involved and the data collected. 

IxRS Service Provider and iDMC members will have access to treatment 
assignment in order to fulfil their roles during the clinical trial.


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Figure 2a Blinding Procedure
Figure 2b Blinding Procedure
AH = antihistamine; H = hour; IVMP = intravenous methylprednisolone; OCR = ocrelizumab; PK = 
pharmacokinetic
If unblinding is necessary for a medical emergency (e.g., in the case of a serious
adverse event for which patient management might be affected by knowledge of
treatment assignment), the investigator will be able to break the code by contacting the 
IxRS. The investigator is not required to contact the Medical Monitor prior to breaking the 
code; however, the code should not be broken except in emergency situations.


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If the investigator wishes to know the patient assignment group in the study for any 
reason other than a medical emergency, he or she should contact the Medical Monitor 
directly prior to unblinding. The investigator should document and provide a justification 
for any non-emergency unblinding. The investigator will be able to break the code by 
contacting the IxRS.
4.3 STUDY TREATMENT
The investigational medicinal product (IMP) for this study is ocrelizumab.
4.3.1 Formulation, Packaging, Storage and Handling
Please see Section 4.3.1.1 of the main study protocol
4.3.2 Dosage, Administration and Compliance
For the additional patients, the first dose of ocrelizumab will be administered as an initial 
dose of two 300-mg infusions (600 mg total) in 250 mL 0.9% sodium chloride each 
separated by 14 days (i.e., Days 1 and 15). From Week 24 visit, patients randomized to 
the conventional infusion will receive 600 mg ocrelizumab in 500 mL 0.9% sodium 
chloride infused over approximately 3.5 hours every 24 weeks for the remainder of the 
study duration and those randomized to the shorter infusion will receive 600 mg 
ocrelizumab in 500 mL 0.9% sodium chloride infused over 2.0 hours, followed by an 
infusion with 100 mL normal saline given as a slow infusion (proposed infusion rate of 60 
mL/hr) over the remaining 1.5 hours, in order to mimic the standard-length infusion (3.5 
hour), given every 24 weeks for the remainder of the study duration. (See also Table 3 
for the actual infusion rates to be applied in shorter infusion group)
Table 3
Ocrelizumab infusion rates for Conventional and Shorter 
Infusion in absence of IRRs (administered in a blinded fashion)
Time in mins
Shorter infusion*
Conventional infusion
Infusion 
rate (mL/hr)
Max dose 
per 
interval 
(mg)
Cumulative 
dose
(mg)
Infusion 
rate 
(mL/hr)
Max dose 
per 
interval 
(mg)
Cumulative 
dose
(mg)
0-15
100
30
30
40
23.18
23.18
16-30
200
60
90
31-60
250
150
240
85
49.27
72.45
61-90
300
180
420
130
75.36
147.81
91-120
300
180
600
169
98.05
245.86
121 – 215*
200
354.14
600
* After the end of administration of the ocrelizumab infusion bag (520 mL over 2 hours using 
above rates), there is a change of bags to the 100 mL normal saline one and the continuation of 
the infusion of 100 mL normal saline at rate 60 mL/hour, for approx.1.5 hours.


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For further instructions on shorter infusion as well as for the conventional infusion, 
please refer to the “Drug Preparation and Blinding Guidelines”. 
It is anticipated that the patient will need to stay at the hospital or clinic for a full day for 
the infusion visits. Ocrelizumab infusions should be initiated and supervised by an 
experienced professional with access to appropriate medical support to manage severe 
reactions such as serious IRRs. Each ocrelizumab infusion should be given as a slow IV 
infusion over approximately 150 minutes (2.5 hours) for the 300 mg dose, approximately 
215 minutes (approximately 3.5 hours) for the 600 mg dose for patients randomized to 
the conventional infusion and approximately 120 minutes (2.0 hours) for the 600 mg 
dose for patients randomized to the shorter infusion. The exact ocrelizumab 
administration rate for each group is blinded in this study. 
To reduce potential IRRs, all patients will receive prophylactic treatment with 100 mg of 
methylprednisolone, or equivalent, administered by slow IV infusion, to be completed 
approximately 30 minutes before the start of each ocrelizumab infusion and an 
antihistaminic drug (e.g., diphenhydramine) approximately 60 minutes before each 
infusion of ocrelizumab. Additional premedication is recommended (see Section 4.3.3 of 
the main study protocol). 
4.3.3 Prophylactic Treatment
See Section 4.3.3 of the main protocol for details.
4.3.4 Investigational Medicinal Product Accountability
See Section 4.3.4 of the main protocol for details.
4.3.5 Continued Access to Ocrelizumab
See Section 4.3.5 of the main study protocol for the details.
4.4 CONCOMITANT THERAPY
See Section 4.4 of the main protocol for details.
4.5 STUDY ASSESSMENTS
See Section 4.5 of the main study protocol for details of the substudy assessments.


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4.5.1 Pharmacokinetic (PK) Sample collection:
Three (3) serum samples will be collected on the first randomized visit. 
•
First sample will be collected 5-30 minutes prior to the methylprednisolone
infusion.
•
Second sample will be collected 30 minutes (±10 minutes) after the switch 
(shorter infusion) or the mimic switch (conventional infusion). To help keep the 
blind, please collect this sample variably within ±10 minutes of the saline/mimic 
switch.
•
Third sample will be collected 30 minutes (±10 minutes) after completion of the 
infusion (at the end of ocrelizumab infusion for the conventional infusion or saline 
infusion for the shorter infusion).
If a PK sample is missed on the first randomized visit, the 3 PK samples should be 
collected at the next blinded visit. 
4.5.2 Infusion Follow-up Telephone contact:
The period of evaluation of the IRRs will be 24 hours after the end of each blinded 
infusion. A structured telephone interview should be conducted by site personnel on the 
following working day after the end of each blinded infusion, starting at week 24 to 
identify and collect information on any possible IRRs or any other changes in the 
patient’s health status, which may have occurred after the discharge.
4.6 TREATMENT, PATIENT, SUBSTUDY AND SITE DISCONTINUATION
4.6.1 Substudy Treatment discontinuation
Reasons for substudy treatment discontinuation are listed in Section 4.7.1 of the main 
study protocol.
4.6.2 Patient discontinuation from Substudy
Patients have the right to voluntarily withdraw from the substudy at any time for any 
reason. Patient’s withdrawal from the substudy after randomization into Group one or 
Group two does not constitute a withdrawal from the main trial. No replacement is 
planned for patients who withdraw.
4.6.3 Substudy Discontinuation
The Sponsor has the right to terminate this substudy at any time. The Sponsor will notify 
the investigator if the Sponsor decides to discontinue the substudy.


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The Sponsor also has the right to terminate the main study at any time. Reasons for 
termination are listed in Section 4.7.3 of the main study protocol. The Sponsor will notify 
the investigators if the Sponsor decides to discontinue the main study. Consequently, 
the substudy could be stopped as well.
4.6.4 Site Discontinuation
The Sponsor has the right to close a site at any time. Reasons for termination are listed 
in Section 4.7.4 of the main study protocol. 
5. ASSESSMENT OF SAFETY 
5.1 SAFETY ASSESSMENT
Adverse events related to the substudy will be collected throughout the substudy, 
according to the procedures outlined in the main study protocol.
5.2 SAFETY INSTRUCTIONS AND GUIDANCE
Safety measures are detailed in the main study protocol.
5.3 REPORTING OF ADVERSE EVENTS
Refer Section 5.4.2 of the main study protocol.
5.4 REPORTING OF SERIOUS ADVERSE EVENTS
Refer Section 5.4.2 of the main study protocol.
5.5 EMERGENCY MEDICAL CONTACTS
As mentioned in the main study protocol, to ensure the safety of study patients an 
Emergency Medical Call Centre Help Desk will access the Roche Medical Emergency 
List, escalate emergency medical calls, provide medical translation service (if 
necessary), connect the investigator with a Roche Medical Responsible (listed on the 
Roche Medical Emergency List), and track all calls. The Emergency Medical Call Centre 
Help Desk will be available 24 hours a day, 7 days a week. Toll-free numbers for the 
Help Desk, as well as Medical Monitor and Medical Responsible contact information, will 
be distributed to all investigators.
5.6 EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, 
INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEE
Please refer to Section 5.7 of the main study protocol.


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An iDMC will regularly review unblinded IRR data during the study as described in the 
iDMC charter. iDMC recommendations leading to change of study conduct will be 
communicated to the health authorities.
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary analyses will be performed using the intent-to-treat (ITT) population. The 
per-protocol (PP) population and safety population will be used for supportive analyses. 
The analyses will be performed when all patients have completed the 24-hour 
observation period after the first randomized infusion. All the analysis will be performed 
for descriptive purposes and no formal hypothesis testing will be performed.
Detailed specifications will be included in the SAP.
ITT Population
All randomized patients will be included in the ITT population. Patients will be analyzed 
according to their randomized treatment.
PP Population
The PP population will include all ITT patients without protocol deviations deemed to 
affect the assessment of the primary endpoint. The list of criteria leading to exclusion 
from the PP population will be finalized prior to database closure and documented in the 
SAP. Patients who receive the opposite infusion type from the randomized one will be 
excluded from the per protocol population.
Safety Population
The safety population will include all randomized patients who received any dose or part 
of a dose of ocrelizumab. Randomized patients who receive the opposite infusion type 
from the randomized one will be summarized in the group according to the treatment 
actually received.
6.1 DETERMINATION OF SAMPLE SIZE
Regarding currently enrolled patients, we assume that approximately 40 and 110 will 
receive the randomized treatment at Dose 3 or at Dose 4 or at subsequent dose, 
respectively. In addition, since no currently enrolled patients will receive shorter infusion 
at Dose 2, we plan to include approximately 550 new patients, of which approximately 
500 are expected to receive the randomized treatment at Dose 2 and be evaluable for 
the primary analysis. In total, approximately 650 patients are expected to be randomized 
into two groups and be evaluable for the primary analysis.
The different IRR rates at Dose 2, 3 or 4 or at subsequent dose are considered in the 
calculation of the pooled IRR rate. In the Opera studies (WA21092 and WA21093), 


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13.7%, 9.6% and 7.8% of patients had at least one IRR at Dose 2, 3 and 4, respectively, 
which leads to an expected pooled IRR rate of approximately 12.4% excluding Dose 1 
for this study. Therefore, we assume an observed IRR rate in the conventional infusion 
group of 12.4% excluding Dose 1. The 95% confidence intervals (CIs) of the IRR rate 
difference between shorter and conventional infusion groups as a function of the 
observed IRR rate in the shorter infusion group are listed in Table 4. The CIs were 
calculated based on the assumption of Binomial distributed IRR rates, which provide 
sufficient precision around the IRR rates for this substudy.
Table 495% confidence interval of IRR rate difference under different 
scenarios.
IRR rate in 
conventional 
infusion (%)
IRR rate in 
shorter 
infusion (%)
Difference 
in IRR 
rate (%)
95% CI
12.4
12.4
0 (-5.1, 5.1)
12.4
13.4
1 (-4.2, 6.2)
12.4
14.4
2 (-3.2, 7.2)
12.4
15.4
3 (-2.3, 8.3)
12.4
16.4
4 (-1.4, 9.4)
12.4
17.4
5 (-0.5, 10.5)
12.4
18.4
6 (0.5, 11.5)
IRR = Infusion-related reaction; CI = Confidence interval
6.2 SUMMARIES OF CONDUCT OF STUDY
Enrolment, screening failures, ocrelizumab administration, and discontinuations from the 
study will be summarized using descriptive statistics (frequency tables for categorical 
endpoints and mean, median, range, standard, deviation [SD] and 25th-75th quartiles for 
the continuous endpoints) according to randomized treatment group. Patient disposition 
and the incidence of treatment discontinuation for different reasons will be tabulated. 
Major protocol violations, including violations of inclusion/exclusion criteria, will also be 
summarized.
6.3 SUMMARY OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Patients’ demographics (age, gender, and self-reported race), medical history and 
neurological examination will be summarized by randomized treatment group. The 
following will also be summarized: multiple sclerosis (MS) disease history (duration since 
first MS symptoms, duration of MS since diagnosis, relapses in the past year), and other 
important variables. 


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200/Protocol MA30143, Version 10.0
6.4 EFFECTIVENESS ANALYSES
No effectiveness analysis is currently planned for this study. 
6.5 SAFETY ANALYSES
The primary endpoint is the proportion of patients with IRRs occurring during or within 24 
hours following the first infusion after randomization to the shorter infusion substudy.
The primary analysis will be based on the ITT population. The proportions of patients 
with IRRs in the two randomized groups will be presented together with 95% confidence 
interval. Supportive analyses based on the PP and the safety population will be 
performed. The difference between the proportions in two arms will be presented with its 
95% CI. A stratified analysis will also be performed, and the details will be specified in 
the SAP.
The following IRR-related variables will be summarized:

Proportion of patients with IRR overall and by dose at randomization

Severity of IRRs

Proportion of patients with serious IRRs

Symptoms of IRRs

IRRs leading to treatment discontinuation

Subgroup analyses according to IRR history (for example, patients with/without 
IRR at any previous dose)
An external iDMC will periodically review safety data up to the primary analysis. 
Analyses required for the iDMC data review will be performed as described in the iDMC 
Charter and IDMC data handling plan.
6.6 INTERIM ANALYSIS
An IA for the primary endpoint will be conducted after approximately 400 patients have 
been randomized and dosed. The data for the IA will be cleaned and signed off by the 
Principal Investigator or delegate. An iDCC will be responsible for conducting the IA, and 
study interim results will only be reviewed by the iDMC and a Sponsor internal DRB. 
Details for the conduct of the IA will be pre-specified in the Sponsor internal DRB 
charter. In addition, regular safety analyses will be performed by the iDCC and reviewed 
by the iDMC according to the iDMC charter. 
The interim analysis became the primary analysis based on the recommendations of the 
Sponsor internal DRB and these data have been submitted to the Health Authorities. As 
per the iDMC charter, the iDMC is no longer operating; the last independent data review 
meeting was held on 6th November 2019 and the close-out meeting was held on 22nd


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201/Protocol MA30143, Version 10.0
January 2020. In accordance with the SAP, the Roche internal study management team 
was unblinded to patients included in the primary analysis but remained blinded to 
patients not included in the primary analysis until all patients have reached their primary 
endpoint (IRRs at the first randomized dose) and data have been cleaned (on 14 
February 2020). After the unblinding of this substudy, patients will continue under the 
main study protocol.
7. DATA COLLECTION AND MANAGEMENT 
See Section 7 of the main study protocol for details on data collection and management. 
8. ETHICAL CONSIDERATIONS
See Section 8 of the main study protocol for details on ethical considerations
9. STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
See Section 9 of the main study protocol for details on study documentation, monitoring, 
and administration. 
An unblinded CRA will be responsible to monitor the “unblinded” data at the site, thus 
would identify and react to any errors. An unblinded centralized monitor will be 
responsible to remotely monitor the "unblinded" data at the study level in order to ensure 
the overall data consistency and quality.
9.1 INDEPENDENT DATA MONITORING 
An iDMC will be employed to monitor and evaluate patient safety until the primary 
analysis is performed. Monitoring details will be described in the iDMC Charter. 
10.REFERENCES
Pritchard CH, Greenwald MW, Kremer JM, et al. Safety of infusing rituximab at a more 
rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study. 
BMC Musculoskeletal Disorders 2014;15:177-85.


Ocrelizumab—F. Hoffmann-La Roche Ltd
202/Protocol MA30143, Version 10.0
Appendix 1 to the Shorter Infusion Substudy: Schedule of Assessments
Only assessments specific to the substudy are listed below, please see Appendix 1 of the main study protocol for all other 
assessments.
Visit
Screening
Treatment Period a
Early study 
treatment 
discontinua
tion 
evaluation
Follow-Up
48 weeks 
after end of 
Treatment 
Period b
1
2 
(Baseline)
3
4
5
6
7
8
9
10
11
12
Week
–4 to –1 
weeks
1
2
(±2 
days)
8
(±3 
days)
24
(±14 
days)
48
(±14 
days)
72
(±14 
days)
96
(±14 
days)
120
(±14 
days)
144
(±14 
days)
168
(±14 
days)
192
(±14 
days)
Informed 
consentc
X
Randomization d
X
PK of 
ocrelizumab e
X
X*
X*
X*
X*
Vital signs f
X
X
X
X
X
X
X
X
X
X
Telephone 
contact 24 hours 
after each 
blinded infusion g
X
X
X
X
X
X
X
PK = Pharmacokinetic


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a
The study visits during the treatment period may be spread over more than one day to complete all the assessments before study drug administration.
b
The follow-up period will begin when the patient discontinues from the study for any reason.  Patients who discontinue treatment early should remain in follow-up for 
48 weeks following the last infusion of ocrelizumab. Please see Appendix 2 of the main study protocol for the details. Patients who complete the 192 weeks Treatment 
Period and decide not to continue in a separate long-term extension study, will be followed-up for at least 48 weeks after the end of the Treatment Period.
c
Written informed consent will be obtained from all patients during screening in order to be eligible for this substudy.
D d
At week 24 visit, all the additional patients will be randomized into 2 groups, one Group will receive 600 mg of ocrelizumab infused over 3.5 hours and the other Group 
will receive 600 mg ocrelizumab over 2.0 hours followed by 100 mL 0.9% sodium chloride given as a slow infusion over the remaining 1.5 hours, in order to mimic the 
standard-length infusion (3.5 hour) for the rest of the study duration. Patients already enrolled in the main study, will be randomized into 2 groups at the next main study visit.
ee
On infusion visits, three serum samples are collected, one 5-30 minutes prior to the methylprednisolone infusion, the second one 30 minutes (±10 minutes) after the 
switch (shorter infusion) or the mimic switch (conventional infusion), and the third sample 30 minutes (±10 minutes) after completion of the infusion (at the end of 
ocrelizumab infusion for the conventional infusion or saline infusion for the shorter infusion ). If a PK sample is missed on the first randomized visit, the 3 PK samples should 
be collected at the next blinded visit.
f
Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures.  Vital signs should be taken within 45 minutes prior to the premedication 
methylprednisolone (or an equivalent) infusion and administration of antihistaminics. In addition, vital signs should be obtained prior to the ocrelizumab/saline infusion, then 
every 15 minutes (± 5 minutes) for the first hour, followed by every 30 minutes (± 10 minutes) until 1 hour after the end of the infusion. Vital signs will be reported in the 
eCRF for all the blinded infusions from premedication till patient leaves the infusion site. 
eg
The period of evaluation of the IRRs will be 24 hours after the end of each blinded infusion. A structured telephone interview should be conducted by the site personnel 
on the following working day after the end of each blinded infusion, starting at week 24 to collect information on any possible IRRs or any other changes in the patient’s 
health status, which may have occurred after the discharge.
*
For patients who are already enrolled in the main study and only at the first infusion post randomization.

SAP_001.pdf: 
 
Official Title: 
A Substudy to Evaluate the Safety of a Shorter Infusion of 
Ocrelizumab in Patients With Early Stage Relapsing Remitting 
Multiple Sclerosis Associated With MA30143 Main Study 
NCT Number: NCT03085810 
Document Date: SAP Version 1: 17 September 2019 
 
 
 


Ocrelizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS
1
STATISTICAL ANALYSIS PLAN
TITLE:
A SUBSTUDY TO EVALUATE THE SAFETY OF 
A SHORTER INFUSION OF OCRELIZUMAB IN 
PATIENTS WITH EARLY STAGE RELAPSING 
REMITTING MULTIPLE SCLEROSIS
ASSOCIATED WITH MA30143 MAIN STUDY
PROTOCOL NUMBER:
MA30143 Shorter Infusion Substudy, ENSEMBLE 
PLUS
VERSION NUMBER:
1.0
EUDRACT NUMBER:
2016-002937-31
IND NUMBER:
100,593
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
 and 
DATE FINAL:
See electronic date stamp below
STATISTICAL ANALYSIS PLAN APPROVAL
 
Date and Time (UTC)        Reason for Signing                         Name
17-Sep-2019 06:13:41
17-Sep-2019 06:13:41
Company Signatory


Ocrelizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS
TABLE OF CONTENTS
1.
BACKGROUND.............................................................................................6
2.
STUDY DESIGN ...........................................................................................8
2.1
Protocol Synopsis ..................................................................11
2.2
Outcome Measures................................................................11
2.2.1
Primary Outcome Measure ....................................................11
2.2.2
Secondary Outcome Measures .............................................11
2.2.3
Exploratory Outcome Measures.............................................12
2.2.4
Pharmacokinetic Analysis:  Objectives and 
Outcome Measures................................................................12
2.2.5
Pharmacodynamic Outcome Measures.................................12
2.2.6
Safety Outcome Measures ....................................................12
2.3
Determination of Sample Size ...............................................12
2.4
Analysis Timing......................................................................13
3.
STUDY CONDUCT .....................................................................................14
3.1
Randomization and Blinding ..................................................14
3.2
Independent Review Facility ..................................................17
3.3
Data Monitoring......................................................................17
4.
STATISTICAL METHODS...........................................................................17
4.1
Analysis Populations..............................................................17
4.2
Analysis of Study Conduct.....................................................19
4.3
Analysis of Treatment Group Comparability ..........................20
4.3.1
Demography ..........................................................................21
4.3.2
MS Disease History at Randomization...................................21
4.3.3
Pre-Randomization IRRs and Serious IRRs ..........................21
4.3.4
Previous Diseases (Other Than MS) Prior to 
Randomization.......................................................................22
4.3.5
Current Diseases (Other Than MS) .......................................22
4.3.6
Previous Treatments (Other Than For MS) Prior 
to Randomization...................................................................23
4.3.7
Concomitant Treatments (Other Than For MS)......................23
4.4
Efficacy Analysis....................................................................23
4.5
Safety Analyses .....................................................................23
2


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Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS

4.5.1
Exposure to Study Medication ...............................................24
4.5.2
Adverse Events......................................................................25
4.5.2.1
Infusion-Related Reactions....................................................25
4.5.2.2
Overview of Adverse Events..................................................27
4.5.2.3
Common Adverse Events ......................................................28
4.5.2.4
Adverse Events by Intensity...................................................30
4.5.2.5
Deaths ...................................................................................30
4.5.2.6
Serious Adverse Events.........................................................30
4.5.2.7
Adverse Events Which Led to Early 
Discontinuation from Ocrelizumab Treatment........................30
4.5.2.8
Adverse Events Which Led to Modification or 
Interruption of Ocrelizumab Treatment ..................................30
4.5.2.9
Pregnancies...........................................................................30
4.5.3
Laboratory Data .....................................................................30
4.5.3.1
Hematology and Biochemistry ...............................................30
4.5.3.2
CD4, CD8 and CD19 .............................................................31
4.5.4
Vital Signs..............................................................................32
4.6
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................32
4.6.1
Pharmacokinetic Analyses.....................................................32
4.6.2
Pharmacodynamic Analyses..................................................32
4.7
Missing Data ..........................................................................32
4.8
Interim Analyses ....................................................................33
5.
REFERENCES............................................................................................33
LIST OF TABLES
Table 1
Dose and Randomized Dose in the ENSEMBLE PLUS 
Substudy .....................................................................................10
Table 2
95% CI of IRR Rate Difference Under Different Scenarios, 
Based on N=650 (Shown as Table 4 in Protocol Version 7.0) ....13
Table 3
95% CI of IRR Rate Difference Under Different Scenarios, 
Based on N=400 .........................................................................13


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Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS
LIST OF FIGURES
Figure 1 
Blinding Procedure......................................................................16
Figure 2
Figure Blinding Procedure...........................................................16
4


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Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS
5
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation 
Definition 
AE
Adverse Event
BMI
Body Mass Index
CCOD
Clinical Cutoff Date
CI 
Confidence Interval 
Cmax
Maximum concentration
CSR
Clinical Study Report
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
Electronic case report form 
DRB 
Data Review Board 
EC
Ethics Committee
HA
Health Authorities
IA 
Interim Analysis 
iDCC 
Independent Data Coordinating Center 
iDMC 
Independent Data Monitoring Committee 
IRB
Institutional Review Board
IRR 
Infusion-related Reaction 
ITT 
Intent-to-Treat 
IxRS 
Interactive Voice/Web Response System 
MS 
Multiple Sclerosis 
OCR
Ocrelizumab
PD
Pharmacodynamic
PK
Pharmacokinetic
PP 
Per Protocol 
PT
Preferred Term
RMS 
Relapsing Multiple Sclerosis 
ROW 
Rest of the World 
RRMS 
Relapsing Remitting Multiple Sclerosis 
SAE
Serious Adverse Event
SAP 
Statistical Analysis Plan
SD 
Standard Deviation 
SOC
System Organ Class
US 
United States 


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Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS
6
1.
BACKGROUND
The ENSEMBLE study (MA30143) is a Phase IIIb prospective, single-arm, open-
label, multicenter study in patients with early stage relapsing remitting multiple 
sclerosis (RRMS).  ENSEMBLE PLUS is a randomized, double-blinded, parallel-
group substudy of ENSEMBLE, initiated after the start of the ENSEMBLE main study
to evaluate the safety of a shorter infusion of ocrelizumab versus conventional 
infusion in a subgroup of eligible patients from the ENSEMBLE main study.  There is 
a single protocol covering the main study, with the substudy featured as an appendix 
in this protocol.
From here on, the ENSEMBLE main study is referred to as “the main study” and the 
ENSEMBLE PLUS substudy is referred to as “the substudy”.  Approximately 650 to 
700 subjects will be enrolled into the substudy.
The scope of this statistical analysis plan (SAP) is to describe the analysis of the 
substudy, to be conducted after the last randomized patient completes the 24-hour 
evaluation period after the 1st randomized infusion.  All safety data up to the clinical 
cutoff date (CCOD) will be included to evaluate the safety of the shorter infusion. 
Database lock and unblinding of the Sponsor will occur several weeks after the CCOD in 
order to clarify all outstanding data queries.
Version 7.0 of the study protocol was updated to include an interim analysis (IA) for the 
primary endpoint after approximately 400 patients have been randomized and dosed. 
The aim of the IA is to evaluate whether an earlier submission of the study results 
(infusion-related reactions [IRRs]) of the shorter infusion versus the conventional 
infusion might be possible with a lower number of patients exposed. It is important to 
note that the currently approved infusion regimen is a barrier to treatment of patients in 
infusion centers due to the overall duration of ocrelizumab treatment (i.e. at least 5.5 
hours).  The shorter infusion (i.e. about 3.5 to 4 hours in total) would significantly reduce 
both the patient burden and the burden of patient management in the infusion center 
(e.g. scheduling two patients in a day rather than one), provided the safety profile of the 
shorter infusion is acceptable at the IA stage. It is therefore of the highest importance 
that the alternative shorter infusion is added as soon as possible to the treatment options 
for physicians and patients.
Therefore, an IA will be conducted after approximately 400 patients have been 
randomized and completed the 24-hour evaluation period after the 1st Randomized 
Dose.  This IA is an administrative interim analysis which will not lead to any changes in 
the substudy protocol or the SAP.  Only patients randomized into the substudy at sites
where protocol version 7.0 has been approved (EC/IRB and HA, as well as any other 
required approval as per local regulations) will be included in the IA.  The CCOD for this 
IA will be 27th September 2019.  During the several weeks following this CCOD, all 
outstanding data queries will be resolved, a database snapshot will be taken for this IA,


Ocrelizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS
and the data will be signed off by the Principal Investigator or delegate. Importantly the 
data used for the primary summary (IRRs at the 1st Randomized Dose) of the IA will be 
the final data for patients included in the IA. An independent unblinded data 
coordinating center (iDCC) will be responsible for preparing a subset of key unblinded 
data summaries from this IA.  These unblinded interim results will be reviewed only by 
the substudy’s independent data monitoring committee (iDMC) and the Sponsor’s
internal substudy data review board (Substudy DRB). A separate Substudy DRB 
Charter document describes how the Substudy DRB members (or their delegates) will 
operate and specifies the subset of key unblinded data summaries to be prepared.  
Following acceptance of the iDMC recommendation to continue the substudy without 
any change or with minor changes, the Substudy DRB will review this subset of key 
unblinded data summaries and decide whether to:
a)
authorize the unblinding of the substudy for data from the relevant patients included 
in the IA (approximately 400) and instruct the substudy team to proceed with the IA,
which would then be filed with health authorities if the IA results demonstrate the 
acceptability of the shorter infusion.  The substudy team and Substudy DRB would 
remain blinded to randomized patients not yet eligible for inclusion in the IA at the 
time of CCOD (approximately 250 to 300).  The final analysis of the substudy, once 
all randomized patients (approximately 650 to 700) have completed the 24-hour
evaluation period after the 1st Randomized Dose and all substudy data have then 
been cleaned and the database locked, will constitute a safety update for the filing 
package. For the primary summary at the final analysis, in order to eliminate 
potential bias from any data changes which might arise after the IA, data used for 
the primary summary (IRRs at the 1st Randomized Dose) in the IA population
(approximately 400) locked at the IA CCOD will be combined with those in the post-
IA population (approximately 250 to 300) locked at the final CCOD. Final analyses 
other than the primary summary will be performed on all data up to the final CCOD.
or
b)
instruct the substudy team to continue the substudy in a blinded manner until all 
patients randomized into the substudy (approximately 650 to 700) have completed 
the 24-hour evaluation period after the 1st Randomized Dose, and all substudy data 
have then been cleaned and the database locked.  This analysis of approximately 
650 to 700 patients will then represent the final analysis of the substudy.
The patients, site personnel and the Sponsor’s employees outside the Substudy DRB 
will remain blinded until the Substudy DRB authorizes unblinding (as described above).
The scope of the analysis of the substudy is defined as follows, based on data available 
at the time of CCOD:

Within the scope of the analysis are all patients randomized into the substudy in 
countries where protocol version 7.0 has been approved and who have completed 
the 24-hour evaluation period after the 1st Randomized Dose
7


Ocrelizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS

Outside the scope of this analysis are i) patients in the main study who were not 
randomized into the substudy and ii) patients randomized into the substudy who 
have not yet completed the 24-hour evaluation period after the 1st Randomized 
Dose and iii) patients randomized into the substudy in countries where protocol 
version 7.0 has not been approved

For in-scope patients randomized into the substudy who have completed the 24-
hour evaluation period after the 1st Randomized Dose, the following data are within
the scope of this analysis:
–
all substudy data
–
relevant data captured at the main study screening assessment
–
all data related to adverse events (AEs), including IRRs, captured in the main 
study prior to randomization into the substudy (but data other than AE/IRR data 
in this period are outside of scope)
–
all AE data captured in the main study after discontinuation from substudy (i.e.,
all AEs with onset on or after date of randomization are within scope, even if 
AE onset is after the patient discontinues randomized substudy treatment or if 
AE onset is after the patient discontinues any ocrelizumab treatment)
2.
STUDY DESIGN
This is a prospective, multicenter, randomized, double-blind, controlled, parallel arm 
substudy evaluating the safety of a shorter duration infusion of ocrelizumab in a 
subgroup of patients with early stage RRMS enrolled in the main study.  Please refer to 
the main study protocol for full details of the design of the ENSEMBLE main study.
Patients randomized into the substudy originate from two sources: i) patients already 
enrolled into the main study who meet substudy entry criteria and consent to participate, 
and ii) patients newly enrolled into the main study with a requirement that they will 
participate in the substudy, subject to meeting substudy entry criteria.  A patient is 
considered to be enrolled in the substudy once written informed consent to participate 
has been provided (as indicated on the “Informed consent of Ensemble Plus” eCRF 
page).
Once substudy eligibility has been confirmed, patients are randomized into one of the 
following two groups in a 1:1 ratio, stratified by region (United States [US], Canada, 
Australia versus Rest of the World [ROW]) and by dose at which the patient is 
randomized:

Conventional Infusion Group: patients receive 600 mg ocrelizumab in 500 mL 0.9% 
sodium chloride infused over approximately 3.5 hours every 24 weeks for the 
remainder of the substudy duration (as in the main study)

Shorter Infusion Group: patients receive a shorter duration infusion of 600 mg 
ocrelizumab in 500 mL 0.9% sodium chloride infused over 2.0 hours followed by 100 
mL 0.9% sodium chloride given as a slow infusion over the remaining 1.5 hours, in 
8


Ocrelizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS
order to mimic the standard-length infusion (3.5 hour) every 24 weeks for the 
remainder of the substudy duration
The ocrelizumab dose and dosing schedule remain the same in this substudy as in 
the main study, the only change being the duration of ocrelizumab infusion for the 
shorter infusion group from the 1st randomized infusion onwards.  In this substudy, 
patient assignment to the randomized treatment group (i.e. actual infusion rate) is 
kept blinded.
As stated above, patients randomized into the substudy originate from two sources, and 
further details of these two sources are provided below:
Patients Already Enrolled into the Main Study: when the substudy was first initiated, 
patients already enrolled into the main study were offered the option to be randomized 
into the substudy.  Subject to providing consent and meeting substudy entry criteria, 
these patients are to be randomized to either conventional infusion or shorter infusion at 
the next scheduled dose of ocrelizumab i.e. at Dose 3 or Dose 4 or Dose 5 (at the time 
the substudy was initiated, it was too late to randomize these patients at Dose 2, and the 
shorter infusion is never used at Dose 1).  Among these patients, the first patient was 
randomized into the substudy on 1st November 2018.  Consequently, for the IA, if the 
infusion schedule is followed exactly, these patients should have received either 1 or at 
most 2 randomized doses of ocrelizumab treatment by the time of the IA CCOD.  By the 
time of the analysis of all randomized patients (N650 to 700 approximately), some of 
the already enrolled patients will by then have received a 3rd Randomized Dose.
Patients Newly Enrolled into the Main Study for the Substudy: after the substudy 
was initiated, additional new patients were enrolled into the main study with a 
requirement that they will participate in the substudy, subject to subsequently meeting 
substudy entry criteria.  These patients then undertook the 4-week main study screening 
period, and then received Dose 1 of their ocrelizumab treatment.  These patients were to 
be randomized to conventional infusion or shorter infusion at the earliest possible dose 
of ocrelizumab i.e. at Dose 2 (the shorter infusion is never used at Dose 1).  Among 
these patients, the first patient was randomized into the substudy on 22nd March 2019.  
Consequently, for the IA, these patients will have received 1 or at most 2 randomized 
doses of ocrelizumab treatment by the time of IA CCOD.  By the time of the analysis of 
all randomized patients (N=650 to 700 approximately), none of the newly enrolled 
patients will by then have received a 3rd Randomized Dose.
It is expected that approximately 650 to 700 patients will be enrolled in this substudy, 
approximately 150 patients already enrolled into the main study plus approximately 
550 newly enrolled patients.
To fully clarify the terms “Randomized Dose” and “Dose” (or “OCR Dose”), refer to 
the Table 1 below which shows several example patients.
9




Ocrelizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS

Example Patient : an already enrolled patient, randomized at OCR Dose 4

Example Patient : an already enrolled patient, randomized at OCR Dose 5

Example Patient : a newly enrolled patient, randomized at OCR Dose 2
Some of the summaries described in the sections below are presented by Randomized 
Dose and then by Dose within Randomized Dose.  For example:
1st Randomized Dose (denoted “RD1” and highlighted in yellow in the table above): 
presented at Dose 2, at Dose 3, at Dose 4 and at Dose 5
2nd Randomized Dose (denoted “RD2” and highlighted in green in the table above): 
presented at Dose 3, at Dose 4, at Dose 5 and at Dose 6
3rd Randomized Dose (denoted “RD3” and highlighted in blue in the table above): 
presented at Dose 4, at Dose 5, at Dose 6 and at Dose 7
Some summaries are also presented “Overall” within each Randomized Dose.  For 
example, for the 1st Randomized Dose, an “Overall” summary consolidates the 1st
Randomized Dose at Dose 2, 3, 4 and 5 across all patients (but each patient is included 
/ counted only once in any “Overall” summary, since each patient can of course only 
receive one 1st Randomized Dose, for example).  So in this case, for the 1st Randomized 
Dose, an “Overall” summary consolidates all the yellow highlighted cells in the table 
above.  Similarly, for the 2nd Randomized Dose, an “Overall” summary consolidates all 
the green highlighted cells in the table above, etc.
2.1
PROTOCOL SYNOPSIS
The protocol synopsis and the schedule of assessments of the substudy are included in 
the current version of the protocol.
2.2
OUTCOME MEASURES
2.2.1
Primary Outcome Measure
The primary endpoint in this substudy is the proportion of patients with IRRs occurring 
during or within 24 hours after the 1st randomized infusion of ocrelizumab.
2.2.2
Secondary Outcome Measures
The following secondary IRR-related variables will be summarized: 

Proportion of patients with IRR overall and by dose at randomization 

Intensity of IRRs 

Proportion of patients with serious IRRs 

Symptoms of IRRs 

IRRs leading to treatment discontinuation 

Subgroup analyses according to IRR history (for example, patients with/without 
IRR at any previous dose) 
11


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Statistical Analysis Plan MA30143 Shorter Infusion Substudy, ENSEMBLE PLUS
2.2.3
Exploratory Outcome Measures
The following exploratory variables will be summarized: 

Proportion of patients with Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 3 or 4 (severe or life-threatening) IRRs 

Number of CTCAE Grade 3 or 4 (severe or life-threatening) IRRs
2.2.4
Pharmacokinetic Analysis: Objectives and Outcome Measures
The pharmacokinetic (PK) analysis will assess any potential relationship between the 
primary endpoint (described above) and the maximum concentration of ocrelizumab
(Cmax).
2.2.5
Pharmacodynamic Outcome Measures
There are no pharmacodynamic endpoints in this study.
2.2.6
Safety Outcome Measures
In addition to the assessment of safety via IRRs, safety will also be regularly assessed 
via reporting of AEs, vital signs and laboratory data (including CD19, CD4 and CD8).
2.3
DETERMINATION OF SAMPLE SIZE
Determination of sample size was described as follows in the protocol (Version 7.0):
Regarding patients already enrolled into the main study, we assume that approximately 
40 and 110 will receive the first dose of randomized treatment at Dose 3 or at Dose 4 / 
subsequent dose, respectively. In addition, since no previously enrolled patients will 
receive shorter infusion at Dose 2, the Sponsor plans to include approximately 550 new 
patients, of which approximately 500 are expected to receive the randomized treatment 
at Dose 2 and be evaluable for the analysis. In total, approximately 650 patients are 
expected to be randomized into two groups and be evaluable for the final clinical study 
report (CSR).
The different IRR rates at Dose 2, 3 or 4 or at subsequent dose are considered in the 
calculation of the pooled IRR rate. In the Opera studies (WA21092 and WA21093),
13.7%, 9.6% and 7.8% of patients had at least one IRR at Dose 2, 3 and 4, respectively, 
which leads to an expected pooled IRR rate of approximately 12.4% excluding Dose 1 
for this substudy. Therefore, we assume an observed IRR rate in the conventional 
infusion group of 12.4% excluding Dose 1. The 95% confidence intervals (CIs) of the 
IRR rate difference between shorter and conventional infusion groups as a function of 
the observed IRR rate in the shorter infusion group are listed in Table 2 (below). The 
CIs were calculated based on the assumption of Binomial distributed IRR rates, which 
provide sufficient precision around the IRR rates for this substudy.
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In summary, the analysis of the substudy will be conducted after the last enrolled patient 
completes the 24-hour evaluation period after the 1st randomized infusion.  An IA will be 
undertaken by the iDCC with a CCOD of 27th September 2019, including approximately 
400 patients.  The iDMC and Substudy DRB only will review a subset of key unblinded 
data summaries from this IA and the Substudy DRB will determine a) whether or not the 
substudy team should be unblinded, the full IA should be undertaken (all summaries, not 
just a subset) and this IA should be filed with health authorities or b) to place all further 
unblinding and preparation of data summaries on hold until all patients randomized into 
the substudy (approximately 650 to 700) have completed the 24-hour evaluation period 
after the 1st Randomized Dose, in which case this would represent the final analysis of 
the substudy.
3.
STUDY CONDUCT
3.1
RANDOMIZATION AND BLINDING
Patients were randomized into two groups (Conventional Infusion or Shorter Infusion) in 
a 1:1 ratio.  An independent IxRS provider conducted randomization (with use of blocked
randomization) and holds the treatment assignment code. Patients were stratified by 
region (US / Canada / Australia vs. ROW) and the Dose at which the patient is 
randomized.  For patients previously enrolled into the main study, randomization takes
place at the next scheduled infusion visit i.e. at Dose 3, 4 or 5.  For newly enrolled 
patients, randomization takes place at Dose 2.
Blinding of the infusion rates and the actual duration of the infusion is achieved by the 
following measures:

The substudy group assignment (randomization) codes are only visible to the 
pharmacy personnel preparing the drug infusions and to the unblinded personnel 
operating the infusion pump (from now on, referred to as “infusion nurse”)

Infusions are pre-loaded and placed into standardized infusion cover bags and 
placed on an infusion rack, and the actual infusion administration pump is covered 
and operated by the infusion nurse

The actual infusion rates and associated activities related to infusion administration 
are blinded to the site study team (including the study coordinator and the treating 
investigator), patient and the Sponsor

The conventional-length infusion is administered as described in the main study 
protocol. The shorter infusion is administered within 2 hours (500 mL infusion 
volume at the rates as presented in Table 3 in the substudy protocol), followed 
immediately by administration of a separate 100mL normal saline (0.9 % NaCl) bag 
without any additional component over the remaining 1.5h with an approximate 
infusion rate of 60mL/hr. For patients randomized to the conventional-length 
infusion, the infusion nurse mimics a switch infusion at approximately 2 hours (timing 
to be adapted depending on the infusion rate adaptation during the first 2 hours). 
The infusion nurse checks and adjusts the infusion rates periodically as needed, 
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both for maintaining the correct rates of the infusion and for maintaining the 
blinding/masking of the two infusion groups (see Figure 1 and Figure 2 below). 
Adjustments needed for managing IRRs are allowed at any time and should follow 
the guidance from the main study protocol. Please refer to substudy protocol 
Section 4.3.2 Dosage, Administration and Compliance for further details on the 
infusion preparation and administration.

The infusion nurse (unblinded) or the clinical nurse (blinded) collect vital signs at the 
time of pre-medication onwards (see Section 4.5.4 of the main study protocol). Vital 
signs will be reported in the electronic case report form (eCRF). The blinded treating 
investigator evaluates and confirms all IRRs occurring during or within 24 hours post-
infusion.

The unblinded information related to the infusion is entered into the IxRS system by 
the unblinded site staff member. The unblinded site staff members must keep 
confidential any data related to the infusion (group allocation, infusion duration and 
content, etc.):
–
they must not further communicate these data, neither verbally nor in writing–
they must maintain the corresponding files in a locked, access-restricted 
location

Additional operational measures are undertaken at local level to ensure the 
appropriate level of blinding of the personnel involved and the data collected

The IxRS service provider and iDMC members have access to treatment 
assignment in order to fulfil their roles during the substudy
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Figure 1
Blinding Procedure
Figure 2
Figure Blinding Procedure
AHantihistamine; Hhour; IVMPintravenous methylprednisolone; OCRocrelizumab; 
PKpharmacokinetic
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3.2
INDEPENDENT REVIEW FACILITY
In this substudy, there is no Independent Review Facility or Reading Center to review 
data for the purpose of making any diagnosis or providing any outcome measure.
3.3
DATA MONITORING
In the interests of patient safety, an iDMC is reviewing cumulative unblinded safety data 
from the substudy at approximately 3-month intervals, as described in the iDMC Charter.  
The iDMC will discontinue its activities once the analysis is completed.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
The primary summaries of IRRs will be performed using the Intent-to-Treat (ITT) 
Population. The Per-Protocol (PP) Population will be used in order to evaluate the 
influence of major protocol deviations and as a sensitivity check of the primary analyses 
of IRRs.  Other than analyses of IRRs, safety analyses will be based on the Safety 
Population only.  The Safety Population will also be used as a sensitivity check of the 
primary summaries of IRRs.  The Pharmacokinetic (PK) Population will be used for 
supportive analyses.
All Patients Population
All patients enrolled into the substudy (i.e. written informed consent has been provided) 
will be included in the All Patients Population, whether or not they were randomized.
ITT Population
All randomized patients will be included in the ITT Population. Patients will be analyzed 
according to their randomized treatment, regardless of treatment actually received.
PP Population
Patients in the ITT Population with the following major protocol deviations (identified by 
category and sub-category) will be excluded from the PP Population.  Consideration will 
be given to whether or not the deviation will impact assessment of the primary endpoint 
(i.e. IRRs):
Category: Main Study Entry Criteria
It is not possible to provide an exhaustive list of sub-categories here.  Some 
examples of this kind of deviation are:

Informed consent not provided by patient for latest version of protocol (“Protocol 
Amendment” eCRF page)

Patient’s age at the main study screening visit was not in the range 18-55 years
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Category: Substudy Inclusion Criteria
Sub-categories:

Informed consent not provided by patient (“Informed consent of Ensemble Plus” 
eCRF page)

Patient unable to comply with the substudy protocol, in the investigator’s 
judgment
Category: Substudy Exclusion Criterion
Sub-category:

Patient has previously experienced a serious IRR with ocrelizumab treatment
Category: Medication-Related
It is not possible to provide an exhaustive list of sub-categories here.  Examples of 
this kind of deviation include failure to administer methylprednisolone and/or anti-
histaminic drugs in line with protocol requirements, since this may increase the 
chance of IRRs in those patients.
Category: Procedural: Infusion-Related
It is not possible to provide an exhaustive list of sub-categories here.  Some 
examples of this kind of deviation are:

Patients who received any randomized treatment other than that to which they 
were randomized (excluded from the PP Population from the time of this 
deviation onwards)

Blinded site staff becoming unintentionally unblinded to a patient’s blinded 
randomized treatment assignment

Patients who were mis-stratified for randomization.  Since the randomization is 
stratified by region and 1st Randomized Dose, an example of this would be a 
patient who started randomized treatment at Dose 2, but was incorrectly 
randomized from the Dose 3 randomization list in the IxRS system (and in this 
situation, it is impossible to know whether the patient would have received the 
same treatment if the stratification had been performed correctly).
Category: Procedural: Other
It is not possible to provide an exhaustive list of sub-categories here.  An example of 
this kind of deviation is non-adherence to schedule of assessments.
Category: Other
It is not possible to provide an exhaustive list of sub-categories here.  This will 
include any major protocol deviations detected during the study conduct not 
classified in one of the above categories/sub-categories.
The data sources of major protocol deviations in the clinical trial database will be 
Roche’s Protocol Deviation Management System (PDMS), plus filenotes created to 
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document randomization/stratification issues encountered with the IxRS system.  Entries 
in the PDMS system are made and maintained by study medical monitors, and will be 
provided in the form of an Excel file to substudy statistical programmers for incorporation 
into the substudy datasets.  Similarly, an Excel file will be prepared to summarize all 
filenotes relating to IxRS technical issues, and again provided to substudy statistical 
programmers for incorporation into the substudy datasets.
The following programmatic data checks will be undertaken:

Check that all patients met all main study entry criteria, based on the question 
”Did subject meet all eligibility criteria?” on the “Subject Eligibility” eCRF page

Check that the patient’s age at the main study screening visit was in the range 
18-55 years

Check that no patient with a serious IRR on ocrelizumab treatment prior to 
randomization was then randomized

Check that each patient provided informed consent for the substudy (based on 
the “Informed Consent of Ensemble Plus” eCRF page)

Check that each patient actually received the correct randomized treatment (the 
actual treatment is collected in the IxRS system)
Safety Population
The Safety Population will include all randomized patients who received any dose or part 
of a dose of ocrelizumab treatment. Patients who received any randomized treatment 
other than that to which they were randomized will be analyzed according to the 
treatment actually received.  Any patient receiving at least one shorter infusion (whether 
or not this is their randomized treatment) at any time during the substudy will be 
assigned to the shorter infusion group at all randomized doses, regardless of the 
randomized dose at which the patient actually first received the shorter infusion.
Pharmacokinetic (PK) Population
The PK Population will include all randomized patients receiving any ocrelizumab 
treatment who had at least one measurable concentration value unless major protocol 
deviations or unavailability of information occurred that may interfere with the PK 
evaluation.
4.2
ANALYSIS OF STUDY CONDUCT
All relevant data up to the point of the CCOD will be included to evaluate substudy 
conduct.  The following summaries will be prepared to evaluate the substudy conduct 
(number of patients and percentage):

List of randomization failures – these are patients who consented to participate in 
the substudy but were not randomized.  A listing of these patients will be 
provided, which will include whether the patient was already or newly enrolled, 
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date of first ocrelizumab treatment, date of informed consent and the reason for 
non-randomization.

Enrollment by country and center.  A summary of randomized treatment 
assignments will be presented.  A summary of the numbers of patients enrolled 
but not randomized will also be presented.

Randomization assignment by stratification factors: region (US, Canada, 
Australia versus ROW) and 1st Randomized Dose.  Listings will be prepared to 
show a) these stratification factors and b) any discrepancies in these stratification 
factors when the clinical trial database and IxRS databases are compared.

Summaries of patient disposition (tabular and graphical), including the number of 
randomized doses received and numbers of patients ongoing in and discontinued 
from the substudy.  This will be presented for all patients, for patients already 
enrolled in the main study, and for patients newly enrolled.

Summary of reasons for early discontinuation from the substudy, for all patients, 
for patients already enrolled in the main study, and for patients newly enrolled.

Summary of reasons for early discontinuation from ocrelizumab treatment, for all 
patients, for patients already enrolled in the main study, and for patients newly 
enrolled.

Summary of reasons for early discontinuation from the main study, for all 
patients, for patients already enrolled in the main study, and for patients newly 
enrolled.

Summaries of ITT, PP, Safety and PK Populations, showing numbers of patients 
in each population

Summary and listing of major protocol deviations, leading to exclusion from the 
PP Population.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
To assess treatment group comparability, summaries of baseline characteristics will be 
presented by randomized treatment group.  These will be for the ITT Population only.
For continuous variables, the mean, median, SD, minimum, and maximum will be 
calculated.  For categorical variables, the number and percentage in each category will 
be displayed.  The units/categories to be used are indicated within the brackets and 
separated by commas.
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4.3.1
Demography
In addition to summary statistics and frequency counts for all patients in the ITT 
Population, demographic characteristics will also be summarized separately for patients 
already enrolled in the main study, and for patients newly enrolled.  The following 
characteristics will be summarized:

Age at Randomization (years): summary statistics displayed will include mean, 
median, SD, minimum, and maximum, percentage and number in each category 
(<40, ≥40).  Note that the main study required patients to be aged 18-55 
inclusive, but there are no specific age requirements for the substudy.

Sex at Screening Visit of Main Study:  the number and percentage of male and 
female patients will be displayed.

Race at Screening Visit of Main Study: the number and percentage of the 
following categories will be displayed:  White; Black or African American; Asian 
(Indian Subcontinent, Other than Indian subcontinent), American Indian or Alaska
Native; Native Hawaiian or other Pacific Islander; Multiple and Unknown

Ethnicity at Screening Visit of Main Study: the number and percentage of the 
following categories will be displayed: Hispanic or Latino, not Hispanic or Latino, 
Not Reported and Unknown

Weight (kg) at Screening Visit of Main Study: summary statistics will be 
displayed, as described for age at randomization.

Body Mass Index (BMI) at Screening Visit of Main Study:  summary statistics will 
be displayed, as described for age at randomization.

Details of demographic characteristics will be listed.
4.3.2
MS Disease History at Randomization

Duration since MS symptom onset at randomization (years):  summary statistics 
calculated will include mean, median, SD, minimum, and maximum (calculated in 
years, i.e., divide by 365.25).  Frequency counts will also be presented.

Duration since MS diagnosis at randomization (years):  summary statistics 
calculated will include mean, median, SD, minimum and maximum (calculated in 
years, i.e., divide by 365.25).  Frequency counts will also be presented.
Duration since MS symptom/diagnosis onset will be calculated up to the randomization 
date.  If month of symptom/diagnosis onset date is missing, the month of January will be 
used.  If symptom/diagnosis onset date is missing, the first (1st) of the month will be 
used.
Details of MS disease history will be listed.
4.3.3
Pre-Randomization IRRs and Serious IRRs
The number of patients with an ocrelizumab infusion, the number and percentage with 
any pre-randomization IRR and the number and percentage with any pre-randomization 
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serious IRR will be presented.  For newly enrolled patients randomized at Dose 2, these 
numbers will be presented at Dose 1 Infusion 1, Dose 1 Infusion 2 and overall.  For 
previously enrolled patients randomized at Dose 3, 4 or 5, these numbers will be 
presented at Dose 1 Infusion 1, Dose 1 Infusion 2, Dose 2, Dose 3, Dose 4 and overall.  
An overall summary of these numbers for all patients in the ITT Population will also be 
presented.
4.3.4
Previous Diseases (Other Than MS) Prior to Randomization
Diseases reported on the “General Medical History and Baseline Conditions Log” eCRF 
page are summarized as previous diseases if disease status was recorded as a) 
"Resolved" or as b) "Ongoing" (with or without treatment) and disease end date was 
known to be before date of substudy randomization or if c) the “End Date Unknown” box 
was checked (which indicates the disease had ended but the end date was unknown).
Diseases reported on the “Adverse Event/IRR/MS Relapse” eCRF page are summarized 
as previous diseases if a) AE onset date was on or after date of first ocrelizumab 
treatment in the main study, and AE end date was before the date of substudy 
randomization or b) if AE onset date was before date of first ocrelizumab treatment in the 
main study, and AE intensity worsened after initiation of ocrelizumab treatment but 
before date of substudy randomization, and AE end date was before the date of 
substudy randomization.
Previous diseases reported via the “General Medical History and Baseline Conditions 
Log” eCRF are summarized separately from those reported via the “Adverse 
Event/IRR/MS Relapse” eCRF page.  In each of these two separate summaries, the total 
number of patients with at least one previous disease and the total number of previous 
diseases will be presented.  The number and percentage of patients reporting previous 
diseases will be presented by system organ class (SOC) and preferred term (PT) (for 
further details of how AEs are coded and reported, please refer to the “Common 
Adverse Events” section later in this document).
4.3.5
Current Diseases (Other Than MS)
Diseases reported on the “General Medical History and Baseline Conditions Log” eCRF 
page are summarized as current diseases if disease status was recorded as "Ongoing" 
(with or without treatment) and disease end date was missing and the “End Date 
Unknown” box was not checked.
Diseases reported on the “Adverse Event/IRR/MS Relapse” eCRF page are summarized 
as current diseases a) AE onset date was on / after date of first ocrelizumab treatment in 
the main study and AE end date was either missing or on / after date of substudy 
randomization or b) if AE onset date was before date of substudy randomization, and AE 
intensity worsened after substudy randomization, and AE end date was unknown or on / 
after the date of substudy randomization.
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Current diseases reported via the “General Medical History and Baseline Conditions 
Log” eCRF are summarized separately from those reported via the “Adverse 
Event/IRR/MS Relapse” eCRF page.  In each of these two separate summaries, the total 
number of patients with at least one current disease and the total number of current 
diseases will be presented.  The number and percentage of patients reporting current 
diseases will be presented by SOC and PT.
4.3.6
Previous Treatments (Other Than For MS) Prior to 
Randomization

Did patient receive any prior treatments, other than for MS? (defined as 
treatments with a stop date before date of randomization):  number and 
percentage of patients (yes or no)

Each previous non-MS treatment: number and percentage of patients receiving 
each treatment
4.3.7
Concomitant Treatments (Other Than For MS)

Did patient receive any concomitant treatments, other than for MS? (defined as 
treatments with a start date on or after date of randomization, or with a start date 
before date of randomization but continuing into the substudy on/after date of 
randomization):  number and percentage of patients (yes or no)

Each previous non-MS treatment: number and percentage of patients receiving 
each treatment
4.4
EFFICACY ANALYSIS
No analyses of efficacy data are planned for this substudy.
4.5
SAFETY ANALYSES
This is a descriptive study and no formal inferential statistical analyses will be performed.
Summaries of the primary endpoint (proportion of patients with IRRs occurring during or 
within 24 hours after the 1st randomized infusion of ocrelizumab, as described below in 
Section 4.5.2.1) will provide point estimates of the between-treatment difference and 
associated symmetric two-sided 95% CIs.  These summaries will be presented both 
unstratified and stratified for the stratification factors of 1st Randomized Dose and region 
(US / Canada / Australia vs. ROW).
Safety data include but are not restricted to AE data, laboratory data, previous and 
concomitant treatment data, infusion information including IRR data, withdrawal data, 
fatalities, vital signs and dosing information.
All summaries of IRRs will be based on the ITT Population (with the exception of 
additional sensitivity analyses for the primary endpoint only, based on PP and Safety 
Populations).  All other safety summaries will be based on the Safety Population.
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The term “Pre-Randomization” will be used refer to the period of time before the 
patient is randomized into the substudy.  The term “Randomized Period” will be used 
to refer to the period of time during which a patient receives randomized treatment in 
the substudy.  If a randomized patient discontinues from randomized treatment, they 
effectively discontinue from the substudy, and after this they will either:
a)
continue to receive ocrelizumab in the main study according to conventional infusion 
guidelines – this period of time will be referred to as “Post Substudy, On Treatment”
b)
discontinue ocrelizumab treatment entirely and enter a safety follow-up period, as 
described in the main study protocol – this period of time will be referred to as “Post 
Substudy, Off Treatment”
4.5.1
Exposure to Study Medication
Within the substudy, in both randomized groups ocrelizumab is given as single infusions 
of 600mg at 24-week intervals.  The only difference between the randomized groups is 
the duration of the infusion.
Patients will be considered to have received a dose of treatment if at least part of that 
infusion was given.  If a dose is completely missed instead of delayed, the next dose
number will be based on the number of previous doses received.
For each patient, the length of exposure to randomized treatment is from the date on 
which the patient first received randomized treatment (Substudy Day 1) until the last 
known alive date or CCOD, whichever is earlier.  For patients who withdrew early from
randomized treatment, the exposure is until the last known alive date (i.e., duration of 
exposure is equivalent to duration of observation period, and these terms are used 
interchangeably in this SAP).  To summarize, the duration of exposure for a patient will 
be calculated as:
(Date of last contact* – date of 1st Randomized Dose) + 1
* Earlier of 1) date of CCOD 2) last known alive date
The following aspects of exposure to ocrelizumab will be summarized by randomized 
group:

Treatment duration (weeks): frequency counts (number of patients and 
percentage) for 0-23 weeks, 24-47 weeks and 48-71 weeks will be presented

Number of doses received: frequency counts (number of patients and 
percentage) and summary statistics (mean, SD and median) will be presented

Total cumulative dose (derived to mg): summary statistics (mean, SD, median, 
lower and upper quartiles, minimum and maximum) will be presented
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
Ocrelizumab infusion duration (minutes): summary statistics (mean, SD, median, 
lower and upper quartiles, minimum and maximum) will be presented by 
Randomized Dose and overall (all randomized doses).

The number and percentage of infused patients with 80% and 80% of the 
planned infusion volume will be presented, along with the number and 
percentage of infused patients who were pre-treated with methylprednisolone (or 
equivalent) only, with antihistamine only and with both methylprednisolone (or 
equivalent) and antihistamine.  These summaries will be presented by 
Randomized Dose and then by Dose within Randomized Dose (and overall 
within Randomized Dose i.e. across all Doses).

The number and percentage of patients in either randomized group with any IRR 
receiving <80% or ≥80% of the planned ocrelizumab volume will be presented, 
along with the number and percentage of infused patients in the shorter infusion 
group with any IRR receiving <80% or ≥80% of the planned saline volume.  
These summaries will be presented by Randomized Dose and then by Dose 
within Randomized Dose (and overall within Randomized Dose i.e. across all 
Doses).
4.5.2
Adverse Events
4.5.2.1
Infusion-Related Reactions
IRRs are collected on the “Adverse event/IRR/MS relapse” and “Infusion Related 
Reaction” eCRF pages.  The symptom(s) of an IRR and the IRR itself may be of different 
intensities.  IRR symptoms (collected on the “Infusion Related Reaction” eCRF page) will 
be coded in MedDRA and summarized by SOC and PT.  IRRs (in fact all AEs) are 
categorized on the “Adverse Event/IRR/MS Relapse” eCRF page as occurring 1) during 
infusion or 2) within 24 hours after end of infusion.
Summaries of pre-randomization IRRs and serious IRRs are described above in Section 
4.3.3.  In all other summaries of IRRs, only IRRs occurring during the substudy will be 
included.  IRRs occurring after withdrawal from the substudy will not be included in these 
IRR summaries (but will be included in AE summaries, which will include all AEs with an 
onset date after the date of randomization, even if the onset is after the patient 
discontinues randomized treatment).
The primary endpoint of this substudy is the proportion of patients with IRRs occurring 
during or within 24 hours after the 1st randomized infusion of ocrelizumab.  A stratified 
method will be applied, to take account of the two stratification factors, region and 1st
Randomized Dose.  The weighted average of the proportion difference across strata 
based on Cochran-Mantel-Haenszel weights is estimated. This approach will result in a 
stratified estimated difference between the proportions in the two randomized groups, 
which will be presented along with an associated 95% CI.  This method is described by 
(Zhao et al. 2001) and its practical implementation is further described by (Zhang 2016).  
The (unstratified) estimated difference between the proportions in the two randomized 
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groups will also be presented along with an associated 95% CI.  This summary will be 
presented for all patients, for patients with at least one pre-randomization IRR and for 
patients with no pre-randomization IRRs.  The primary endpoint will be summarized for 
the ITT Population, and also for the PP and Safety Populations additionally, as 
sensitivity analyses.  The primary endpoint will be further described in graphical bar-
chart format (ITT Population only).
If the IA leads to an early unblinding of the substudy team to patients included in the IA, 
in order to eliminate potential bias from any data changes which might arise after the IA, 
data used for the primary summary (IRRs at 1st Randomized Dose) in the IA population
(N=400 approximately) locked at the IA CCOD will be combined with those in the post-IA 
population (N=250 to 300 approximately) locked at the final CCOD to perform the 
primary summary at the final analysis. Final analyses other than the primary summary 
will be performed on all data up to the final CCOD.
An IRR overview summary will be presented, showing the number and percentage of 
infused patients with any IRR and any serious IRR.  This summary will be presented by 
Randomized Dose and then by Dose within Randomized Dose (and overall within 
Randomized Dose i.e. across all Doses), and overall (all randomized doses).  This 
summary will be presented for all patients, for patients with at least one pre-
randomization IRR and for patients with no pre-randomization IRRs.
Further summaries of IRRs will be presented by Randomized Dose and then by Dose 
within Randomized Dose as follows:

The number and percentage of patients with IRR symptoms will be presented by 
SOC (in decreasing order of overall incidence) and PT (in decreasing order of 
overall incidence).

The number and percentage of patients with IRRs by most extreme intensity will 
be presented (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = 
life-threatening, grade 5 = fatal).  Multiple IRRs in one patient are counted only 
once at the most extreme (highest) intensity observed.

The number and percentage of patients with IRRs, grouped by most extreme 
intensity into not severe (Grade 1 or 2) and severe (Grade 3 to 5) will be 
presented.  Again, multiple IRRs in one patient are counted only once at the most 
extreme (highest) intensity observed.

The number and percentage of patients with IRRs leading to intervention in 
ocrelizumab infusion, with intervention defined as infusion slowed down, or 
infusion interrupted or infusion discontinued

The number and percentage of patients with IRR symptoms leading to 
discontinuation of ocrelizumab infusion will be presented by SOC (in decreasing 
order of overall incidence) and PT (in decreasing order of overall incidence).
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
The number and percentage of patients with IRR symptoms leading to
interruption of ocrelizumab infusion will be presented by SOC (in decreasing 
order of overall incidence) and PT (in decreasing order of overall incidence).

The number and percentage of patients with IRR symptoms leading to slowing 
down of ocrelizumab infusion will be presented by SOC (in decreasing order of 
overall incidence) and PT (in decreasing order of overall incidence).

The number and percentage of patients with IRRs who received pre-medications 
(methylprednisolone (or equivalent) only, antihistamine only, methylprednisolone 
(or equivalent) plus antihistamine)

The number and percentage of patients with IRR symptoms will be presented by 
SOC (in decreasing order of overall incidence) and PT (in decreasing order of 
overall incidence), shown separately for the following two time periods: a) during 
ocrelizumab/saline infusion and b) within 24 hours after the end of 
ocrelizumab/saline infusion

The number and percentage of patients with IRR symptoms will be presented by 
SOC (in decreasing order of overall incidence) and PT (in decreasing order of 
overall incidence), shown separately for the following two time periods: a) from 
the start of ocrelizumab infusion to switch/dummy switch to saline infusion and b) 
from switch/dummy switch to saline infusion to end of infusion.

The number and percentage of patients with IRRs by outcome (recovered / 
resolved, recovered / resolved with sequelae, recovering / resolving, not 
recovered / not resolved, fatal and unknown)

The number and percentage of patients with IRRs who received symptomatic 
treatments for any IRR
All IRRs and symptoms occurring before and during the substudy will be listed, with 
separate listings created for IRRs occurring prior to randomization and for IRRs 
occurring post-randomization during the substudy.
4.5.2.2
Overview of Adverse Events
To provide an overview of patient safety results, an AE profile summary table will be 
presented.  For each randomized group, this will show the following:
Total number of patients (and percentage) with at least one AE
Total number of AEs
Total number of deaths (and percentage)
Total number of patients (and percentage) with at least one of:
–
AE with fatal outcome
–
Serious AE (SAE)
–
Serious infection (defined using AEs falling into the MedDRA “Infections and 
Infestations” SOC and “serious” responses to the question “Is the event non-
serious or serious?” from the “Adverse Event/IRR/MS Relapse” eCRF page)
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–
SAE leading to withdrawal from ocrelizumab treatment (withdrawal from 
ocrelizumab treatment defined as “drug withdrawn” in response to the SAE, 
taken from the “Adverse Event/IRR/MS Relapse” eCRF page)
–
SAE leading to ocrelizumab dose modification/interruption
(modification/interruption defined as “dose delayed”, “dose reduced” or “drug 
temporarily interrupted” in response to the SAE, taken from the “Adverse 
Event/IRR/MS Relapse” eCRF page)
–
AE leading to withdrawal from ocrelizumab treatment (withdrawal from 
ocrelizumab treatment defined as “drug withdrawn” in response to the AE, 
taken from the “Adverse Event/IRR/MS Relapse” eCRF page)
–
AE leading to ocrelizumab dose modification/interruption
(modification/interruption defined as “dose delayed”, “dose reduced” or “drug 
temporarily interrupted” in response to the AE, taken from the “Adverse 
Event/IRR/MS Relapse” eCRF page)
–
IRRs leading to withdrawal from ocrelizumab treatment at the 1st Randomized
Dose
–
Malignancies (defined using AEs falling into the Standard MedDRA Query 
“'Malignant tumours (narrow)” from the “Adverse Event/IRR/MS Relapse” eCRF 
page)
–
Infections (defined using AEs falling into the MedDRA “Infections and 
Infestations” SOC from the “Adverse Event/IRR/MS Relapse” eCRF page)
The AE profile summary described above will be repeated per 100 patient-years 
(100PY) exposure, in order to adjust for any differences between randomized groups in 
the duration of observation period.  Estimates of incidence rates per 100PY will be 
provided, along with associated 95% CIs.  For further details, please refer to the 
“Common Adverse Events” section later in this document.
4.5.2.3
Common Adverse Events
AEs will be defined as all AEs including IRRs and serious MS relapses, but excluding 
non-serious MS relapses.  Therefore, those AEs recorded on the “Adverse 
event/IRR/MS relapse” eCRF page will be included.
AEs reported from randomization onwards at all randomized doses will be included in 
summary tables.  These summary tables will show all AEs combined, and will not show 
any separate summaries by Randomized Dose nor Dose.
All AEs with an onset date after the date of randomization will be included, even if 
the onset is after the patient discontinues randomized treatment.  AEs will be flagged 
by substudy period based on time of onset, as described at the end of Section 2 
(periods are “Randomized Period”, “Post Substudy, On Treatment” and “Post 
Substudy, Off Treatment”).
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For each AE recorded, the term entered by the investigator describing the event (the 
“reported term”) will be assigned a standardized term (the “preferred term” (PT)) based 
on the Medical Dictionary for Regulatory Activities (MedDRA) World Health Organization 
(WHO) dictionary of terms.  All analyses of AE data will be performed using the PTs 
unless otherwise specified.  All AEs will be mapped to PTs and system organ classes 
(SOCs).
Summaries of AEs will be generated summarizing the incidence of treatment-emergent
AEs only.  These are defined as either: a) AEs with an observed or imputed date of AE 
onset which is on or after the date of 1st Randomized Dose or b) AEs with an observed 
or imputed date of AE onset which is before the date of 1st Randomized Dose and which 
worsens in intensity.  An AE with a completely missing non-imputed start date will be 
assumed to be treatment emergent unless the AE event has a complete non-imputed 
end date which is prior to the date of the 1st Randomized Dose.  In this substudy, the 
term “treatment-emergent” will always be used to mean “randomization-emergent” (it 
does not refer to the first dose of ocrelizumab treatment in the main study).
For each randomized group, the incidence count for each AE PT will be defined as the 
number of patients reporting at least one treatment-emergent occurrence of the event.  
The incidence rate will be calculated as the incidence count divided by the total number 
of patients in the population.  In some summaries, AEs will also be evaluated by 
exposure time (incidence rate per 100 patient-years (100PY) exposure), in order to 
adjust for any differences between randomized groups in the duration of observation 
period.  Estimates of incidence rates per 100PY will be provided, along with associated 
95% CIs calculated using an exact method based on the Poisson distribution.  Each 
table will also present the overall number of patients experiencing at least one AE and 
the total number of AEs reported.  Multiple occurrences of the same AE in the same 
patient will be counted only once at the greatest intensity/highest grade for this PT.  For 
AEs leading to death, the most extreme intensity will be overwritten by Grade 5 (death).
SAEs are defined as all serious AEs, including serious MS relapses and serious IRRs.
The number and percentage of patients experiencing adverse events will be presented 
by SOC and PT.  This summary will be repeated per 100PY to account for the duration 
of patient exposure.
The most frequent AEs (5% in either randomized group) will be presented by PT.
The number and percentage of patients experiencing AEs suspected to be caused by 
ocrelizumab will be presented by SOC and PT.
All AEs occurring post-randomization will be listed.
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4.5.2.4
Adverse Events by Intensity
The number and percentage of patients experiencing AEs will be presented by most 
extreme intensity by SOC and PT.  This summary will be repeated showing only AEs 
with maximum intensity of Grade 3, 4 or 5.
4.5.2.5
Deaths
All patient deaths occurring post-randomization will be listed.
4.5.2.6
Serious Adverse Events
The number and percentage of patients experiencing an SAE will be summarized by 
SOC and PT.  This summary will be repeated per 100PY to account for the duration of 
patient exposure.
The number and percentage of patients experiencing SAEs suspected to be caused by 
ocrelizumab will be presented by SOC and PT.
The number and percentage of patients experiencing SAEs will be presented by most 
extreme intensity by SOC and PT.
All SAEs occurring post-randomization will be listed.
4.5.2.7
Adverse Events Which Led to Early Discontinuation from 
Ocrelizumab Treatment
The number of patients experiencing an AE which led to early discontinuation from 
ocrelizumab treatment will be summarized by SOC and PT.
All AEs which led to early discontinuation from ocrelizumab treatment will be listed.
4.5.2.8
Adverse Events Which Led to Modification or Interruption of 
Ocrelizumab Treatment
The number of patients experiencing an AE which led to modification or interruption of 
ocrelizumab treatment will be summarized by SOC and PT.
4.5.2.9
Pregnancies
Information on pregnancy tests and pregnancy outcomes post-randomization will be 
listed.
4.5.3
Laboratory Data
4.5.3.1
Hematology and Biochemistry
All available laboratory assessments (hematology and biochemistry separately) will be 
summarized in the IA (N=400 approximately) and in the analysis of all randomized 
patients (N=650 to 700 approximately).
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To summarize laboratory data, all assessments, both scheduled and unscheduled, will 
be included.  Visit windows will be applied as follows:

Randomization: most recent available assessment prior to substudy randomization
(Substudy Day 1)

24 weeks after 1st Randomized Dose: include all assessments after substudy 
randomization (Substudy Day 2) up to 36 weeks after 1st Randomized Dose
(Substudy Day 253)

48 weeks after 1st Randomized Dose: include all assessments from the day after 36
weeks after 1st Randomized Dose (Substudy Day 254) to 60 weeks after 1st
Randomized Dose (Substudy Day 421)

72 weeks after 1st Randomized Dose: include all assessments from the day after 60 
weeks after 1st Randomized Dose (Substudy Day 422) to 84 weeks after 1st
Randomized Dose (Substudy Day 589)

96, 120, 144 etc weeks after 1st Randomized Dose: continue to define windows in 
the same way as described above
If multiple values of the same laboratory parameter occur within the same time window, 
the worst value for that parameter will be presented in the summary table.
Absolute value and change from randomization values at each visit (24 weeks after 1st
Randomized Dose, 48 weeks after 1st Randomized Dose etc.) will be summarized
(mean, SD, median, minimum and maximum).
A summary of the number and percentage of patients with single and replicated 
laboratory abnormalities will presented for each laboratory parameter.
4.5.3.2
CD4, CD8 and CD19
All available CD4, CD8 and CD19 assessments will be summarized in the IA (N=400 
approximately) and in the analysis of all randomized patients (N=650 to 700 
approximately).
Visit windows will be applied to CD4, CD8 and CD19 assessments in the same way as 
described above for hematology and biochemistry.
Summary statistics will be presented for CD19 values, separately for patients 
experiencing IRRs during/post-infusion versus patients not experiencing IRRs.  
Additionally, box plots of CD19 values versus IRR maximum intensity will be presented
(by Randomized Dose).  These are considered exploratory summaries.
Absolute value and change from randomization values at each visit (24 weeks after 1st
Randomized Dose, 48 weeks after 1st Randomized Dose etc.) will be summarized
(mean, SD, median, minimum and maximum).
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4.5.4
Vital Signs
Vital signs parameters are systolic blood pressure, diastolic blood pressure and pulse 
rate (body temperature is not included -- measurement of body temperature after the 
main study screening visit was required in earlier versions of the protocol, but in later 
versions this was only required at screening, but at any time sites could record body 
temperature for specific reasons e.g. temperature increase).
Vital signs parameters prior to start of each ocrelizumab infusion (baseline) and at 15, 
30, 45 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5 hours post start of ocrelizumab infusion
and 1 hour post end of ocrelizumab/saline infusion will be summarized (mean, SD, 
median, minimum and maximum).  The change from baseline will also be summarized 
(mean, SD, median, minimum and maximum).  Additionally, box plots of each vital signs 
parameter during the time of the infusion will be presented (by Randomized Dose).
Vital signs abnormalities are defined as follows:

Systolic blood pressure <90mmHg or >140mmHg

Diastolic blood pressure <50mmHg or >90mmHg

Pulse rate <60pm or >100bpm
The number and percentage of patients with any vital signs abnormalities and with each 
abnormality described above will be presented, for all patients, for patients experiencing 
IRRs during/post-infusion and for patients not experiencing IRRs.  These summaries will 
be presented by Randomized Dose and then by Dose within Randomized Dose (and 
overall within Randomized Dose i.e., across all Doses).
4.6
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
4.6.1
Pharmacokinetic Analyses
All summaries involving PK data will be based on the PK Population.
For all patients combined (both randomized groups), a box plot will be prepared to show 
the maximum ocrelizumab serum concentration plotted versus IRR maximum intensity 
(none, mild, moderate, severe, life-threatening and fatal) for each randomized dose.  
This plot will be repeated for conventional infusion patients only, then for shorter infusion 
patients only.
4.6.2
Pharmacodynamic Analyses
There are no pharmacodynamic endpoints in this study.
4.7
MISSING DATA
All methods for handling missing data are described above, section by section, for each 
endpoint.  These relate mostly to imputation of missing or incomplete dates.
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4.8
INTERIM ANALYSES
An interim analysis will be undertaken, as described fully in Section 1, “Background”, 
and in subsequent sections.  This is an administrative IA which will not lead to any 
changes in the substudy protocol nor the substudy SAP.  Since this is a descriptive 
analysis and no inferential analyses will be undertaken, considerations of alpha 
spending are not relevant.
5.
REFERENCES
Zhang H. Proportion difference and confidence interval based on Cochran-Mantel-
Haenszel method in stratified multi-center clinical trial. PharmaSUG China 
2016;Paper 25.
Zhao PL, Troxell JK, Quan H, et al. Confidence Interval for the Difference in Binomial 
Proportions from Stratified 2x2 Samples. Proceedings of the Annual Meeting of 
the American Statistical Association, August 5-9 2001.
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