Clinical trial NCT03606460
Conditions: Multiple Sclerosis
Sponsor: Genentech, Inc.
Start date: 2018-09-14; Completion date: 2019-05-31
Enrollment: 141 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is an open-label, non-randomized study to evaluate rate and severity of infusion-related reactions (IRRs) of ocrelizumab infused over a shorter time period than the approved administration rate in participants with PPMS or RMS in the United States (U.S.). Participants will be enrolled into two cohorts. Cohort 1 will examine the effect of administering ocrelizumab per a shorter infusion protocol for Dose 2 or Dose 3. This cohort will consist of patients who have already received one or two doses of ocrelizumab according to the approved infusion protocol (i.e., per the currently U.S. label) and have reported no serious IRRs and who will then receive the next infusion of ocrelizumab at a higher rate in order to deliver 600 mg over the course of approximately 2 hours. Cohort 2 will examine the effect of administering ocrelizumab per a shorter infusion protocol for the second infusion of Dose 1. This cohort will consist of ocrelizumab naïve patients who, after receiving Infusion 1/Dose 1 of ocrelizumab at the approved rate (300 mg over approximately 2.5 hours or longer) have no reported serious IRRs, will then receive the second 300-mg shorter infusion over approximately 1.5 hours.

Detailed description:

Arms: arm 1: This cohort will examine the effect of administering ocrelizumab per a shorter infusion protocol for Dose 2 or Dose 3. Participants who have already received one or two doses of ocrelizumab according to the approved infusion protocol and have reported no serious infusion-related reactions (IRRs) will be enrolled. They will then receive the next infusion of ocrelizumab (Dose 2 or Dose 3) at a dosage of 600 milligram (mg) over the course of approximately 2 hours. Dose 2 is administered at Week 24, Dose 3 is administered at Week 48 after initial infusion. arm 2: This cohort will examine the effect of administering ocrelizumab per a shorter infusion protocol for the second infusion of Dose 1. Ocrelizumab-naïve participants will be enrolled who, after receiving Dose 1 of ocrelizumab at the approved rate have no reported serious IRRs, will then receive the second 300-mg shorter infusion over approximately 1.5 hours.
Interventions: intervention 1: Ocrelizumab Dose 1 intervention 2: Ocrelizumab Dose 2 and Dose 3
Intervention descriptions: intervention 1: 300 mg infusion administered to ocrelizumab-naive participants per approved protocol (over approximately 2.5 hours or longer) as per standard of care followed by a second 300 mg shorter infusion over approximately 1.5 hours. intervention 2: 600 mg infusion of ocrelizumab administered at a shorter rate (i.e. over the course of approximately 2 hours) at Week 24 and at Week 48

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase IIIb, Open-Label Study to Evaluate the Safety and 
Tolerability of Shorter Infusions of Ocrelizumab in Patients With 
Primary Progressive and Relapsing Multiple Sclerosis 
NCT Number: 
NCT03606460 
Document Date: 
Protocol Version 1: 06-June-2018 
 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
Ocrelizumab—Genentech, Inc.
Protocol ML40638, Version 1
PROTOCOL
TITLE:
A PHASE IIIB, OPEN-LABEL STUDY TO EVALUATE 
THE SAFETY AND TOLERABILITY OF SHORTER 
INFUSIONS OF OCRELIZUMAB IN PATIENTS WITH 
PRIMARY PROGRESSIVE AND RELAPSING MULTIPLE 
SCLEROSIS
PROTOCOL NUMBER:
ML40638
VERSION NUMBER:
1
EUDRACT NUMBER:
Not applicable
IND NUMBER:
100593
TEST PRODUCT:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
 M.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
See electronic date stamp below
 
06-Jun-2018 21:09:48
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Ocrelizumab—Genentech, Inc.
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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 7
PROTOCOL SYNOPSIS ...................................................................................... 8
1.
BACKGROUND .......................................................................................... 13
1.1
Background on Multiple Sclerosis.......................................... 13
1.2
Background on Ocrelizumab ................................................. 13
1.3
Study Rationale and Benefit-Risk Assessment...................... 13
2.
OBJECTIVES AND ENDPOINTS ............................................................... 14
3.
STUDY DESIGN......................................................................................... 15
3.1
Description of the Study......................................................... 15
3.2
End of Study and Length of Study......................................... 16
3.3
Rationale for Study Design.................................................... 16
3.3.1
Rationale for Ocrelizumab Dose and Schedule..................... 16
4.
MATERIALS AND METHODS .................................................................... 17
4.1
Patients.................................................................................. 17
4.1.1
Inclusion Criteria.................................................................... 17
4.1.2
Exclusion Criteria................................................................... 18
4.2
Method of Treatment Assignment and Blinding..................... 20
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 20
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 20
4.3.1.1
Ocrelizumab .......................................................................... 20
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 21
4.3.3
Mandatory Premedication:  Methylprednisolone 
and Antihistaminic Drug......................................................... 23
4.3.4
Other Prophylactic Treatment................................................ 23
4.3.5
Investigational Medicinal Product Accountability ................... 24
4.3.6
Continued Access to Ocrelizumab......................................... 24
4.4
Concomitant Therapy ............................................................ 24


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4.4.1
Permitted Therapy................................................................. 24
4.4.2
Prohibited Therapy ................................................................ 25
4.5
Study Assessments ............................................................... 25
4.5.1
Informed Consent Forms and Screening Log........................ 25
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 26
4.5.3
Physical Examinations........................................................... 26
4.5.4
Vital Signs.............................................................................. 26
4.5.5
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 26
4.5.6
Safety Follow-Up Period........................................................ 27
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 27
4.6.1
Study Treatment Discontinuation........................................... 27
4.6.2
Patient Discontinuation from Study........................................ 27
4.6.3
Study Discontinuation............................................................ 28
4.6.4
Site Discontinuation............................................................... 28
5.
ASSESSMENT OF SAFETY....................................................................... 28
5.1
Safety Plan ............................................................................ 28
5.1.1
Risks Associated with Corticosteroids ................................... 28
5.1.2
Risks Associated with Antihistamines.................................... 29
5.1.3
Risks Associated with Ocrelizumab....................................... 29
5.1.3.1
Identified Risks and Adverse Drug Reactions........................ 29
5.1.3.2
Potential Risks....................................................................... 31
5.1.3.3
Management of Patients Who Experience 
Adverse Events ..................................................................... 32
5.1.3.4
Dose Modifications ................................................................ 32
5.1.3.5
Management Guidelines........................................................ 32
5.2
Safety Parameters and Definitions ........................................ 33
5.2.1
Adverse Events ..................................................................... 33
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 33
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 34


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5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 35
5.3.1
Adverse Event Reporting Period ........................................... 35
5.3.2
Eliciting Adverse Event Information....................................... 35
5.3.3
Assessment of Severity of Adverse Events ........................... 35
5.3.4
Assessment of Causality of Adverse Events ......................... 36
5.3.5
Procedures for Recording Adverse Events............................ 37
5.3.5.1
Infusion-Related Reactions.................................................... 37
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 37
5.3.5.3
Adverse Events That are Secondary to Other 
Events.................................................................................... 38
5.3.5.4
Persistent or Recurrent Adverse Events................................ 38
5.3.5.5
Abnormal Laboratory Values ................................................. 39
5.3.5.6
Abnormal Vital Sign Values ................................................... 39
5.3.5.7
Abnormal Liver Function Tests.............................................. 40
5.3.5.8
Deaths ................................................................................... 40
5.3.5.9
Preexisting Medical Conditions.............................................. 41
5.3.5.10
Lack of Efficacy or Worsening of Multiple 
Sclerosis................................................................................ 41
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 41
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 42
5.4.1
Emergency Medical Contacts................................................ 43
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 43
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 43
5.4.2.2
Events That Occur after Study Drug Initiation........................ 43
5.4.3
Reporting Requirements for Pregnancies.............................. 44
5.4.3.1
Pregnancies in Female Patients............................................ 44
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 44
5.5
Follow-Up of Patients after Adverse Events .......................... 45
5.5.1
Investigator Follow-Up........................................................... 45
5.5.2
Sponsor Follow-Up ................................................................ 45


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5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 45
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 46
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 46
6.1
Determination of Sample Size ............................................... 46
6.2
Summaries of Conduct of Study............................................ 48
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 48
6.4
Efficacy Analyses .................................................................. 48
6.5
Safety Analyses..................................................................... 48
7.
DATA COLLECTION AND MANAGEMENT ............................................... 49
7.1
Data Quality Assurance......................................................... 49
7.2
Electronic Case Report Forms............................................... 49
7.3
Source Data Documentation.................................................. 49
7.4
Use of Computerized Systems .............................................. 50
7.5
Retention of Records............................................................. 50
8.
ETHICAL CONSIDERATIONS.................................................................... 50
8.1
Compliance with Laws and Regulations ................................ 50
8.2
Informed Consent.................................................................. 51
8.3
Institutional Review Board or Ethics Committee.................... 52
8.4
Confidentiality........................................................................ 52
8.5
Financial Disclosure .............................................................. 53
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 53
9.1
Study Documentation ............................................................ 53
9.2
Protocol Deviations................................................................ 53
9.3
Site Inspections ..................................................................... 53
9.4
Administrative Structure......................................................... 53
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 54
9.6
Protocol Amendments ........................................................... 55


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10. REFERENCES ........................................................................................... 56
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 15
Table 2
Shorter Infusion Rates for 600-mg Ocrelizumab (Cohort 1)........ 21
Table 3
Shorter Infusion Rates for 300-mg Ocrelizumab (Cohort 2, 
Infusion 2 of Dose 1)................................................................... 22
Table 4
Guidelines for Management of Specific Adverse Events ............ 32
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 36
Table 6
Causal Attribution Guidance ....................................................... 37
Table 7
Determination of Sample Size..................................................... 47
LIST OF FIGURES
Figure 1
Study Schema:  Cohort 1............................................................ 16
Figure 2
Study Schema:  Cohort 2............................................................ 16
LIST OF APPENDICES
Appendix 1
Schedule of Activities:  Cohort 1 ................................................. 57
Appendix 2
Schedule of Activities:  Cohort 2 ................................................. 59
Appendix 3
2017 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis ..................................................................................... 61
Appendix 4
New York Heart Association Classification of 
Functional Cardiac Capacity ....................................................... 62
Appendix 5
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (PML) ...................................................... 63


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PROTOCOL ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY 
AND TOLERABILITY OF SHORTER INFUSIONS OF 
OCRELIZUMAB IN PATIENTS WITH PRIMARY 
PROGRESSIVE AND RELAPSING MULTIPLE 
SCLEROSIS 
PROTOCOL NUMBER:
ML40638
VERSION NUMBER:
1
EUDRACT NUMBER:
Not applicable
IND NUMBER:
100593
TEST PRODUCT:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
 M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to the contact provided below.
Genentech, Inc.
1 DNA Way
South San Francisco, CA 94080


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PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND 
TOLERABILITY OF SHORTER INFUSIONS OF OCRELIZUMAB IN 
PATIENTS WITH PRIMARY PROGRESSIVE AND RELAPSING 
MULTIPLE SCLEROSIS 
PROTOCOL NUMBER:
ML40638
VERSION NUMBER:
1
EUDRACT NUMBER:
Not applicable
IND NUMBER:
100593
TEST PRODUCT:
Ocrelizumab (RO4964913)
PHASE:
Phase IIIb
INDICATION:
PPMS and RMS
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the safety of administering ocrelizumab per a shorter infusion protocol 
(i.e., shorter than the currently approved U.S. labeling rate) in patients with primary progressive 
multiple sclerosis (PPMS) and relapsing multiple sclerosis (RMS).  Specific objectives and 
corresponding endpoints for the study are outlined below.
Primary Objective
Corresponding Endpoint
To evaluate the occurrence of severe 
IRRs with ocrelizumab 600 mg IV 
administered over the course of 2 
hours
Rate and frequency of NCI CTCAE v4.0 Grade 3 and 
4 IRRs in patients who receive the 600 mg shorter 
infusion
Secondary Objective
Corresponding Endpoints
To evaluate the occurrence of overall 
IRRs with ocrelizumab administered 
per a shorter infusion protocol for both 
cohorts
Rate and frequency of NCI CTCAE v4.0 Grade 14 
IRRs in patients who receive the shorter infusion for 
both cohorts
Rate and frequency of NCI CTCAE v4.0 Grade 3 
and 4 IRRs in patients who receive the 300 mg 
shorter infusion
IRRinfusion-related reaction; IVintravenous; NCI CTCAE v4.0National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0.
Study Design
Description of Study
This study is an open-label, non-randomized study to evaluate rate and severity of 
infusion-related reactions (IRRs) of ocrelizumab infused over a shorter time period than the 
approved administration rate in patients with PPMS or RMS in the U.S.  The study will have 
2 cohorts:  


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
Cohort 1 will examine the effect of administering ocrelizumab per a shorter infusion protocol
for Dose 2 or Dose 3 (Week 24 or 48 from the initial infusion).  This cohort will consist of 
patients who have already received one or two doses of ocrelizumab according to the 
approved infusion protocol (i.e., per the currently U.S. label) and have reported no serious 
IRRs and who will then receive the next infusion of ocrelizumab at a higher rate in order to 
deliver 600 mg over the course of approximately 2 hours.

Cohort 2 will examine the effect of administering ocrelizumab per a shorter infusion protocol 
for the second infusion of Dose 1.  This cohort will consist of ocrelizumab-naïve patients 
who, after receiving Infusion 1/Dose 1 of ocrelizumab at the approved rate (300 mg over 
approximately 2.5 hours or longer) have no reported serious IRRs, will then receive the 
second 300-mg shorter infusion over approximately 1.5 hours.
All patients will have two safety follow-up telephone calls:  the first within 24 hours of the 
ocrelizumab infusion and the second 30 days after their last ocrelizumab dose.  
Number of Patients
Approximately 150 patients with PPMS and RMS at approximately 5 study sites in the U.S. who 
fulfill the eligibility criteria listed below may participate in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Eligible to receive ocrelizumab per the United States Package Insert (USPI)

Able to comply with the study protocol, in the investigator’s judgment

Age 1855 years, inclusive

Have a diagnosis of PPMS or RMS, confirmed per the revised 2017 McDonald criteria 
(Thompson et al. 2017) 

Expanded Disability Status Scale (EDSS) score of 0 to 6.5, inclusive
EDSS does not need to be performed if results within 6 months are available.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year during the treatment period and for at least 6 months after the last dose of study 
treatment (per the USPI)
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).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, established hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.The 
reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Experienced serious IRR(s) (see Section 5.2.2 for seriousness criteria) for those who have 
previously received ocrelizumab 

History of life-threatening infusion reaction to ocrelizumab


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
Known presence of other neurological disorders, including but not limited to, the following:
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 central nervous system degenerative 
disorder (e.g., hereditary paraparesis; MELAS [mitochondrial myopathy, encephalopathy, 
lactic acidosis, stroke] syndrome)
Neuromyelitis optica
History or known presence of systemic autoimmune disorders potentially causing 
progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, 
Sjogren’s syndrome, Behçet’s disease)
History or known presence of sarcoidosis
History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression)
History of progressive multifocal leukoencephalopathy (PML)

Pregnancy or lactation, or intention to become pregnant during the study
Women of childbearing potential must have a negative serum or urine pregnancy test 
result prior to initiation of study drug.

Any concomitant disease that may require chronic treatment with systemic corticosteroids 
or immunosuppressants during the course of the study

Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), 
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine, and 
gastrointestinal or any other significant disease that may preclude patient from participating 
in the study

Congestive heart failure (New York Heart Association [NYHA] Class IIIIV functional 
severity)

Known active bacterial, viral, fungal, mycobacterial infection or other infection (including 
tuberculosis [TB] or atypical mycobacterial disease but excluding fungal infection of nail 
beds) or any severe episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to 
baseline visit

History of or currently active primary or secondary immunodeficiency

History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis)

History of recurrent aspiration pneumonia requiring antibiotic therapy

History of malignancy, including solid tumors and hematological malignancies, except basal 
cell, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix of the 
uterus that have been excised with clear margins

History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies

History of alcohol or drug abuse within 24 weeks prior to enrollment

Receipt of a live vaccine within 6 weeks prior to enrollment

Systemic corticosteroid therapy within 4 weeks prior to enrollment
There should be 4 weeks from last dose of systemic corticosteroid therapy prior to first 
infusion.  

Contraindications to or intolerance of oral or IV corticosteroids, including IV 
methylprednisolone (or equivalent steroid) administered according to the country label, 
including:
Psychosis not yet controlled by a treatment
Hypersensitivity to any of the constituents preceding

Treatment with alemtuzumab (Lemtrada)


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
Treatment with a B-cell targeted therapies other than ocrelizumab (e.g., rituximab, 
atacicept, belimumab, or ofatumumab)

Treatment with a drug that is experimental 

Any of the following abnormal laboratory results per local laboratory standards and 
investigator assessment.  Results should be available per medical history within 6 months 
prior to the study; otherwise, assessments should be repeated prior to Day 1:
Lymphocyte count 
CD4 count 
AST or ALT 
Platelet count 
Total neutrophil count 
Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, or 
positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA 
polymerase chain reaction [PCR]) or hepatitis C antibody (HepCAb)
End of Study
The end of this study is defined as the date when the last patient, last visit occurs. The last 
scheduled visit is 30 days after the last dose.
Length of Study
The total length of the study for both cohorts is up to approximately 8 weeks.  
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product for this study is ocrelizumab, which is approved for the 
treatment of PPMS and RMS.
Non-Investigational Medicinal Products
Premedicate with slow IV infusion of 100-mg methylprednisolone (or equivalent) completed 
approximately 30 minutes prior to each ocrelizumab infusion and with an antihistaminic drug 
(e.g., diphenhydramine) approximately 3060 minutes before each infusion of ocrelizumab to 
reduce the frequency and severity of IRRs.
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be considered
3060 minutes before ocrelizumab infusion to further reduce the frequency and severity of IRRs.
Statistical Methods
Primary Analysis
For the primary analysis, the number and proportion of patients who experience Grade 3 or 4 
IRRs following the 600 mg shorter infusion will be provided with a 2-sided 95% exact Clopper-
Pearson confidence interval (CI) of the proportion.
Determination of Sample Size  
This study will enroll approximately 150 patients.  
Based on the sample size of 100 patients in Cohort 1 and 50 patients in Cohort 2, the 95% CIs 
for some assumed Grade 3 or 4 IRRs are provided in the Determination of Sample Size table
(Table 7). 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
CI
confidence interval
CNS
central nervous system
CTCAE
Common Terminology Criteria for Adverse Events
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EDSS
Expanded Disability Status Scale
FDA
Food and Drug Administration
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
Ig
immunoglobulin
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRR
infusion-related reaction
IV
intravenous
IxRS
Interactive Voice/Web Response System
LLN
lower limit of normal
MRI
magnetic resonance imaging
MS
multiple sclerosis
NCI
National Cancer Institute
PML
progressive multifocal leukoencephalopathy 
PPMS
primary progressive multiple sclerosis
RA
rheumatoid arthritis
RMS
relapsing multiple sclerosis
RRMS
relapsing/remitting MS
SPMS
secondary progressive MS
ULN
upper limit of normal
U.S.
United States
USPI
United States Package Insert


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1.
BACKGROUND
1.1
BACKGROUND ON MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative 
disease of the central nervous system (CNS) that affects approximately 400,000 people 
in the United States (U.S.) and 2.3 million worldwide (National Multiple Sclerosis 
Society).  MS primarily affects young adults, with 70%80% of patients having an age of 
onset (i.e., initial clinical presentation to a physician) between 20 and 40 years, with 
approximately 64%70% of diagnosed patients being women (Goodin 2014).  MS is 
subcategorized into three main phenotypic disease patterns including relapsing-remitting 
MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).  
The term “RMS” (i.e., relapsing multiple sclerosis) applies to those patients with either 
RRMS or SPMS who continue to suffer relapses.  
1.2
BACKGROUND ON OCRELIZUMAB
Ocrelizumab is a recombinant humanized monoclonal antibody that selectively targets 
CD20-expressing B cells (Klein et al. 2013), which are believed to play a critical role 
in MS.    
CD20 is a cell surface antigen found on pre-B cells, mature B cells, and memory B cells,
but it is not expressed on lymphoid stem cells and plasma cells (Stashenko et al. 1980; 
Loken et al. 1987; Tedder and Engel 1994).  While ocrelizumab selectively depletes 
CD20-expressing B cells (Kappos et al. 2011), the capacity of B-cell reconstitution and 
pre-existing humoral immunity are preserved (Martin and Chan 2006; DiLillo et al. 2008).  
In addition, innate immunity and total T-cell numbers are not affected (WA21493 Clinical 
Study Report).
Ocrelizumab is indicated for the treatment of adult patients with relapsing or primary 
progressive forms of MS (United States Package Insert [USPI]). See the Ocrelizumab 
Investigator's Brochure for additional details on nonclinical and clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
This is an exploratory, open-label investigation to evaluate the rate and severity of 
infusion-related reactions (IRRs) of the ocrelizumab 600-mg infusion from the second 
treatment course onward, over the course of 2 hours instead of the currently approved
duration of 3.5 hours.  Specifically, this study will explore, for the first time, the effect of a 
shorter infusion on the rate and severity of IRRs.  Different doses of ocrelizumab have 
been studied over the years in various patient populations, showing consistently that the 
proportion of reported IRRs is dose-dependent.  However, there is no direct evidence on 
whether a shorter infusion time would pose an additional safety risk to patients.
According to the currently approved U.S. label, ocrelizumab must be administered at a 
600-mg dose through slow intravenous (IV) infusion. The first dose is given as two 
doses, separated by 14 days, and administered as two 300-mg infusions over the course 


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of 2.5 hours, while subsequent doses are given as a single 600-mg infusion over 
3.5 hours.  
The most common safety events reported with ocrelizumab are IRRs.  IRRs occur more 
frequently during the first infusion of the first dose.  The majority of IRRs (90% of 
patients reporting IRRs) were of mild to moderate intensity, and the intensity of IRRs 
decreased with subsequent dosing.  The most frequently reported IRR symptoms during 
infusion in the ocrelizumab group were pruritus, rash, throat irritation, and flushing 
(33.0%, 29.2%, 29.8%, and 16.8% of patients with IRR, respectively) (see the 
Ocrelizumab Investigator’s Brochure).  
A Phase II, parallel-group, dose-finding trial (WA21493) evaluated ocrelizumab 
compared with placebo and Avonex(interferon-β1a) in patients with RRMS for up to 
96 weeks. In this study, both the 600-mg and 1000-mg dose were administered over 
4 cycles.  After the first cycle, during which only the 600-mg dose was divided in half and
given over a 15-day interval, subsequent cycles involved administration as a single,
undivided dose.  Doses were administered over approximately 240 minutes.  The 
infusion schedule in this study shows that, both for the 600- and 1000-mg dose,
approximately 400 mg of ocrelizumab were infused within 2 to 2.5 hours.  However, in 
the remaining 1.5 to 2 hours of the infusion, only 200 mg remained to be infused for the 
lower dose, while in the 1000-mg dose, 600 mg were given within the same timeframe.  
Based on this infusion schedule, a dose/infusion rate/IRR relationship was not clearly 
observed.
The lack of dose/infusion rate/IRR relationship based on the current clinical data is 
supportive of the hypothesis that administration of ocrelizumab over a shorter infusion 
time should not pose a potential additional risk to patients in terms of increased risk of 
IRRs, but would help convenience of use and compliance for both patients and 
healthcare practices. In addition, procedures are in place to further mitigate risk of IRR,
such as a pre-treatment schedule and guidance around infusion adjustment, if required. 
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety of administering ocrelizumab per a shorter infusion 
protocol (i.e., shorter than the currently approved U.S. labeling rate) in patients with 
PPMS and RMS.  Specific objectives and corresponding endpoints for the study are 
outlined below.


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Table 1
Objectives and Corresponding Endpoints
Primary Objective
Corresponding Endpoint
To evaluate the occurrence of severe 
IRRs with ocrelizumab 600 mg IV 
administered over the course of 2 
hours
Rate and frequency of NCI CTCAE v4.0 Grade 3 and 
4 IRRs in patients who receive the 600 mg shorter 
infusion
Secondary Objective
Corresponding Endpoints
To evaluate the occurrence of overall 
IRRs with ocrelizumab administered 
per a shorter infusion protocol for both 
cohorts
Rate and frequency of NCI CTCAE v4.0 Grade 14 
IRRs in patients who receive the shorter infusion for 
both cohorts
Rate and frequency of NCI CTCAE v4.0 Grade 3 
and 4 IRRs in patients who receive the 300 mg 
shorter infusion
IRRinfusion-related reaction; IVintravenous; NCI CTCAE v4.0National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This study is an open-label, non-randomized study to evaluate rate and severity of IRRs 
of ocrelizumab infused over a shorter time period than the approved administration rate 
in patients with PPMS or RMS in the U.S.  The study will have 2 cohorts:  

Cohort 1 will examine the effect of administering ocrelizumab per a shorter infusion 
protocol for Dose 2 or Dose 3 (Week 24 or 48 from the initial infusion).  This cohort 
will consist of patients who have already received one or two doses of ocrelizumab 
according to the approved infusion protocol (i.e., per the currently U.S. label) and 
have reported no serious IRRs and who will then receive the next infusion of 
ocrelizumab at a higher rate in order to deliver 600 mg over the course of 
approximately 2 hours.

Cohort 2 will examine the effect of administering ocrelizumab per a shorter infusion 
protocol for the second infusion of Dose 1.  This cohort will consist of ocrelizumab-
naïve patients who, after receiving Infusion 1/Dose 1 of ocrelizumab at the approved 
rate (300 mg over approximately 2.5 hours or longer) have no reported serious 
IRRs, will then receive the second 300-mg shorter infusion over approximately 
1.5 hours.
All patients will have two safety follow-up telephone calls:  the first within 24 hours of the 
ocrelizumab infusion and the second 30 days after their last ocrelizumab dose.  
Figures 1 and 2 present the study overview by Cohort 1 and Cohort 2.  A schedule of 
activities is provided in Appendix 1 for Cohort 1 and Appendix 2 for Cohort 2.


 
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Figure 1 Study Schema:  Cohort 1 
 
Note:  For Cohort 1, Dose 1 will be received prior to study enrollment per standard of care.  
Day 1 may occur at Week 24 or 48, depending on the previous treatment cycle. 
 
 
Figure 2 Study Schema:  Cohort 2 
  
Note:  For Cohort 2, Day 1 of Dose 1 is per standard of care. 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs.  The 
last scheduled visit is 30 days after the last dose. 
The total length of the study for both cohorts is up to approximately 8 weeks.      
In addition, the Sponsor may decide to terminate the study at any time. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Ocrelizumab Dose and Schedule 
Although IRRs are the most frequently reported adverse event for ocrelizumab, the 
majority of these events occur with the first infusion of the first dose and decrease over 
subsequent infusions.  The majority of IRRs are mild to moderate (Grade 1 or 2) in 
severity.  Among patients with MS who did not experience an IRR with the first infusion 


 
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of ocrelizumab in clinical trials (OPERA I [Study WA21092], OPERA II [WA21093], and 
Oratorio [Study WA25046]), 20% had subsequent IRRs (Hauser et al. 2018).  The 
higher cumulative dose rate of the 1000-mg infusion in the Phase II Study WA21493 
provides relevant information suggesting that a shorter infusion can be administered in 
this population with acceptable safety outcomes.   
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 150 patients with PPMS and RMS at approximately 5 study sites in the 
U.S. who fulfill the eligibility criteria listed below may participate in this study. 
4.1.1 
Inclusion Criteria 
 
Signed Informed Consent Form 
 
Eligible to receive ocrelizumab per the USPI 
 
Able to comply with the study protocol, in the investigator’s judgment 
 
Age 1855 years, inclusive 
 
Have a diagnosis of PPMS or RMS, confirmed per the revised 2017 McDonald 
criteria (Thompson et al. 2017)  
 
Expanded Disability Status Scale (EDSS) score of 0 to 6.5, inclusive  
– 
EDSS does not need to be performed if results within 6 months are available. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 6 months after the last 
dose of study treatment (per the USPI) 
 
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). 
 
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices.The reliability of sexual abstinence should be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Experienced serious IRR(s) (see Section 5.2.2 for seriousness criteria) for those 
who have previously received ocrelizumab

History of life-threatening infusion reaction to ocrelizumab

Known presence of other neurological disorders, including but not limited to, the 
following:

History or known presence of infectious causes of myelopathy (e.g., syphilis, 
Lyme disease, human T-lymphotropic virus 1 [HTLV-1], herpes zoster 
myelopathy)

History of genetically inherited progressive CNS degenerative disorder (e.g., 
hereditary paraparesis; MELAS [mitochondrial myopathy, encephalopathy, 
lactic acidosis, stroke] syndrome)

Neuromyelitis optica

History or known presence of systemic autoimmune disorders potentially 
causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody 
syndrome, Sjogren’s syndrome, Behçet’s disease)

History or known presence of sarcoidosis

History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression)

History of progressive multifocal leukoencephalopathy (PML)

Pregnancy or lactation, or intention to become pregnant during the study
–
Women of childbearing potential must have a negative serum or urine 
pregnancy test result prior to initiation of study drug.

Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study

Significant, uncontrolled disease, such as cardiovascular (including cardiac 
arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, 
endocrine, and gastrointestinal or any other significant disease that may preclude 
patient from participating in the study

Congestive heart failure (New York Heart Association [NYHA] Class IIIIV functional 
severity)

Known active bacterial, viral, fungal, mycobacterial infection or other infection 
(including tuberculosis [TB] or atypical mycobacterial disease but excluding fungal 
infection of nail beds) or any severe episode of infection requiring hospitalization or 
treatment with IV antibiotics within 4 weeks prior to baseline visit or oral antibiotics 
within 2 weeks prior to baseline visit

History of or currently active primary or secondary immunodeficiency


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
History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, 
tuberculosis)

History of recurrent aspiration pneumonia requiring antibiotic therapy

History of malignancy, including solid tumors and hematological malignancies, 
except basal cell, in situ squamous cell carcinoma of the skin, and in situ carcinoma 
of the cervix of the uterus that have been excised with clear margins

History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies

History of alcohol or drug abuse within 24 weeks prior to enrollment

Receipt of a live vaccine within 6 weeks prior to enrollment

Systemic corticosteroid therapy within 4 weeks prior to enrollment

There should be 4 weeks from last dose of systemic corticosteroid therapy prior 
to first infusion.  

Contraindications to or intolerance of oral or IV corticosteroids, including IV 
methylprednisolone (or equivalent steroid) administered according to the country 
label, including:

Psychosis not yet controlled by a treatment

Hypersensitivity to any of the constituents preceding

Treatment with alemtuzumab (Lemtrada)

Treatment with a B-cell targeted therapies other than ocrelizumab (e.g., rituximab, 
atacicept, belimumab, or ofatumumab)

Treatment with a drug that is experimental 

Any of the following abnormal laboratory results per local laboratory standards and 
investigator assessment.  Results should be available per medical history within 6 
months prior to the study; otherwise, assessments should be repeated prior to 
Day 1:

Lymphocyte count 

CD4 count 

AST or ALT 

Platelet count 

Total neutrophil count 

Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] 
positive, or positive hepatitis B core antibody [total HBcAb] confirmed by a 
positive viral DNA polymerase chain reaction [PCR]) or hepatitis C antibody 
(HepCAb)


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study in which all patients will receive ocrelizumab.  Patients 
meeting the eligibility criteria for the study will be enrolled into either Cohort 1 or 
Cohort 2.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is ocrelizumab, which is 
approved for the treatment of PPMS and RMS.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Ocrelizumab
Ocrelizumab is a liquid formulation containing 30-mg/mL ocrelizumab in 20 mM sodium 
acetate at pH 5.3, with 4% trehalose dihydrate and 0.02% polysorbate 20.  The drug 
product is a single-use liquid formulation in a 15-cc, type I USP, glass vial fitted with a 
20-mm, fluoro-resin, laminated stopper and an aluminum seal with a flip-off plastic cap
and contains a nominal 300 mg ocrelizumab.  No preservative is used as each vial is 
designed for single use.
The ocrelizumab drug product must be diluted before administration.  Solutions of 
ocrelizumab for IV administration are prepared by dilution of the drug product into an 
infusion bag containing 0.9% sodium chloride to a final drug concentration of 1 to 
2 mg/mL.
Ocrelizumab may contain fine translucent and/or reflective particles associated with 
enhanced opalescence.  Do not use the solution if discolored or if the solution contains 
discrete foreign particulate matter.
Administer the diluted infusion solution through a dedicated line using an infusion set 
with a 0.2 or 0.22 micron in-line filter.
The infusion solution must be administered using an infusion set with an in-line, sterile, 
non-pyrogenic, low-protein-binding filter (pore size of up to 0.2 micrometer).
The prepared infusion solution of ocrelizumab is physically and chemically stable for 
24 hours at 28C and subsequently 8 hours at room temperature.  The prepared 
infusion solution should be used immediately.  If not used immediately, it can be stored 
up to 24 hours at 28C.  Infusion solution must be completely administered to the 
patient within 32 hours of preparation (not exceeding 24 hours at 28C and 8 hours at 
room temperature). In the event an IV infusion cannot be completed the same day, the 
remaining solution should be discarded.
For information on the formulation and handling of ocrelizumab, see the Ocrelizumab
Investigator's Brochure.


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4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimen is summarized in Section 3.1.  
Patients in Cohort 1 will receive 600-mg IV ocrelizumab per a shorter infusion protocol 
for Dose 2 or Dose 3.  After their infusion, patients in Cohort 1 will have a brief telephone 
interview within 24 hours of the infusion to assess patient status.  Patients will then 
continue to Safety Follow-up 30 days after their last dose of ocrelizumab and complete 
the study.  
Patients in Cohort 2 will receive Dose 1 of ocrelizumab as 2 split 300-mg IV infusions 
14 days apart.  The first infusion will be administered per the U.S. label; the second 
infusion will be administered per a shorter infusion protocol.  Patients will have a 
telephone call within 24 hours of infusion and then continue to Safety Follow-up 30 days 
after their last dose and complete the study.  
For shorter infusion rates, see Table 2 and Table 3 below.
Table 2
Shorter Infusion Rates for 600-mg Ocrelizumab (Cohort 1)
Time (min)
Infusion rate
(mL/hr)
Infusion rate
(mg/hr)
Max Dose per 
Interval  (mg)
Cumulative 
Dose
(mg)
015
100
120
30
30
1530
200
240
60
90
3060
250
300
150
240
6090
300
360
180
420
90120
300
360
180
600
Infusion time:  120 min.  
Preparation per U.S. label:  600 mg ocrelizumab/500 mL normal saline toward a drug 
concentration of approximately 1.2 mg/mL.


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Table 3
Shorter Infusion Rates for 300-mg Ocrelizumab (Cohort 2, 
Infusion 2 of Dose 1)
Time (min)
Infusion rate
(mL/hr)
Infusion rate
(mg/hr)
Max Dose per 
Interval  (mg)
Cumulative 
Dose
(mg)
015
100
120
30
30
1530
100
120
30
60
3060
200
240
120
180
6090
200
240
120
300
Infusion time:  90 min.  
Preparation per U.S. label:  300 mg ocrelizumab/250 mL normal saline toward a drug 
concentration of approximately 1.2 mg/mL.
Although ocrelizumab may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator.  Ocrelizumab infusions 
should always be administered in a hospital or clinic environment under close 
supervision of the investigator or a medically qualified staff member.  
To reduce potential IRRs, all patients will receive prophylactic treatment with 100 mg of 
methylprednisolone (or equivalent steroid), to be completed approximately 30 minutes 
before the start of each ocrelizumab infusion, and with an antihistaminic drug (e.g., 
diphenhydramine) approximately 3060 minutes before each ocrelizumab infusion.
Refer to Section 5.1.1 and Section 5.1.2 for the risks associated with these mandatory 
premedications.
It is also strongly recommended that the infusion is accompanied by prophylactic 
treatment with an analgesic/antipyretic such as acetaminophen/paracetamol (1 g) 
3060 minutes prior to the start of an infusion to reduce potential IRRs.  
Since transient hypotension may occur during ocrelizumab infusion, the investigator may 
wish to withhold anti-hypertensive medications 12 hours prior to ocrelizumab infusion. 
Ocrelizumab must not be administered as an IV push or bolus.  Well-adjusted infusion 
pumps should be used to control the infusion rate, and ocrelizumab should be infused 
through a dedicated line.  It is important not to use evacuated glass containers, which 
require vented administration sets, to prepare the infusion because this causes foaming 
as air bubbles pass through the solution. 


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After completion of the infusion, the IV cannula should remain in situ for at least 1 hour 
to allow for administration of drugs intravenously, if necessary, in the event of a delayed 
reaction.  If no adverse events occur during this period of time, the IV cannula may be 
removed and the patient may be discharged.
See the Ocrelizumab Investigator’s Brochure for detailed instructions on drug 
preparation, storage, and approved administration.
Because of possible need to vary infusion rates depending on tolerance of the infusion,
the total infusion time may exceed the time stated. Unless an IRR occurs 
necessitating discontinuation, the entire contents of the infusion bag must be 
administered to the patient.
Guidelines for treatment discontinuation are provided in Section 4.6.1.
Any overdose or incorrect administration of ocreliuzmab should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.3.4.
4.3.3
Mandatory Premedication:  Methylprednisolone and 
Antihistaminic Drug
Premedicate with slow IV infusion of 100-mg methylprednisolone (or equivalent) 
completed approximately 30 minutes prior to each ocrelizumab infusion and with an 
antihistaminic drug (e.g., diphenhydramine) approximately 3060 minutes before each 
infusion of ocrelizumab to reduce the frequency and severity of IRRs.
Any overdose or incorrect administration of methylprednisolone should be reported as 
adverse events on the Adverse Event eCRF page.  Adverse events associated with an 
overdose or incorrect administration of methylprednisolone or antihistamine should be 
recorded as “Overdose or Incorrect Administration of Methylprednisolone or 
Antihistamine” on the Adverse Event eCRF as the primary adverse event without the 
signs and symptoms associated with it.
4.3.4
Other Prophylactic Treatment
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be 
considered 3060 minutes before ocrelizumab infusion to further reduce the frequency 
and severity of IRRs.


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4.3.5
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (ocrelizumab) may be provided by the 
Sponsor where required by patient/site.  The study site will acknowledge receipt of IMPs
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.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log or in an IxRS, as required.
4.3.6
Continued Access to Ocrelizumab
Ocrelizumab is commercially available in the U.S. where this study is being conducted.
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMP (ocrelizumab) or any other study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing ocrelizumab in accordance with the Roche Global Policy 
on Continued Access to Investigational Medicinal Product, available at the following Web 
site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 4 weeks prior to initiation of 
study drug 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
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Maintenance therapy


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
Anti-hypertensive medications  

Since transient hypotension may occur during ocrelizumab infusion, the 
investigator may wish to withhold anti-hypertensive medications 12 hours prior 
to ocrelizumab infusion.

Corticosteroids
–
Patients who experience a relapse may receive treatment with IV or oral 
corticosteroids, if judged to be clinically appropriate by the investigator. Such 
patients should not discontinue study treatment solely based on the occurrence 
of a relapse, unless the patient or investigator feels he or she has met the 
criteria for withdrawal (Section 4.6.2).
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience infusion-
associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or 
equivalent medications per local standard practice.  Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with supportive therapies 
as clinically indicated (e.g., supplemental oxygen and 2-adrenergic agonists).
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited during the program and for at least 7 days 
prior to initiation of ocrelizumab, unless otherwise specified below:

Therapies for MS (see Section 4.1.2 for restrictions prior to initiation of ocrelizumab) 
other than systemic corticosteroids

Immunosuppressants, lymphocyte-depleting agents, or lymphocyte-trafficking 
blockers while patient is B-cell depleted
See the Ocrelizumab Investigator’s Brochure for a more detailed safety profile.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1 for 
Cohort 1 and Appendix 2 for Cohort 2.  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 (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 


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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
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
will be recorded at baseline.  In addition, all medications (e.g., prescription drugs, over-
the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by the patient within 4 weeks prior to initiation of study treatment will be recorded.  
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A physical examination per standard of care will be conducted at the screening visit.  
Any abnormality identified at baseline should be recorded on the eCRF.  New or 
worsened clinically significant abnormalities should be recorded as adverse events, if 
appropriate.
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.
4.5.4
Vital Signs
Vital signs will include measurements of heart rate, temperature, and systolic and 
diastolic blood pressure.
Vital signs should be taken approximately 45 minutes prior to premedication.  In addition, 
vital signs should be obtained prior to the ocrelizumab infusion and then approximately 
every 15 minutes for the first hour, followed by approximately every 30 minutes until 
1 hour after the end of the infusion.  
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms.
4.5.5
Laboratory, Biomarker, and Other Biological Samples
Samples for the laboratory tests will collected on the days indicated in the schedule of 
activities.

Hematology:  CBC, including CD19, per standard of care


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
Pregnancy test  

On infusion visits, a urine pregnancy test must be performed prior to 
premedication in all women of childbearing potential.  If a urine pregnancy test 
is positive, it must be confirmed by a serum pregnancy test.  Ocrelizumab must
be withheld until pregnancy status is confirmed.
4.5.6
Safety Follow-up Period
Patients who receive ocrelizumab in this study or who discontinue from treatment or the 
study early, should enter the Safety Follow-up Period and be assessed 30 days counting 
from the date of their last ocrelizumab infusion via telephone.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Immediately stop and permanently discontinue ocrelizumab if there are signs of a 
life-threatening or disabling infusion reaction 

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
4.6.2
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 withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw from the study will not be replaced.


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Ocrelizumab is not approved at the shorter infusion rate.  The safety plan for patients in 
this study is based on clinical experience with ocrelizumab in completed and ongoing 
studies.  The anticipated important safety risks for ocrelizumab are outlined below.  
Please refer to the Ocrelizumab Investigator's Brochure for a complete summary of 
safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.
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.


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5.1.2
Risks Associated with Antihistamines
The adverse reactions depend on the sedating properties of the antihistamine and 
include, but are not limited to, nausea, drowsiness, headaches, dry mouth, and allergic 
reactions such as rash.  Please refer to local prescribing information.
5.1.3
Risks Associated with Ocrelizumab
5.1.3.1
Identified Risks and Adverse Drug Reactions
5.1.3.1.1
Infusion-Related Reactions
All CD20depleting agents administered via the intravenous route, including 
ocrelizumab, have been associated with acute IRRs.  Symptoms of IRRs may occur 
during any ocrelizumab infusion, but have been more frequently reported during the first 
infusion.  Physicians should alert patients that IRRs can occur within 24 hours of the 
infusion.  These reactions may present as pruritus, rash, urticaria, erythema, throat 
irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, 
hypotension, pyrexia, fatigue, headache, dizziness, nausea, and tachycardia. 
Patients should be observed for at least one hour after the completion of the infusion for 
any symptom of IRR.  They will be informed about the possibility of delayed post-infusion 
symptoms and instructed to contact their study physician if they develop such symptoms.
Hypotension, as a symptom of IRR, may occur during ocrelizumab infusions.  Therefore, 
withholding of antihypertensive treatments should be considered for 12 hours prior to 
and throughout each ocrelizumab infusion. 
5.1.3.1.2
Infections 
Infection is an identified risk associated with ocrelizumab treatment, predominantly 
involving mild to moderate respiratory tract infections.  Non-disseminated herpes 
virus-associated infections, mostly mild to moderate, were also reported more frequently 
with ocrelizumab (approximately 5% to 6%, simplex and zoster) than with comparators 
(approximately 3%). 
During the controlled period of the pivotal trials, the proportion of RMS patients with 
serious infections was lower in the ocrelizumab group (1.3%) than in the interferon beta-
1a group (2.9%); in PPMS, the proportion of patients with serious infections was similar 
in both groups:  6.7% in the placebo group compared with 6.2% in the ocrelizumab 
group.
Serious, opportunistic, and fatal infections have occurred in patients with lupus and 
rheumatoid arthritis (RA) treated with ocrelizumab in Phase III clinical trials.  Data from 
completed studies regarding infection risks with ocrelizumab treatment in these patient 
populations are provided in the Ocrelizumab Investigator’s Brochure. 
No opportunistic infections were reported by any MS patient treated with ocrelizumab
during the controlled period of the pivotal trials. 


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There were no reports of hepatitis B reactivation in MS patients treated with ocrelizumab, 
but it had been reported in one RA patient treated with ocrelizumab.  HBV screening 
should be performed in all patients before initiation of treatment with ocrelizumab as per 
local guidelines.  Patients with active hepatitis B virus should not be treated with 
ocrelizumab.  Patients with positive serology should consult liver disease experts before 
the start of treatment and should be monitored and managed following local medical 
standards to prevent hepatitis B reactivation. 
Delay ocrelizumab administration in patients with an active infection until the infection is 
resolved.  
For PML, see Potential Risks (Section 5.1.3.2).
5.1.3.1.3
Decrease in Immunoglobulins
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins (Igs) over 
the controlled period of the studies, mainly driven by reduction in IgM, with no observed 
association with serious infections.  The proportion of patients with decrease in Igs 
below the lower limit of normal (LLN) increased over time and with successive dosing.  
Based on additional patient exposure, in cases of continuous decrease over time, a 
higher risk of serious infection cannot be ruled out (see Potential Risks, Section 5.1.3.2).
5.1.3.1.4
Delayed Return of Peripheral B Cells
Treatment with ocrelizumab leads to rapid depletion of CD19B cells in blood by 
14 days post-treatment (first timepoint of assessment) as an expected pharmacologic 
effect.  This was sustained throughout the treatment period.  The longest follow-up time 
after the last ocrelizumab infusion from Phase II Study WA21493 in 51 patients indicates 
that the median time to repletion (returned to baseline/LLN, whichever occurred first) of 
B cells was 72 weeks (range:  27175 weeks). 
5.1.3.1.5
Impaired Immunization Response 
The safety of immunization with live or live-attenuated vaccines following ocrelizumab
therapy has not been studied, and vaccination with live-attenuated or live vaccines is not 
recommended during treatment and until B-cell repletion.
After treatment with ocrelizumab over 2 years, the proportion of patients with positive 
antibody titers against S. pneumoniae, mumps, rubella, varicella were generally similar 
to the proportions at baseline.
In a randomized, open-label study, RMS patients treated with ocrelizumab were able to 
mount humoral responses, albeit decreased, to tetanus toxoid, 23-valent pneumococcal 
polysaccharide, keyhole limpet hemocyanin neoantigen, and seasonal influenza 
vaccines. It is still recommended to vaccinate patients treated with ocrelizumab with 
seasonal influenza vaccines that are inactivated.


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Physicians should review the immunization status of patients before starting treatment 
with ocrelizumab.  Patients who require vaccination should complete their immunizations
at least 6 weeks prior to initiation of ocrelizumab.  Please see the Ocrelizumab 
Investigator’s Brochure for more details.
5.1.3.2
Potential Risks 
5.1.3.2.1
Progressive Multifocal Leukoencephalopathy
PML is an important potential risk for ocrelizumab and it has only been reported with 
ocrelizumab where the risk for PML was preexisting, specifically because of prior 
natalizumab treatment.  Refer to Appendix 5 for guidance for diagnosis of PML.  Please 
see the Ocrelizumab Investigator's Brochure for more details.
5.1.3.2.2
Serious Infections Related to Decrease in Immunoglobulins
(particularly in patients previously exposed to 
immunosuppressive/immunomodulatory drugs or with 
pre-existing hypogammaglobulinemia)
Based on additional patient exposure an apparent association between sustained 
decrease in immunoglobulins (IgA, IgG, IgM) and serious infections with ocrelizumab 
treatment was observed.  However, no pattern (e.g., type of infections, safety laboratory 
abnormalities beyond the decrease in Ig, latency, duration) was found that could identify 
a subset of patients at higher risk of serious infections.
5.1.3.2.3
Hypersensitivity Reactions 
No hypersensitivity reactions to ocrelizumab were reported in the controlled clinical trials. 
Hypersensitivity may be difficult to distinguish from IRRs in terms of symptoms.  A 
hypersensitivity reaction may present during any infusion, although typically would not 
present during the first infusion.  For subsequent infusions, more severe symptoms than 
previously experienced, or new severe symptoms, should prompt consideration of a 
potential hypersensitivity reaction.  If a hypersensitivity reaction is suspected during 
infusion, the infusion must be stopped immediately and permanently.  Patients with 
known IgE-mediated hypersensitivity to ocrelizumab must not be treated.
5.1.3.2.4
Malignancies including Breast Cancer
An increased risk of malignancy with ocrelizumab may exist.  In controlled trials in adults 
with multiple sclerosis, malignancies, including breast cancer, occurred more frequently 
in ocrelizumab-treated patients.  Breast cancer occurred in 6 of 781 females treated with 
ocrelizumab and none of 668 females treated with Rebifor placebo.  Patients should 
follow standard breast cancer screening as per local guidelines.  Please see the 
Ocrelizumab Investigator's Brochure for more details. 
5.1.3.2.5
Neutropenia
In the controlled treatment period, decreased neutrophils were observed in 12% and 15% 
of MS patients treated with ocrelizumab in PPMS and RMS, respectively.  Most were 


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mild to moderate in severity, and approximately 1% of the patients had Grade 3 or 4 
neutropenia; and no temporal association with infections was identified.  
Detailed information for all risks can be found in the current Ocrelizumab Investigator’s 
Brochure.
5.1.3.3
Management of Patients Who Experience Adverse Events
Guidelines for management of specific adverse events are outlined in Table 4.  
Additional guidelines are provided in the subsections below.
5.1.3.4
Dose Modifications
Slowing of the infusion rate or interruption of the infusion may be necessary in the event 
of an infusion reaction.  In rare patients, ocrelizumab treatment may need to be 
discontinued. Guidance is provided in Section 5.1.3.3.
5.1.3.5
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 4.  
Table 4
Guidelines for Management of Specific Adverse Events
Event
Action to Be Taken
Mild to moderate IRR

If the event that a patient experiences is a mild to moderate IRR 
(e.g. headache), the infusion rate should be reduced to half the 
rate at the time of the event.

This reduced rate should be maintained for at least 30 minutes.  
If tolerated, the infusion rate may then be increased according to 
the patient’s initial infusion schedule.
Severe IRR (or complex of 
flushing, fever, and throat 
pain)

If a patient experiences a severe IRR or a complex of flushing, 
fever, and throat pain symptoms, the infusion should be 
interrupted immediately and the patient should receive 
symptomatic treatment.

The infusion should be restarted only after all symptoms have 
resolved.

The initial infusion rate at restart should be half of the infusion 
rate at the time of onset of the reaction.
Life-threatening or 
disabling IRR (e.g., 
anaphylaxis)

Immediately stop ocrelizumab if there are signs of a 
life-threatening or disabling IRR during an infusion, such as 
acute hypersensitivity or acute respiratory distress syndrome.

The patient should receive appropriate treatment.

Permanently discontinue ocrelizumab in these patients.
IRRinfusion-related reaction.


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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 5.2.2.
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)

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)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
–
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see
Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 30 days 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.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 5
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 6):

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 
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Table 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as "systemic reaction." Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
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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 timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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


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


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If the death is attributed to progression of MS, "Multiple Sclerosis Progression" should be 
recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Multiple Sclerosis
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  If there is any uncertainty 
as to whether an event is due to disease progression, it should be reported as an 
adverse event, per standard of care.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

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.
–
Cholecystectomy for gallstones and diagnostic testing

Hospitalization to receive trial medication, such as infusions of ocrelizumab, unless 
this is prolonged (more than 24 hours)

Hospitalization following an MS relapse as long as the reason for hospitalization is 
to receive standard treatment with IV methylprednisolone


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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
5.4
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 Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/Ethics 
Committee (EC).


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Genentech Medical Monitor contact information:
Medical Monitors:
 M.D. (Primary)
(
 USA)
 M.D., Ph.D. (Secondary)
(
, USA)
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 30 days after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system.
In the event that the EDC system is unavailable, the 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 30 days after the last dose 
of study treatment are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 30 days after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
–
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with ocrelizumab, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "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.


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Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria, 
the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).  Adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
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, email, 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 
30 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 


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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, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Ocrelizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
Refer to the Ocrelizumab Investigator’s Brochure for a list of serious adverse drug 
reactions.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
This study will enroll approximately 150 patients.  
Based on the sample size of 100 patients in Cohort 1 and 50 patients in Cohort 2, the 95% 
confidence intervals (CIs) for some assumed Grade 3 or 4 IRRs are provided in the table 
below.


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Table 7
Determination of Sample Size
Sample Size
Number of Pts 
with Grade 3 or 
4 IRRs
P (%)
Exact LCL (%)
Exact UCL (%)
50
1
2
0.05
10.65
50
2
4
0.49
13.71
50
3
6
1.25
16.55
50
4
8
2.22
19.23
50
5
10
3.33
21.81
50
6
12
4.53
24.31
50
7
14
5.82
26.74
50
8
16
7.17
29.11
50
9
18
8.58
31.44
100
1
1
0.03
5.45
100
2
2
0.24
7.04
100
3
3
0.62
8.52
100
4
4
1.10
9.93
100
5
5
1.64
11.28
100
6
6
2.23
12.60
100
7
7
2.86
13.89
100
8
8
3.52
15.16
100
9
9
4.20
16.40
150
1
0.67
0.02
3.66
150
2
1.33
0.16
4.73
150
3
2
0.41
5.73
150
4
2.67
0.73
6.69
150
5
3.33
1.09
7.61
150
6
4
1.48
8.50
150
7
4.67
1.90
9.38
150
8
5.33
2.33
10.24
150
9
6
2.78
11.08
IRRinfusion-related reaction; LCLlower confidence limit; UCLupper confidence limit based on 
95% confidence interval.


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6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, infusion experience, discontinuation, and completion of the study will be 
summarized.  Patient disposition and the incidence of treatment discontinuation for 
reasons other than disease progression will be tabulated.  Major protocol violations, 
including violations of inclusion/exclusion criteria, will also be summarized.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Patients’ demographics, medical history, and neurological examination will be 
summarized.  MS disease history (duration since MS first symptom, duration since MS 
diagnosis), MS disease status (MS treatment naïve or experienced), and MS prior 
treatment (for those being treated) will be summarized.  
6.4
EFFICACY ANALYSES
Not applicable.
6.5
SAFETY ANALYSES
Safety analyses will include all patients who received at least one dose of study 
treatment. 
For the primary analysis, the number and proportion of patients who experience Grade 3 
or 4 IRRs following the 600-mg shorter infusion will be provided with a 2-sided 95% 
exact Clopper-Pearson CI of the proportion. 
For secondary analyses, the number and proportion of patients who experience 
Grade 14 IRRs following the 600-mg shorter infusion and the number and proportion of 
patients who experience Grade 3 or 4 IRRs following the 300-mg shorter infusion will be 
provided with a 2-sided 95% exact Clopper-Pearson CI of the proportion.
The number and proportion of patients who require slowing, interruption, or stopping of 
ocrelizumab due to IRRs following the 300-mg or 600-mg shorter infusion will be 
provided with a 2-sided 95% exact Clopper-Pearson CI of the proportion.
All adverse events occurring on or after treatment will be coded, summarized by 
NCI CTCAE v4.0 grade, and tabulated by body system and Preferred Term for individual 
adverse events within each body system.  Grade 3 to 5 adverse events, serious adverse 
events, adverse events leading to treatment discontinuation, time to withdrawal from the 
study due to an adverse event, adverse events leading to infusion adjustment, and 
treatment-related adverse events will be summarized.  In addition, all serious adverse 
events and deaths will be listed.
Associated laboratory parameters, such as hepatic function, renal function, and 
hematology values, will be grouped and presented together.  Marked abnormalities will 
also be flagged.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
Study data will be collected in an EDC system. The Sponsor will be responsible for the 
management of all data collected during this study.  Ongoing quality review and 
oversight will be performed.  In the event of discrepant data, the Sponsor will request 
data clarification from the sites, who will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checks to be performed on the data.  
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and be provided access to study specific eCRF completion.  eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data review and to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 


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entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
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 (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 


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Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
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.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.


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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 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication (see
Section 9.5).


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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.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.


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Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests,), as specified in Section 4.5.  Accredited local 
laboratories will be used for routine monitoring; local laboratory ranges will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
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.


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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
Clinical Study Report for WA21493: Phase II, multicenter, randomized, parallel-group, 
partially blinded, placebo and Avonexcontrolled dose finding study to evaluate 
the efficacy as measured by brain MRI lesions, and safety of 2 dose regimens of 
ocrelizumab in patients with RRMS. Report No. 1034917, November 2012.
DiLillo DJ, Hamaguchi Y, Ueda Y, et al. Maintenance of long-lived plasma cells and 
serological memory despite mature and memory B cell depletion during CD20 
immunotherapy in mice. J Immunol 2008;180:361371.
Goodin DS. The epidemiology of multiple sclerosis: insights to disease pathogenesis. 
Handb Clin Neurol 2014;122:231266.
Hauser SL, de Seze J, Kappos L. Ocrelizumab safety in patients with multiple sclerosis: 
updated analyses with a focus on infusion-related reactions [poster]. Presented at 
the 3rd annual Americas Committee for Treatment and Research in Multiple 
Sclerosis (ACTRIMS) Forum; San Diego, CA, USA; February 13, 2018.
Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple 
sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 
2011;378:17791787.
Klein C, Lammens A, Schafer W, et al. Epitope interactions of monoclonal antibodies 
targeting CD20 and their relationship to functional properties. MAbs 2013;5:2233.
Loken MR, Shah VO, Dattilio KL, et al. Flow cytometric analysis of human bone marrow. 
II. Normal B lymphocyte development. Blood 1987;70:13161324.
Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic.
Annu Rev Immunol 2006;24:467496.
National Multiple Sclerosis Society. Multiple Sclerosis FAQs. Discover more about 
Multiple Sclerosis. Available at: http://www.nationalmssociety.org/What-is-MS/MS-
FAQ-s. Accessed October 29, 2015.
Stashenko P, Nadler LM, Hardy R, et al. Characterization of a human B lymphocyte-
specific antigen. J Immunol 1980;125:16781685.
Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. 
Immunol Today 1994;15:450454.
Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 
revisions of the McDonald criteria. Lancet Neurol 2018;17(2):162173.


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Appendix 1
Schedule of Activities:  Cohort 1
Screening 
(Up to 28 days 
prior to Day 1)
Treatment Visit 
(Day 1) a
Telephone Call 
(24 hours after 
infusion)
Safety Follow-up
(Day 30) b
Informed consent c
x
Medical history and demographic data d
x
Review inclusion and exclusion criteria
x
Physical examination e
x
Vital signs f
x
EDSS 
(x) g
Hematology
x
Pregnancy test h
x
Adverse event assessment i
x
x
Concomitant treatment review
x
x
x j
Methylprednisolone and antihistamine premedication k
x
Ocrelizumab administration
x l
eCRFelectronic Case Report Form; EDSSExpanded Disability Status Scale; IRRinfusion-related reaction; IVintravenous.
a   Day 1 may occur at Week 24 or 48, depending on the previous treatment cycle.
b Patients who receive ocrelizumab in this study or who discontinue from treatment or the study early, should enter the Safety Follow-up 
Period and be assessed 30 days counting from the date of their last ocrelizumab infusion via telephone.  
c Written informed consent will be obtained from all patients in order to be eligible for the study and prior to any study procedures.
d Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 4 weeks prior to the 
visit.  Demographic data will include age, sex, and self‑reported race/ethnicity.
e A physical examination may be conducted, per standard of care.  Any abnormality identified should be recorded on the eCRF.  New or 
worsened clinically significant abnormalities should be recorded as adverse events, if appropriate.


Appendix 1 (cont.)
Schedule of Activities:  Cohort 1
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f
Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, and temperature.  Vital signs should be taken 
approximately 45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the 
ocrelizumab infusion then approximately every 15 minutes for the first hour, followed by approximately every 30 minutes until 1 hour after the 
end of the infusion.  
g   EDSS does not need to be performed if results within 6 months are available. 
h   On infusion visits, a urine pregnancy test must be performed prior to premedication in all women of childbearing potential.  If a urine
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Ocrelizumab must be withheld until pregnancy status is 
confirmed.
i
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, discontinuation of medications) should be reported.  After initiation of study drug, 
related serious adverse events must be collected and reported regardless of the time elapsed from the last study drug administration, even if 
the study has been closed.  Unrelated serious adverse events must be collected and reported during the study and Safety Follow-up. 
Non-serious adverse events have to be reported until the end of Safety Follow-up.  
j
Medications used after treatment discontinuation should be recorded during Safety Follow-up.
k All patients must receive prophylactic treatment with 100 mg methylprednisolone (or equivalent), to be completed approximately 30 minutes 
before the start of each ocrelizumab infusion, and with an antihistaminic drug (e.g., diphenhydramine) approximately 3060 minutes before 
each infusion of ocrelizumab.  Prophylactic treatment with an analgesic/antipyretic (e.g., 1 g acetaminophen) is strongly recommended 
3060 minutes prior to the start of ocrelizumab infusion to reduce the risk of IRRs.
l  Ocrelizumab will be administered as one 600-mg IV infusion over the course of approximately 2 hours (shorter infusion) for Infusion 2 or 3, 
depending on how many prior doses the patient has received.


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Appendix 2
Schedule of Activities:  Cohort 2
Screening
(Up to 28 days 
prior to Day 1)
Treatment
Visit 
(Day 15)
Telephone Call 
(24 hours after 
infusion)
Safety 
Follow-up
(Day 30) a
Informed consent b
x
Medical history and demographic data c
x
Review inclusion and exclusion criteria
x
Physical examination d
x
Vital signs e
x
EDSS 
(x) f
Hematology
x
Pregnancy test g
x
Adverse event assessment h
x
x
Concomitant treatment review
x
x
x i
Methylprednisolone and antihistamine premedication j
x
Ocrelizumab administration
x k


Appendix 2 (cont.)
Schedule of Activities:  Cohort 2
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eCRFelectronic Case Report Form; EDSSExpanded Disability Status Scale; IRRinfusion-related reaction; IVintravenous.
a Patients who receive ocrelizumab in this study or who discontinue from treatment or the study early, should enter the Safety Follow-up Period 
and be assessed 30 days counting from the date of their last ocrelizumab infusion via telephone.  
b Written informed consent will be obtained from all patients in order to be eligible for the study and prior to any study procedures.
c Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 4 weeks prior to the 
visit.  Demographic data will include age, sex, and self‑reported race/ethnicity.
d A physical examination may be conducted, per standard of care.  Any abnormality identified should be recorded on the eCRF.  New or 
worsened clinically significant abnormalities should be recorded as adverse events, if appropriate.
e Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, and temperature.  Vital signs should be taken 
approximately 45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the 
ocrelizumab infusion then approximately every 15 minutes for the first hour, followed by approximately every 30 minutes until 1 hour after the 
end of the infusion.  
f EDSS does not need to be performed if results within 6 months are available. 
g On infusion visits, a urine pregnancy test must be performed prior to premedication in all women of childbearing potential.  If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test.  Ocrelizumab must be withheld until pregnancy status is confirmed.
h After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, discontinuation of medications) should be reported.  After initiation of study drug, 
related serious adverse events must be collected and reported regardless of the time elapsed from the last study drug administration, even if 
the study has been closed.  Unrelated serious adverse events must be collected and reported during the study and Safety Follow-up. 
Non-serious adverse events have to be reported until the end of Safety Follow-up.  
i
Medications used after treatment discontinuation should be recorded during Safety Follow-up.
j
All patients must receive prophylactic treatment with 100 mg methylprednisolone (or equivalent), to be completed approximately 30 minutes 
before the start of each ocrelizumab infusion, and with an antihistaminic drug (e.g., diphenhydramine) approximately 3060 minutes before 
each infusion of ocrelizumab.  Prophylactic treatment with an analgesic/antipyretic (e.g., 1 g acetaminophen) is strongly recommended 3060 
minutes prior to the start of ocrelizumab infusion to reduce the risk of IRRs.
k Ocrelizumab will be administered as a split infusion for Dose 1:  300-mg IV per standard of care for Infusion 1 and 300-mg IV over the course of 
approximately 1.5 hours (shorter infusion) for Infusion 2.


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Appendix 3
2017 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis


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Appendix 4
New York Heart Association Classification of 
Functional Cardiac Capacity
Class
Description
I
No limitation:  Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation.
II
Slight limitation of physical activity:  Such patients are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitations, dyspnea, 
or angina.
III
Marked limitation of physical activity:  Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms.
IV
Inability to carry on physical activity without discomfort:  Symptoms of 
congestive heart failure are present even at rest.  With any physical 
activity, increased discomfort is experienced.
From:  Criteria Committee, New York Heart Association, Inc. Diseases of the heart 
and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, 
Brown and Co, 1964:114.


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Appendix 5
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (PML)
ACTION STEPS IF PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY (PML) IS SUSPECTED: 

If the clinical presentation is suggestive of PML, further investigations should include 
brain magnetic resonance imaging (MRI) evaluation as soon as possible.  If MRI 
evaluation reveals lesions suspicious for PML (see Figure 1), a lumbar puncture 
with evaluation of the cerebrospinal fluid (CSF) for the detection of JC virus (JCV) 
DNA using a validated assay should be undertaken.  A diagnosis of PML can 
potentially be made by evaluating clinical and MRI findings plus the identification of 
JCV in the CSF. 

There is no known treatment or cure for PML.  Treatment considerations are 
discussed in the medical literature (Calabrese et al. 2007).
MRI ASSESSMENT 

Although there are no pathognomonic findings that differentiate PML from MS, a 
brain MRI scan that includes fluid-attenuated inversion recovery (FLAIR) and 
T2-weighted and T1-weighted sequences, with and without gadolinium, should be 
performed to assess patients with neurological changes suggestive of PML (see 
Figure 1). 

Comparison with a baseline scan may assist with interpretation of the findings on 
the newly acquired MRI (see Table 2 for differences in lesion characteristics that 
may help differentiate between PML and multiple sclerosis [MS]). 
CSF ASSESSMENT 

The detection of JCV DNA in the CSF of a patient with clinical and MRI features 
suggestive of PML establishes the diagnosis of PML. 

If JCV DNA is not detected in CSF and if clinical suspicion of PML remains high, a 
repeat lumbar puncture should be performed. 

If diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy 
may be considered to establish a definitive diagnosis.


Appendix 5
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (PML).(cont.)
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CSFcerebrospinal fluid; JCVJC virus; MRImagnetic resonance imaging; MS multiple 
sclerosis; PMLprogressive multifocal leukoencephalopathy.
Table 1
Source:  Kappos et al. 2007.


Appendix 5
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (PML).(cont.)
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Table 2
MRI Lesion Characteristics Typical of PML and MS
Source:  Yousry et al. 2006.

SAP_001.pdf: 
 
Official Title: 
A Phase IIIb, Open-Label Study to Evaluate the Safety and 
Tolerability of Shorter Infusions of Ocrelizumab in Patients With 
Primary Progressive and Relapsing Multiple Sclerosis 
NCT Number: 
NCT03606460 
Document Date: 
SAP Version 1: 26-June-2019 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL 
 
Approved by 
 Ph.D. on June 26, 2019 
 
CONFIDENTIAL 
 
This is a Genentech, Inc. document that contains confidential information.  Nothing herein is to be 
disclosed without written consent from Genentech, Inc. 
 
Ocrelizumab—Genentech, Inc. 
Statistical Analysis Plan ML40638 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE IIIB, OPEN-LABEL STUDY TO EVALUATE THE 
SAFETY AND TOLERABILITY OF SHORTER INFUSIONS OF 
OCRELIZUMAB IN PATIENTS WITH PRIMARY 
PROGRESSIVE AND RELAPSING MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: 
ML40638 
STUDY DRUG: 
Ocrelizumab (RO4964913) 
VERSION NUMBER: 
1 
IND NUMBER: 
100,593 
EUDRACT NUMBER: 
Not applicable 
SPONSOR: 
Genentech, Inc. 
PLAN PREPARED BY: 
 
DATE FINAL: 
26 June, 2019 
 
 
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2/Statistical Analysis Plan ML40638 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Protocol Synopsis .................................................................... 6 
2.2 
Outcome Measures ................................................................. 6 
2.2.1 
Primary Endpoint ..................................................................... 6 
2.2.2 
Secondary Endpoints .............................................................. 6 
2.2.3 
Safety Outcome Measures ...................................................... 6 
2.3 
Determination of Sample Size ................................................. 7 
2.4 
Analysis Timing ....................................................................... 8 
3. 
STUDY CONDUCT ....................................................................................... 9 
3.1 
RANDOMIZATION ISSUES .................................................... 9 
4. 
STATISTICAL METHODS ............................................................................ 9 
4.1 
Analysis Populations ............................................................... 9 
4.1.1 
Intent-to-Treat Population ........................................................ 9 
4.1.2 
Safety Population .................................................................... 9 
4.2 
Analysis of Study Conduct ..................................................... 10 
4.3 
Analysis of Treatment Group Comparability .......................... 10 
4.3.1 
Demographics and Baseline Characteristics ......................... 10 
4.3.2 
Multiple Sclerosis Disease History ......................................... 11 
4.4 
Efficacy Analysis .................................................................... 11 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 11 
4.6 
Safety Analyses ..................................................................... 11 
4.6.1 
Exposure to Study Medication ............................................... 11 
4.6.2 
Adverse Events ..................................................................... 11 
4.6.3 
Laboratory Data ..................................................................... 13 
4.6.4 
Vital Signs .............................................................................. 13 
4.6.5 
Subgroup Analyses ............................................................... 13 
4.7 
Missing data .......................................................................... 13 
4.8 
Interim Analyses .................................................................... 13 
5. 
REFERENCES ........................................................................................... 14 
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LIST OF TABLES 
Table 1 
List of Abbreviations and Definition of Terms ................................ 4 
Table 2 
Determination of Sample Size ....................................................... 8 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 15 
Appendix 2 
 Schedule of Activities:  Cohort 1 ................................................ 19 
 
 Schedule of Activities:  Cohort 2 ................................................ 21 
 
 
 
 
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Table 1 
List of Abbreviations and Definition of Terms 
 
BSOC 
body system organ class 
฀C 
Celsius 
CI 
confidence interval 
CNS 
Central Nervous System 
CTCAE 
Common Terminology Criteria For Adverse Events 
eCRF 
electronic Case Report Form 
EDSS 
Expanded Disability Status Scale 
ITT 
Intent-to-Treat 
IRR 
Infusion Related Reactions 
IV 
Intravenous 
kg 
Kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of Mercury 
MS 
Multiple Sclerosis 
NCI 
National Cancer Institute 
PPMS 
Primary Progressive Multiple Sclerosis 
PT 
Preferred Term 
RMS 
Relapsing Multiple Sclerosis 
SD 
Standard Deviation 
U.S. 
United States 
USPI 
United States Package Insert 
 
 
 
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1. 
BACKGROUND 
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative 
disease of the central nervous system (CNS) that affects approximately 400,000 people 
in the United States (U.S.) and 2.3 million worldwide (National Multiple Sclerosis 
Society).   
Ocrelizumab is a recombinant humanized monoclonal antibody that selectively targets 
CD20-expressing B cells (Klein et al. 2013), which are believed to play a critical role 
in MS. Ocrelizumab is indicated for the treatment of adult patients with relapsing or 
primary progressive forms of MS (United States Package Insert [USPI]).  See the 
Ocrelizumab Investigator's Brochure for additional details on nonclinical and clinical 
studies. 
According to the currently approved U.S. label, ocrelizumab must be administered at a 
600-mg dose through slow intravenous (IV) infusion.  The first dose is given as two 
doses, separated by 14 days, and administered as two 300-mg infusions over the course 
of 2.5 hours, while subsequent doses are given as a single 600-mg infusion over 
3.5 hours.   
The most common safety events reported with ocrelizumab are infusion related 
reactions (IRRs). IRRs occur more frequently during the first infusion of the first dose.  
The majority of IRRs (>90% of patients reporting IRRs) were of mild to moderate 
intensity, and the intensity of IRRs decreased with subsequent dosing. Different doses of 
ocrelizumab have been studied over the years in various patient populations, showing 
consistently that the proportion of reported IRRs is dose-dependent.  However, there is 
no direct evidence on whether a shorter infusion time would pose an additional safety 
risk to patients. This study will explore, for the first time, the effect of a shorter infusion 
on the rate and severity of IRRs.   
Refer to the study protocol regarding more details of the study background.  
2. 
STUDY DESIGN 
This study is an open-label, non-randomized study to evaluate rate and severity of IRRs 
of ocrelizumab infused over a shorter time period than the approved administration rate 
in patients with Primary Progressive MS (PPMS) or Relapsing MS (RMS) in the U.S.  
The study will have 2 cohorts:   
• 
Cohort 1 will examine the effect of administering ocrelizumab per a shorter infusion 
protocol for Dose 2 or Dose 3 (Week 24 or 48 from the initial infusion).  This cohort 
will consist of patients who have already received one or two doses of ocrelizumab 
according to the approved infusion protocol (i.e., per current U.S. label) and have 
reported no serious IRRs and who will then receive the next infusion of ocrelizumab 
at a higher rate in order to deliver 600 mg over the course of approximately 2 hours. 
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• 
Cohort 2 will examine the effect of administering ocrelizumab per a shorter infusion 
protocol for the second infusion of Dose 1.  This cohort will consist of ocrelizumab-
naïve patients who, after receiving Infusion 1/Dose 1 of ocrelizumab at the approved 
rate (300 mg over approximately 2.5 hours or longer) have no reported serious 
IRRs, will then receive the second 300-mg shorter infusion over approximately 
1.5 hours. 
 
All patients will have two safety follow-up telephone calls:  the first within 24 hours of the 
ocrelizumab infusion and the second 30 days after their last ocrelizumab dose.   
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Endpoint 
The primary endpoint is the rate and frequency of National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0) Grade 3 and 4 
IRRs in patients who receive the 600 mg shorter infusion. 
2.2.2 
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
• 
Rate and frequency of NCI CTCAE v4.0 Grade 1−4 IRRs in patients who receive the 
shorter infusion for both cohorts 
• 
Rate and frequency of NCI CTCAE v4.0 Grade 3 and 4 IRRs in patients who receive 
the 300 mg shorter infusion 
2.2.3 
Safety Outcome Measures 
In addition to IRRs collected as the primary and secondary endpoints, additional safety 
outcome measures of interest include the number and proportion of patients who require 
slowing down, interruption, or discontinuation of ocrelizumab due to IRRs following the 
300-mg or 600-mg shorter infusion and the following: 
• 
Count and proportion of patients who experienced 
o Treatment-emergent adverse events 
o CTCAE v4.0 Grade 3 to 5 adverse events 
o Serious treatment-emergent adverse events  
o Treatment-emergent adverse events of special interest as applicable 
o Adverse events leading to treatment discontinuation 
o Adverse events leading to withdrawal from study 
o Adverse events leading to infusion adjustment 
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o Treatment-related adverse events 
o Adverse events with fatal outcome 
• 
Summary of patients who experienced abnormalities (as appropriate), i.e., hepatic 
function, renal function and hematology values. 
• 
Descriptive statistics (n, mean, standard deviation [SD], median, min, max), 
including change from baseline analysis, of vital signs - 
o Sitting and supine diastolic blood pressure (mmHg) 
o Sitting and supine systolic blood pressure (mmHg) 
o Pulse rate (beats/minute) 
o Temperature (฀C) 
o Weight (kg) 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
This study will enroll approximately 150 patients, with 100 from Cohort 1 and 50 from 
Cohort 2. 
Based on the sample size of 100 patients in Cohort 1 and 50 patients in Cohort 2, the 95% 
confidence intervals (CIs) for some assumed Grade 3 or 4 IRRs are provided in the table 
below. 
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Table 2 
Determination of Sample Size 
Sample Size 
Number of Pts 
with Grade 3 or 
4 IRRs 
IRR Rate (%) 
Exact LCL (%) 
Exact UCL (%) 
50 
1 
2 
0.05 
10.65 
50 
2 
4 
0.49 
13.71 
50 
3 
6 
1.25 
16.55 
50 
4 
8 
2.22 
19.23 
50 
5 
10 
3.33 
21.81 
50 
6 
12 
4.53 
24.31 
50 
7 
14 
5.82 
26.74 
50 
8 
16 
7.17 
29.11 
50 
9 
18 
8.58 
31.44 
100 
1 
1 
0.03 
5.45 
100 
2 
2 
0.24 
7.04 
100 
3 
3 
0.62 
8.52 
100 
4 
4 
1.10 
9.93 
100 
5 
5 
1.64 
11.28 
100 
6 
6 
2.23 
12.60 
100 
7 
7 
2.86 
13.89 
100 
8 
8 
3.52 
15.16 
100 
9 
9 
4.20 
16.40 
150 
1 
0.67 
0.02 
3.66 
150 
2 
1.33 
0.16 
4.73 
150 
3 
2 
0.41 
5.73 
150 
4 
2.67 
0.73 
6.69 
150 
5 
3.33 
1.09 
7.61 
150 
6 
4 
1.48 
8.50 
150 
7 
4.67 
1.90 
9.38 
150 
8 
5.33 
2.33 
10.24 
150 
9 
6 
2.78 
11.08 
Pts=Patients; IRR=infusion-related reaction; LCL=lower confidence limit; UCL=upper confidence 
limit based on 95% confidence interval. 
 
2.4 
ANALYSIS TIMING 
The first 50 patients in cohort 1 were summarized for baseline characteristics and 
presented at the 2019 American Academy of Neurology (AAN) and Consortium of 
Multiple Sclerosis Centers (CMSC) 2019 congresses.  
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Final analysis will be conducted when all planned 150 patients (100 patients from Cohort 
1 and 50 patients from Cohort 2, respectively) have completed the 30-day follow-up after 
the study drug administration and the database is cleaned and locked.  
Regular safety reviews will be conducted by Data Management and the sponsor. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Not applicable. 
4. 
STATISTICAL METHODS  
This study is designed to evaluate the safety (i.e. IRRs) of ocrelizumab administered 
over a shorter time period than the approved administration rate in patients with PPMS 
or RMS in the U.S. No efficacy outcome is collected in this study.  
Descriptive statistics, i.e. frequency and proportion of patients, will be used to 
summarize the incidence of IRR events and potential incidence of modifications (i.e. 
slowing, interruption, or discontinuation) to the study drug following IRRs in respective 
study cohorts. When applicable, 95% confidence intervals (CIs) will be provided using 
exact Clopper-Pearson method for the proportion to quantify the uncertainty of the 
observed value. 
4.1 
ANALYSIS POPULATIONS 
Based on the study design and objectives, all safety analyses and exposure summaries 
will be performed using the safety population. Demographic, baseline characteristics, 
and patient disposition will be summarized using intent-to-treat (ITT) population. 
4.1.1 
Intent-to-Treat Population 
All enrolled patients will be included in the ITT population. Patients who prematurely 
withdrew from the study for any reason and who did not have any assessments for any 
reason will still be included in the ITT population. 
 
4.1.2 
Safety Population 
The safety population is defined as all enrolled patients who received any dose of study 
treatment, even if the infusion was incomplete.  
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4.2 
ANALYSIS OF STUDY CONDUCT 
Enrollment, infusion experience, discontinuation, and completion of the study will be 
summarized.  Patient disposition and the incidence of treatment discontinuation for 
reasons other than disease progression will be tabulated. Pre-infusion medications and 
concomitant medications will be summarized. Major protocol violations, including 
violations of inclusion/exclusion criteria, will be listed. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
All patients will be treated in this study and treatment group comparability is not 
applicable. Instead, analysis will be conducted by the treatment cohort.  
For continuous variables, the mean, median, SD, minimum, and maximum will be 
calculated. For categorical variables, number and percentage in each category will be 
displayed. The units/categories to be used are indicated within the brackets and 
separated by commas. 
4.3.1 
Demographics and Baseline Characteristics 
The following patient demographics and baseline characteristics will be summarized for 
the ITT population:  
• 
Age (years) 
• 
Age (years) group: (age categories ≤ 40, > 40, and age categories ≥18− <40, ≥ 
40−≤55) 
• 
Sex 
• 
Self-reported race and ethnicity 
• 
Baseline weight 
• 
EDSS score 
• 
EDSS category: (EDSS categories < 4, ≥ 4, and EDSS categories < 2.5, ≥ 2.5) 
• 
Female fertility status 
• 
MS type (RMS, PPMS) 
Demographics and baseline characteristics will be summarized further by MS diagnosis 
categories (RMS, PPMS). 
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4.3.2 
Multiple Sclerosis Disease History  
MS medical history will be summarized by system organ classes and preferred 
terms for the safety population. A listing of medical history will also be provided 
by treatment cohort. 
4.4 
EFFICACY ANALYSIS 
Not applicable. 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable. 
4.6 
SAFETY ANALYSES 
4.6.1 
Exposure to Study Medication 
Patients will receive only one infusion in this study. Patients will be considered to have 
received study medication even if the infusion was incomplete.   
Descriptive statistics (n, mean, SD, median, minimum, maximum, 25th and 75th 
percentiles) of infusion duration (hours) and actual dose administered (mg and mL) and 
count and proportion of patients by infusion duration category (hours) (≤ 1.5, >1.5 to 
≤2, >2 to ≤2.5, >2.5 to ≤3, >3) will be tabulated.   
Infusion start and stop date and time, total duration (hours), actual dose administered 
(mL), type of dose adjustment, and reason for infusion modification will be listed 
separately for all patients and for only those who experienced slowed, interrupted, or 
discontinued infusion. 
4.6.2 
Adverse Events 
Adverse event analyses will be generated by summarizing and listing treatment-
emergent adverse events only.  Treatment-emergent events are defined as those 
adverse events with an observed or imputed onset date on or after the start date of 
study treatment and up to 30 days after the last dose of study drug.  Only where the 
most extreme intensity is greater than the initial intensity will events with an onset date 
prior to the start of study treatment (and with an end date on or after the start of study 
treatment) be considered treatment-emergent.  An adverse event with a completely 
missing non-imputed start date will be assumed to be treatment-emergent unless the 
adverse event has a complete non-imputed end date that is prior to start of study 
treatment. 
 
For each adverse event recorded, the term entered by the investigator describing the 
event (the “reported term”) will be assigned a standardized term (the “preferred term” 
[PT]) based on the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0.  
All adverse events will be mapped to PTs and body system organ class (BSOC).  All 
analyses of adverse events data will be performed using the PTs unless otherwise 
specified.   
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All adverse events will be summarized by NCI CTCAE v4.0 grade, and tabulated by 
body system and PT for individual adverse events within each body system. Multiple 
occurrences of the same event within a patient will be counted once. Adverse events will 
be sorted by body system (in decreasing order of overall incidence) and then by PT (in 
decreasing order of overall incidence). 
CTCAE V4.0 Grade 3 to 5 adverse events, serious adverse events, adverse events 
leading to treatment discontinuation, adverse events leading to infusion adjustment, 
treatment-related adverse events, and adverse events with a fatal outcome will be 
summarized.  In addition, all serious adverse events and deaths will be listed as 
applicable.  Serious adverse events will be defined as all serious adverse events 
including serious IRRs. 
All IRRs will be included in the adverse event analyses.  An IRR and its corresponding 
symptoms are collected on the electronic Case Report Form (eCRF). The symptom(s) of 
an IRR and the IRR itself may be of different intensities. As other symptoms can be 
recorded as free-text on the eCRF page, symptoms will be coded using MedDRA and 
summarized by PT. 
IRRs are categorized by the time of the event occurring during the infusion and within 24 
hours of completion of the infusion. The number and percentage of patients with at least 
one IRR will be presented by cohort and infusion (patients with multiple events within an 
infusion will count only once). In addition, the total number of IRRs will be summarized 
(multiple events will be counted). The total and percentage (based on the total number of 
patients with at least one IRR) will be summarized by most extreme intensity. The 
number of patients who experienced an IRR that led to slowing down, interruption, or 
discontinuation of study drug will be summarized.  
Symptoms of IRRs and serious IRRs will also be listed. 
For the primary analysis, the number and proportion of patients who experience Grade 3 
or 4 IRRs following the 600-mg shorter infusion will be provided with a 2-sided 95% 
exact Clopper-Pearson CI of the proportion.  
For secondary analyses, the number and proportion of patients who experience 
Grade 1−4 IRRs following the 600-mg shorter infusion and the 300-mg shorter infusion, 
and the number and proportion of patients who experience Grade 3 or 4 IRRs following 
the 300-mg shorter infusion will be provided with a 2-sided 95% exact Clopper-Pearson 
CI of the proportion.  
The number and proportion of patients who require slowing, interruption, or 
discontinuation of ocrelizumab due to IRRs following the 300-mg or 600-mg shorter 
infusion will be provided with a 2-sided 95% exact Clopper-Pearson CI of the proportion.    
In addition, the number and proportion patients with local and/or systemic infusion site 
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reactions will be summarized.  Listings of infusion related reactions will be presented 
separately for all patients and for only those patients for whom the IRR led to infusion 
slowing down, interruption, and discontinuation.  
4.6.3 
Laboratory Data 
Not applicable.  
4.6.4 
Vital Signs 
Baseline, post-baseline, and change from baseline in vital signs will be summarized. 
Baseline for vital signs is defined as the last measurement prior to pre-infusion 
medication at Day 1 for both cohort 1 and cohort 2. 
4.6.5 
Subgroup Analyses 
The primary and secondary endpoints will be summarized and analyzed by subgroup of 
RMS and PPMS patients. The number and proportion of patients and associated 95% 
CIs will be presented for these analyses, if applicable.  Adverse events will be 
summarized further by RMS and PPMS patients. 
4.7 
MISSING DATA 
Missing and partial dates for adverse events and concomitant medications will be 
handled according to Roche STREAM algorithm. 
4.8 
INTERIM ANALYSES 
One planned analysis was performed for the first 50 patients in cohort 1 (see Section 
2.4). 
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5. 
REFERENCES 
Clinical Study Report for WA21493: Phase II, multicenter, randomized, parallel-group, 
partially blinded, placebo and Avonex® controlled dose finding study to evaluate 
the efficacy as measured by brain MRI lesions, and safety of 2 dose regimens of 
ocrelizumab in patients with RRMS. Report No. 1034917, November 2012.  
DiLillo DJ, Hamaguchi Y, Ueda Y, et al. Maintenance of long-lived plasma cells and 
serological memory despite mature and memory B cell depletion during CD20 
immunotherapy in mice. J Immunol 2008;180:361-371.  
Goodin DS. The epidemiology of multiple sclerosis: insights to disease pathogenesis. 
Handb Clin Neurol 2014;122:231-266.  
Hauser SL, de Seze J, Kappos L. Ocrelizumab safety in patients with multiple sclerosis: 
updated analyses with a focus on infusion-related reactions [poster]. Presented at 
the 3rd annual Americas Committee for Treatment and Research in Multiple 
Sclerosis (ACTRIMS) Forum; San Diego, CA, USA; February 1-3, 2018.  
Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: 
a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 
2011;378:1779-1787.  
Klein C, Lammens A, Schafer W, et al. Epitope interactions of monoclonal antibodies 
targeting CD20 and their relationship to functional properties. MAbs 2013;5:22-33.  
Loken MR, Shah VO, Dattilio KL, et al. Flow cytometric analysis of human bone marrow. 
II. Normal B lymphocyte development. Blood 1987;70:1316-1324.  
Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic. 
Annu Rev Immunol 2006;24:467-496.  
National Multiple Sclerosis Society. Multiple Sclerosis FAQs. Discover more about 
Multiple Sclerosis. Available at: http://www.nationalmssociety.org/What-is-
MS/MSFAQ-s. Accessed October 29, 2015.  
Stashenko P, Nadler LM, Hardy R, et al. Characterization of a human B 
lymphocytespecific antigen. J Immunol 1980;125:1678-1685.  
Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. 
Immunol Today 1994;15:450-454.  
Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 
revisions of the McDonald criteria. Lancet Neurol 2018;17(2):162-173. 
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Appendix 1  
Protocol Synopsis 
TITLE: 
AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND 
TOLERABILITY OF SHORTER INFUSIONS OF OCRELIZUMAB IN 
PATIENTS WITH PRIMARY PROGRESSIVE AND RELAPSING 
MULTIPLE SCLEROSIS  
PROTOCOL NUMBER: 
ML40638 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
100593 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
Phase IIIb 
INDICATION: 
PPMS and RMS 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
This study will evaluate the safety of administering ocrelizumab per a shorter infusion protocol 
(i.e., shorter than the currently approved U.S. labeling rate) in patients with primary progressive 
multiple sclerosis (PPMS) and relapsing multiple sclerosis (RMS).  Specific objectives and 
corresponding endpoints for the study are outlined below. 
 
Primary Objective 
Corresponding Endpoint 
• To evaluate the occurrence of severe 
IRRs with ocrelizumab 600 mg IV 
administered over the course of 2 
hours 
• Rate and frequency of NCI CTCAE v4.0 Grade 3 and 
4 IRRs in patients who receive the 600 mg shorter 
infusion 
 
Secondary Objective 
Corresponding Endpoints 
• To evaluate the occurrence of overall 
IRRs with ocrelizumab administered 
per a shorter infusion protocol for both 
cohorts 
• Rate and frequency of NCI CTCAE v4.0 Grade 1−4 
IRRs in patients who receive the shorter infusion for 
both cohorts 
• Rate and frequency of NCI CTCAE v4.0 Grade 3 
and 4 IRRs in patients who receive the 300 mg 
shorter infusion 
IRR=infusion-related reaction; IV=intravenous; NCI CTCAE v4.0=National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0. 
 
Study Design 
Description of Study 
This study is an open-label, non-randomized study to evaluate rate and severity of 
infusion-related reactions (IRRs) of ocrelizumab infused over a shorter time period than the 
approved administration rate in patients with PPMS or RMS in the U.S.  The study will have 
2 cohorts:   
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• 
Cohort 1 will examine the effect of administering ocrelizumab per a shorter infusion protocol 
for Dose 2 or Dose 3 (Week 24 or 48 from the initial infusion).  This cohort will consist of 
patients who have already received one or two doses of ocrelizumab according to the 
approved infusion protocol (i.e., per the currently U.S. label) and have reported no serious 
IRRs and who will then receive the next infusion of ocrelizumab at a higher rate in order to 
deliver 600 mg over the course of approximately 2 hours. 
• 
Cohort 2 will examine the effect of administering ocrelizumab per a shorter infusion protocol 
for the second infusion of Dose 1.  This cohort will consist of ocrelizumab-naïve patients 
who, after receiving Infusion 1/Dose 1 of ocrelizumab at the approved rate (300 mg over 
approximately 2.5 hours or longer) have no reported serious IRRs, will then receive the 
second 300-mg shorter infusion over approximately 1.5 hours. 
 
All patients will have two safety follow-up telephone calls:  the first within 24 hours of the 
ocrelizumab infusion and the second 30 days after their last ocrelizumab dose.   
Number of Patients 
Approximately 150 patients with PPMS and RMS at approximately 5 study sites in the U.S. who 
fulfill the eligibility criteria listed below may participate in this study. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Eligible to receive ocrelizumab per the United States Package Insert (USPI) 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
Age 18−55 years, inclusive 
• 
Have a diagnosis of PPMS or RMS, confirmed per the revised 2017 McDonald criteria 
(Thompson et al. 2017)  
• 
Expanded Disability Status Scale (EDSS) score of 0 to 6.5, inclusive 
EDSS does not need to be performed if results within 6 months are available. 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% 
per year during the treatment period and for at least 6 months after the last dose of study 
treatment (per the USPI) 
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). 
Examples of contraceptive methods with a failure rate of <1% per year include bilateral 
tubal ligation, male sterilization, established hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The 
reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Experienced serious IRR(s) (see Section 5.2.2 for seriousness criteria) for those who have 
previously received ocrelizumab  
• 
History of life-threatening infusion reaction to ocrelizumab 
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• 
Known presence of other neurological disorders, including but not limited to, the following: 
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 central nervous system degenerative 
disorder (e.g., hereditary paraparesis; MELAS [mitochondrial myopathy, encephalopathy, 
lactic acidosis, stroke] syndrome) 
Neuromyelitis optica 
History or known presence of systemic autoimmune disorders potentially causing 
progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, 
Sjogren’s syndrome, Behçet’s disease) 
History or known presence of sarcoidosis 
History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression) 
History of progressive multifocal leukoencephalopathy (PML) 
• 
Pregnancy or lactation, or intention to become pregnant during the study 
Women of childbearing potential must have a negative serum or urine pregnancy test 
result prior to initiation of study drug. 
• 
Any concomitant disease that may require chronic treatment with systemic corticosteroids 
or immunosuppressants during the course of the study 
• 
Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), 
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine, and 
gastrointestinal or any other significant disease that may preclude patient from participating 
in the study 
• 
Congestive heart failure (New York Heart Association [NYHA] Class III−IV functional 
severity)  
• 
Known active bacterial, viral, fungal, mycobacterial infection or other infection (including 
tuberculosis [TB] or atypical mycobacterial disease but excluding fungal infection of nail 
beds) or any severe episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to 
baseline visit 
• 
History of or currently active primary or secondary immunodeficiency 
• 
History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis) 
• 
History of recurrent aspiration pneumonia requiring antibiotic therapy 
• 
History of malignancy, including solid tumors and hematological malignancies, except basal 
cell, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix of the 
uterus that have been excised with clear margins 
• 
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies 
• 
History of alcohol or drug abuse within 24 weeks prior to enrollment 
• 
Receipt of a live vaccine within 6 weeks prior to enrollment  
• 
Systemic corticosteroid therapy within 4 weeks prior to enrollment 
There should be 4 weeks from last dose of systemic corticosteroid therapy prior to first 
infusion.   
• 
Contraindications to or intolerance of oral or IV corticosteroids, including IV 
methylprednisolone (or equivalent steroid) administered according to the country label, 
including: 
Psychosis not yet controlled by a treatment 
Hypersensitivity to any of the constituents preceding 
• 
Treatment with alemtuzumab (Lemtrada) 
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• 
Treatment with a B-cell targeted therapies other than ocrelizumab (e.g., rituximab, 
atacicept, belimumab, or ofatumumab) 
• 
Treatment with a drug that is experimental  
• 
Any of the following abnormal laboratory results per local laboratory standards and 
investigator assessment.  Results should be available per medical history within 6 months 
prior to the study; otherwise, assessments should be repeated prior to Day 1: 
Lymphocyte count  
CD4 count  
AST or ALT  
Platelet count  
Total neutrophil count  
Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, or 
positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA 
polymerase chain reaction [PCR]) or hepatitis C antibody (HepCAb) 
 
End of Study 
The end of this study is defined as the date when the last patient, last visit occurs.  The last 
scheduled visit is 30 days after the last dose. 
Length of Study 
The total length of the study for both cohorts is up to approximately 8 weeks.   
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The investigational medicinal product for this study is ocrelizumab, which is approved for the 
treatment of PPMS and RMS. 
Non-Investigational Medicinal Products 
Premedicate with slow IV infusion of 100-mg methylprednisolone (or equivalent) completed 
approximately 30 minutes prior to each ocrelizumab infusion and with an antihistaminic drug 
(e.g., diphenhydramine) approximately 30−60 minutes before each infusion of ocrelizumab to 
reduce the frequency and severity of IRRs. 
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be considered 
30−60 minutes before ocrelizumab infusion to further reduce the frequency and severity of IRRs. 
Statistical Methods 
Primary Analysis 
For the primary analysis, the number and proportion of patients who experience Grade 3 or 4 
IRRs following the 600 mg shorter infusion will be provided with a 2-sided 95% exact Clopper-
Pearson confidence interval (CI) of the proportion. 
Determination of Sample Size   
This study will enroll approximately 150 patients.   
Based on the sample size of 100 patients in Cohort 1 and 50 patients in Cohort 2, the 95% CIs 
for some assumed Grade 3 or 4 IRRs are provided in the Determination of Sample Size table 
(Table 2).  
 
 
 
 
 
 
 
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Appendix 2  
Schedule of Activities:  Cohort 1 
 
Screening  
(Up to 28 days 
prior to Day 1) 
Treatment Visit  
(Day 1) a 
Telephone Call  
(24 hours after 
infusion) 
Safety Follow-up 
(Day 30) b 
Informed consent c 
x 
 
 
 
Medical history and demographic data d 
x 
 
 
 
Review inclusion and exclusion criteria 
x 
 
 
 
Physical examination e 
x 
 
 
 
Vital signs f 
 
x 
 
 
EDSS  
(x) g 
 
 
 
Hematology 
x 
 
 
 
Pregnancy test h 
 
x 
 
 
Adverse event assessment i 
 
 
x 
x 
Concomitant treatment review 
x 
x 
 
x j 
Methylprednisolone and antihistamine premedication k 
 
x 
 
 
Ocrelizumab administration  
 
x l 
 
 
eCRF=electronic Case Report Form; EDSS=Expanded Disability Status Scale; IRR=infusion-related reaction; IV=intravenous. 
a   Day 1 may occur at Week 24 or 48, depending on the previous treatment cycle. 
b Patients who receive ocrelizumab in this study or who discontinue from treatment or the study early, should enter the Safety Follow-up 
Period and be assessed 30 days counting from the date of their last ocrelizumab infusion via telephone.   
c Written informed consent will be obtained from all patients in order to be eligible for the study and prior to any study procedures. 
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d Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 4 weeks prior to the 
visit.  Demographic data will include age, sex, and self‑reported race/ethnicity. 
e A physical examination may be conducted, per standard of care.  Any abnormality identified should be recorded on the eCRF.  New or 
worsened clinically significant abnormalities should be recorded as adverse events, if appropriate. 
f Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, and temperature.  Vital signs should be taken 
approximately 45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the 
ocrelizumab infusion then approximately every 15 minutes for the first hour, followed by approximately every 30 minutes until 1 hour after the 
end of the infusion.   
g   EDSS does not need to be performed if results within 6 months are available.  
h   On infusion visits, a urine pregnancy test must be performed prior to premedication in all women of childbearing potential.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Ocrelizumab must be withheld until pregnancy status is 
confirmed. 
i After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, discontinuation of medications) should be reported.  After initiation of study drug, 
related serious adverse events must be collected and reported regardless of the time elapsed from the last study drug administration, even if 
the study has been closed.  Unrelated serious adverse events must be collected and reported during the study and Safety Follow-up.  
Non-serious adverse events have to be reported until the end of Safety Follow-up.   
j Medications used after treatment discontinuation should be recorded during Safety Follow-up. 
k All patients must receive prophylactic treatment with 100 mg methylprednisolone (or equivalent), to be completed approximately 30 minutes 
before the start of each ocrelizumab infusion, and with an antihistaminic drug (e.g., diphenhydramine) approximately 30−60 minutes before 
each infusion of ocrelizumab.  Prophylactic treatment with an analgesic/antipyretic (e.g., 1 g acetaminophen) is strongly recommended 
30−60 minutes prior to the start of ocrelizumab infusion to reduce the risk of IRRs. 
l  Ocrelizumab will be administered as one 600-mg IV infusion over the course of approximately 2 hours (shorter infusion) for Infusion 2 or 3, 
depending on how many prior doses the patient has received.  
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Appendix 3  
Schedule of Activities:  Cohort 2 
 
Screening 
(Up to 28 days 
prior to Day 1) 
Treatment 
Visit  
(Day 15) 
Telephone Call  
(24 hours after 
infusion) 
Safety  
Follow-up 
(Day 30) a 
Informed consent b 
x 
 
 
 
Medical history and demographic data c 
x 
 
 
 
Review inclusion and exclusion criteria 
x 
 
 
 
Physical examination d 
x 
 
 
 
Vital signs e 
 
x 
 
 
EDSS  
(x) f 
 
 
 
Hematology 
x 
 
 
 
Pregnancy test g 
 
x 
 
 
Adverse event assessment h 
 
 
x 
x 
Concomitant treatment review 
x 
x 
 
x i 
Methylprednisolone and antihistamine premedication j 
 
x 
 
 
Ocrelizumab administration  
 
x k 
 
 
Clinical Study Report: Ocrelizumab — Genentech, Inc.
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Ocrelizumab—Genentech, Inc. 
22/Statistical Analysis Plan ML40638 
eCRF=electronic Case Report Form; EDSS=Expanded Disability Status Scale; IRR=infusion-related reaction; IV=intravenous. 
a Patients who receive ocrelizumab in this study or who discontinue from treatment or the study early, should enter the Safety Follow-up Period 
and be assessed 30 days counting from the date of their last ocrelizumab infusion via telephone.   
b Written informed consent will be obtained from all patients in order to be eligible for the study and prior to any study procedures. 
c Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 4 weeks prior to the 
visit.  Demographic data will include age, sex, and self‑reported race/ethnicity. 
d A physical examination may be conducted, per standard of care.  Any abnormality identified should be recorded on the eCRF.  New or 
worsened clinically significant abnormalities should be recorded as adverse events, if appropriate.  
e Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, and temperature.  Vital signs should be taken 
approximately 45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the 
ocrelizumab infusion then approximately every 15 minutes for the first hour, followed by approximately every 30 minutes until 1 hour after the 
end of the infusion.   
f  EDSS does not need to be performed if results within 6 months are available.  
g On infusion visits, a urine pregnancy test must be performed prior to premedication in all women of childbearing potential.  If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test.  Ocrelizumab must be withheld until pregnancy status is confirmed. 
h After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, discontinuation of medications) should be reported.  After initiation of study drug, 
related serious adverse events must be collected and reported regardless of the time elapsed from the last study drug administration, even if 
the study has been closed.  Unrelated serious adverse events must be collected and reported during the study and Safety Follow-up.  
Non-serious adverse events have to be reported until the end of Safety Follow-up.   
i Medications used after treatment discontinuation should be recorded during Safety Follow-up. 
j All patients must receive prophylactic treatment with 100 mg methylprednisolone (or equivalent), to be completed approximately 30 minutes 
before the start of each ocrelizumab infusion, and with an antihistaminic drug (e.g., diphenhydramine) approximately 30−60 minutes before 
each infusion of ocrelizumab.  Prophylactic treatment with an analgesic/antipyretic (e.g., 1 g acetaminophen) is strongly recommended 30−60 
minutes prior to the start of ocrelizumab infusion to reduce the risk of IRRs. 
k Ocrelizumab will be administered as a split infusion for Dose 1:  300-mg IV per standard of care for Infusion 1 and 300-mg IV over the course of 
approximately 1.5 hours (shorter infusion) for Infusion 2. 
 
 
Clinical Study Report: Ocrelizumab — Genentech, Inc.
CSR ML40638
391