A Phase IV Multicenter, Open-Label Study Evaluating B Cell Levels In Infants Potentially Exposed To Ocrelizumab During Pregnancy
Phase: PHASE4
Conditions: Multiple Sclerosis, Clinically Isolated Syndrome
Sponsor: Hoffmann-La Roche

Official Title: 
A Phase IV Multicenter, Open-Label Study Evaluating B Cell Levels in 
Infants Potentially Exposed to Ocrelizumab During Pregnancy – The 
Minore Study 
NCT Number: 
NCT04998812 
Document Date: 
Protocol Version 3: 05-Jun-2023 

CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland.  
However, it may be implemented in individual countries by Roche's local affiliates, including Genentech, 
Inc. in the United States.  The information contained in this document, especially any unpublished data, 
is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in 
confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board.  It is understood that this information will not 
be disclosed to others without written authorization from Roche except to the extent necessary to obtain 
informed consent from persons to whom the drug may be administered. 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
Protocol MN42988, Version 3 
PROTOCOL 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL
STUDY EVALUATING B-CELL LEVELS IN
INFANTS POTENTIALLY EXPOSED TO
OCRELIZUMAB DURING PREGNANCY – THE
MINORE STUDY 
PROTOCOL NUMBER: MN42988 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2021-000062-14 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998812 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
AUTHORS: 
(Medical Monitor) 
SPONSOR: 
F. Hoffmann-La Roche Ltd
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
2/Protocol MN42988, Version 3 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
3 
See electronic date 
stamp on the final 
page of this document. 
2 
31 March 2022 
1 
4 March 2021 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
3/Protocol MN42988, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol MN42988 has been primarily amended with the following key changes in 
response to the U.S. Food and Drug Administration feedback.  Changes, along with 
rationale, are summarized below. 
• 
The available evidence of pregnancy and infant outcomes in women receiving 
ocrelizumab for the treatment of multiple sclerosis (MS) has been updated to 
present data from an analysis performed with a cut-off date of 31 March 2022, 
replacing data from an analysis up to 31 March 2021 (Section 1.3). 
• 
In the endpoint for the exploratory objective “to evaluate the evolution of B-cell 
levels between birth and the first year of life”, language has been clarified that 
trajectory (absolute and percentage changes) of B-cell (CD19+  cell) levels in the 
infant will be measured from Week 6 of life to 1 month after the first or second dose 
of the measles, mumps and rubella (MMR) vaccine or Month 13 of age in case 
MMR vaccine is not planned to be administered (Section 2 [Table 1]). 
• 
The phrase “to include but not be limited to” that was used to describe the planned 
laboratory assessments has been removed and details of the assessments 
(including markers of lymphocyte subtypes [T-, B-, and NK-cells]) added (Sections 2 
[Table 1], 4.5.2.7, and 4.5.3.2 [Tables 3 and 4], and Appendix 1). 
• 
Language has been amended to remove the estimation that approximately 50% of 
enrolled women should have potential fetal exposure (i.e., received their last dose of 
ocrelizumab  < 3 months before the last menstrual period [LMP] or during the first 
trimester [up to gestational Week 13]) (Sections 3.1, 3.1.1 [Figure 1], 3.1.2, and 6.1). 
• 
The sample size has been updated from approximately 44 to approximately 
33 pregnant women with clinically isolated syndrome (CIS) or MS.  Given that 
women with CIS or MS are not routinely treated with ocrelizumab shortly before the 
LMP or during pregnancy and, therefore, represent a special population, the 
reduction in sample size increases the feasibility to conduct and conclude the study 
in a timely manner (Sections 3.1, 3.1.1 [Figure 1], 4.1 and 6.1). 
• 
It has been clarified that all visit samples to be collected during the pregnancy and 
early postpartum period may be collected by home nurse visit, to reduce patient 
burden (Section 3.1.3). 
• 
The total length of the study has been increased from approximately 25 months to 
approximately 33 months, due to the extension of the enrollment period from 
approximately 8 months to approximately 16 months (Section 3.2). 
• 
Language has been modified to clarify that relative exclusions related to 
medications is according to medication washout period (Section 4.1.2). 
• 
Rituximab has been removed from the list of medications with washout period of 
6 months and added to the list of medications with 12-month washout period 
(Section 4.1.2). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
4/Protocol MN42988, Version 3 
• 
Language has been included to detail that the Expanded Disability Status Scale 
(EDSS) assessment may also be performed by the investigator via telephone, using 
a specific licensed questionnaire that has been included in Appendix A4−2 
(Section 4.5.2.6). 
• 
The B-cell subsets that are part of the list of planned maternal laboratory 
assessments have been specified (Section 4.5.2.7 [Table 2]). 
• 
Language has been added to clarify that while vaccination schedules are not exactly 
the same from country to country, all participating countries are expected to provide 
the specific vaccines for the planned titer assessments (Section 4.5.3.2). 
• 
The list of antibody titers of responses to vaccines administered as per local practice 
has been updated to detail that the following may be included:  anti-measles 
antibody (Ab) IgG, anti-rubella Ab IgG, anti-mumps Ab IgG, PCV-13 Ab (all 
serotypes), anti-tetanus toxoid IgG, anti-diphtheria IgG, Bordetella pertussis Ab IgG, 
hepatitis B surface Ab, Hemophilus influenza B IgG (Section 4.5.3.2 [Table 4]). 
• 
A section has been added detailing how the investigator can contact Medical 
Monitors, for patient safety; subsequent sections have been renumbered 
(Section 5.1.3.2). 
• 
Due to the reduction in sample size, language has been amended to reduce the 
number of evaluable infants expected in this study from at least 40 to 
approximately 30 (Section 6.1). 
• 
The precisions (width of the two-sided 95% CIs based on normal approximation) for 
different event rates (an “event” is defined as B-cell levels below the lower limit of 
normal) presented in Table 5 have been amended for a sample size of 30; the 
precisions for a sample size of 40 infants, with a subgroup of 20 infants whose 
mothers received the last dose of ocrelizumab 0 to 3 months before the LMP or 
during the first trimester, have been removed. Additionally, language has been 
included to detail that if no event is observed from the 30 infants during the study, 
there is a 95% confidence that the event rate is below 0.114 (Section 6.1). 
• 
The population of the primary estimand has been amended to include infants 
exposed to ocrelizumab up to 6 months before the mother’s LMP or during the first 
trimester (up to gestational Week 13) of pregnancy and not exposed after the first 
trimester (infants’ full analysis set) (Section 6.4.1).  
• 
A reference to Appendix 7 (B-cell reference ranges by week of life [absolute and 
percentage counts]) has been added (Section 6.4.1). 
• 
Language has been added to detail the intercurrent events of the primary estimand 
(Section 6.4.1). 
• 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with Roche practices (Section 8.4). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
5/Protocol MN42988, Version 3 
• 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section 9.6). 
• 
The name of a Roche policy on data sharing has been corrected (Section 9.6). 
• 
The EDSS by telephone questionnaire has been included in the protocol 
(Appendix 4 [Appendix A4-2]). 
• 
An appendix detailing B-cell reference ranges by week of life (absolute and 
percentage counts) has been added (Appendix 7). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  The amendment represents cumulative 
changes to the original protocol. 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
6/Protocol MN42988, Version 3 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 22 
1.1 
Background on Multiple Sclerosis ............................................ 22 
1.2 
Background on Ocrelizumab.................................................... 23 
1.3 
Study Rationale and Benefit−Risk Assessment ....................... 23 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 26 
3. 
STUDY DESIGN ........................................................................... 29 
3.1 
Description of the Study ........................................................... 29 
3.1.1 
Overview of Study Design........................................................ 30 
3.1.2 
Screening/Baseline Period ...................................................... 33 
3.1.3 
Pregnancy and Early Postpartum Period ................................. 33 
3.1.4 
Vaccination Period ................................................................... 34 
3.1.5 
Follow-Up Visit after Early Discontinuation .............................. 35 
3.2 
End of Study and Length of Study ........................................... 35 
3.3 
Rationale for Study Design ...................................................... 35 
3.3.1 
Rationale for Ocrelizumab Dose and Schedule ....................... 37 
3.3.2 
Rationale for Patient Population .............................................. 37 
4. 
MATERIALS AND METHODS ...................................................... 38 
4.1 
Study Participants .................................................................... 38 
4.1.1 
Inclusion Criteria ...................................................................... 38 
4.1.2 
Exclusion Criteria ..................................................................... 39 
4.2 
Method of Treatment Assignment and Blinding ....................... 41 
4.3 
Study Treatment Relevant to the Study Design ....................... 41 
4.3.1 
Study Treatment Formulation and Packaging .......................... 41 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 41 
4.3.2.1 
Study Treatment ...................................................................... 42 
4.3.2.2 
Premedication .......................................................................... 42 
4.4 
Concomitant Therapy .............................................................. 42 
4.4.1 
Prohibited Therapy .................................................................. 42 

 
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4.5 
Study Assessments ................................................................. 43 
4.5.1 
Informed Consent Forms and Screening Log .......................... 43 
4.5.2 
Mother’s Assessments ............................................................. 43 
4.5.2.1 
Demographics, Medical and MS History .................................. 43 
4.5.2.2 
Physical and Obstetric Examinations ....................................... 44 
4.5.2.3 
Vital Signs ................................................................................ 44 
4.5.2.4 
Neurological Examination ........................................................ 44 
4.5.2.5 
Assessment of Relapses ......................................................... 45 
4.5.2.6 
Assessment of Disability .......................................................... 45 
4.5.2.7 
Laboratory, Biomarker, and Other Biological Samples ............ 46 
4.5.3 
Infant’s Assessments ............................................................... 48 
4.5.3.1 
Pregnancy Outcome and Infant Characteristics ....................... 48 
4.5.3.2 
Laboratory, Biomarker, and Other Biological Samples ............ 49 
4.5.4 
Infant Vaccination Schedule .................................................... 51 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 51 
4.6.1 
Study Treatment Discontinuation ............................................. 51 
4.6.2 
Discontinuation from the Study ................................................ 51 
4.6.3 
Study Discontinuation .............................................................. 52 
4.6.4 
Site Discontinuation ................................................................. 52 
5. 
ASSESSMENT OF SAFETY ......................................................... 53 
5.1 
Safety Reporting Requirements for Studied Medicinal 
Products .................................................................................. 53 
5.1.1 
Safety Parameters and Definitions .......................................... 53 
5.1.1.1 
Adverse Events ........................................................................ 53 
5.1.1.2 
Assessment of Serious Adverse Events and Non-Serious 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) and Other Non-Serious 
Adverse Events ........................................................................ 53 
5.1.2 
Methods and Timing for Capturing/Assessing 
Safety Parameters ................................................................... 55 
5.1.2.1 
Adverse Event Reporting Period .............................................. 55 
5.1.2.2 
Procedures for Recording Adverse Events .............................. 56 
5.1.3 
Reporting Requirements from HCP to Sponsor ....................... 56 
5.1.3.1 
Immediate Reporting Requirements from HCP to Sponsor ..... 56 

 
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5.1.3.2 
Medical Monitors and Emergency Medical Contacts .............. 57 
5.1.3.3 
Reporting Requirements for Non-Serious Adverse Events ...... 57 
5.1.3.4 
If EDC System Is Temporarily Unavailable .............................. 58 
5.1.3.5 
Reporting Requirements for Pregnancies, 
Abortions/Congenital Anomalies/Birth Defects ........................ 58 
5.1.4 
Follow-Up of Patients after Adverse Events............................. 59 
5.1.4.1 
Investigator Follow-Up ............................................................. 59 
5.1.4.2 
Sponsor Follow-Up .................................................................. 59 
5.2 
Safety Reporting Requirements for Non-Studied Medicinal 
products ................................................................................... 59 
5.3 
Reporting of Product Complaints without Adverse Events ....... 60 
5.4 
Expedited Reporting to Health Authorities, Physicians, 
Institutional Review Boards, and Ethics Committees ............... 60 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 61 
6.1 
Determination of Sample Size ................................................. 61 
6.2 
Summaries of Conduct of Study .............................................. 62 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 62 
6.4 
Primary Analyses ..................................................................... 62 
6.4.1 
Primary Endpoint ..................................................................... 62 
6.4.2 
Secondary Endpoints ............................................................... 63 
6.4.3 
Exploratory Endpoints .............................................................. 64 
6.4.4 
Subgroup Analyses .................................................................. 64 
6.5 
Safety Analyses ....................................................................... 64 
6.6 
Interim analysis ........................................................................ 65 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 65 
7.1 
Data Quality Assurance ........................................................... 65 
7.2 
Electronic Case Report Forms ................................................. 65 
7.3 
Source Data Documentation .................................................... 65 
7.4 
Use of Computerized Systems ................................................ 66 
7.5 
Retention of Records ............................................................... 66 
8. 
ETHICAL CONSIDERATIONS ...................................................... 67 
8.1 
Compliance with Laws and Regulations .................................. 67 
8.2 
Informed Consent .................................................................... 67 

 
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8.3 
Institutional Review Board or Ethics Committee ...................... 68 
8.4 
Confidentiality .......................................................................... 69 
8.5 
Financial Disclosure ................................................................. 69 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 70 
9.1 
Study Documentation .............................................................. 70 
9.2 
Protocol Deviations .................................................................. 70 
9.3 
Management of Study Quality .................................................. 70 
9.4 
Site Inspections ....................................................................... 70 
9.5 
Administrative Structure ........................................................... 70 
9.6 
Dissemination of Data and Protection of Trade Secrets .......... 71 
9.7 
Protocol Amendments ............................................................. 72 
10. 
REFERENCES.............................................................................. 73 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 26 
Table 2 
B-Cell Subsets ............................................................................. 48 
Table 3 
Prioritization Order for Infant Blood Sample Assessments at 
Week 6 of Life (± 7 days) ............................................................ 50 
Table 4 
Prioritization Order for Infant Blood Sample Assessments 
1 Month (+ 30 days) after First/Second Dose of MMR 
Vaccine OR at Month 13 of Age (+ 30 Days) .............................. 51 
 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design ........................................................... 31 
 
 
LIST OF APPENDICES 
 
Schedule of Assessments:  Screening through the End of 
Treatment Period ........................................................................ 79 
 
Potentially Teratogenic Drugs ..................................................... 89 
 
Guidance for Diagnosis of Progressive 
Multifocal Leukoencephalopathy ............................................... 101 
 
Expanded Disability Status Scale (EDSS) ................................ 110 

 
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Methods for Assessing and Recording Adverse Events ........... 122 
 
Time Windows for Infant Growth Velocity and Child 
Developmental Milestone Assessments ................................... 130 
 
B-cell Reference Ranges by Week of Life:  Absolute and 
Percentage Counts .................................................................... 131 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
11/Protocol MN42988, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY 
EVALUATING B-CELL LEVELS IN INFANTS 
POTENTIALLY EXPOSED TO OCRELIZUMAB 
DURING PREGNANCY – THE MINORE STUDY 
PROTOCOL NUMBER: MN42988 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2021-000062-14 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998812 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
AUTHORS: 
 
(Medical Monitor) 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your study monitor. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
12/Protocol MN42988, Version 3 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY 
EVALUATING B-CELL LEVELS IN INFANTS POTENTIALLY 
EXPOSED TO OCRELIZUMAB DURING PREGNANCY – THE 
MINORE STUDY 
PROTOCOL NUMBER: 
MN42988 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2021-000062-14 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998812 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
Phase IV 
INDICATION: 
Multiple Sclerosis 
SPONSOR: 
F.  Hoffmann-La Roche Ltd 
 
Background 
The most recent report combining clinical trial and post-marketing experience suggests no 
increased risk of adverse pregnancy/fetal outcomes with ocrelizumab use, including in those 
pregnancies considered to have fetal ocrelizumab exposure (hypothetically, an embryo/fetus is 
considered exposed in utero if the last infusion of ocrelizumab was within 3 months of 
conception, during pregnancy, or if the date was unknown).  However, very limited systematic 
data are available to date on laboratory outcomes (particularly B-cell levels) and infections in 
infants potentially exposed to ocrelizumab during pregnancy, and no information on their ability 
to mount immune responses. 
Objectives and Endpoints 
This study will evaluate the potential placental transfer of ocrelizumab in women with clinically 
isolated syndrome (CIS) or multiple sclerosis (MS) [in line with the locally approved indications] 
whose last dose of ocrelizumab was administered any time from 6 months before the last 
menstrual period (LMP) through to the first trimester (up to gestational Week 13) of pregnancy, 
and the corresponding pharmacodynamic effects (B-cell levels) in the infant.  Specific objectives 
and corresponding endpoints for the study are outlined below. 
Objectives 
Corresponding Endpoints 
Primary Outcome Measure 
• To evaluate whether infants 
potentially exposed to 
ocrelizumab during pregnancy 
present with postpartum 
B-cell depletion 
• Proportion of infants with B-cell levels (CD19 + cells, 
absolute counts) below the LLN, measured at Week 6 
of life 
Secondary Outcome Measures 
• To evaluate B-cell levels in 
infants potentially exposed to 
ocrelizumab during pregnancy 
• B-cell levels (CD19 + cells, absolute counts and percentage 
of lymphocytes) measured at Week 6 of life 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
13/Protocol MN42988, Version 3 
Objectives 
Corresponding Endpoints 
Secondary Outcome Measure (cont.) 
• To evaluate whether there is 
placental transfer of 
ocrelizumab from the mother 
to the infant 
• Serum concentration of ocrelizumab in the umbilical cord 
blood at birth (target time frame of blood sampling: within 
1 hour after delivery) 
• Serum concentration of ocrelizumab in the infant at Week 6 
of life 
• To evaluate whether infants 
potentially exposed to 
ocrelizumab during pregnancy 
are able to mount humoral 
immune responses to 
clinically relevant vaccines 
• Mean titers of antibody immune response(s) to common 
childhood vaccinations with full or partial doses given prior 
to 1 year, which include responses to diphtheria, tetanus, 
pertussis, Hib, PCV-13, MMR, and HBV 
• Proportion of infants with positive humoral response 
(seroprotective titers; as defined for the individual vaccine) 
to vaccines 
• To evaluate the levels of 
ocrelizumab in the mother 
during pregnancy  
• Serum concentration of ocrelizumab in the mother during 
pregnancy (time frame of blood sampling:  Week 24−30, 
Week 35) and at delivery (time frame of blood sampling:  
within 24 hours after delivery) 
Safety Objectives 
• To evaluate the safety of 
ocrelizumab in the mother, 
and the safety of infants 
potentially exposed to 
ocrelizumab 
• Rate and nature of adverse events in the mother 
throughout the study, including changes in clinical and 
laboratory results 
• Rate and nature of adverse events in the infant throughout 
the study, including infections and hospitalizations 
• To evaluate pregnancy and 
neonatal outcomes 
• Proportion of pregnancies resulting in live births (term and 
preterm, with and without congenital anomalies), 
therapeutic abortions, or stillbirths 
• Infant characteristics at birth, including but not limited to 
body weight, head circumference and length 
Exploratory Objectives 
• To evaluate the infant’s 
growth velocity and 
developmental milestones in 
the first year of life 
• Assessment of growth velocity based on age-adjusted body 
length, weight and head circumference, using growth 
charts according to the WHO Child Growth Standards, as 
well as absolute values, at Months 2, 4, 6, 9, and 12 
• Assessment of child developmental milestones in the 
domains of communication, gross motor, fine motor, 
problem solving, and personal-social at Months 2, 4, 6, 9, 
and 12, using the ASQ-3 
• To evaluate humoral immunity 
to clinically relevant 
pathogens in mothers during 
pregnancy 
• Mean titers of antibody immune response(s) to 
vaccinations, measured in the third trimester (time frame of 
blood sampling:  Week 35) 
• Percentage of women with positive humoral response 
(seroprotective titers; as defined for the individual vaccine) 
to vaccines (time frame of blood sampling:  Week 35) 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
14/Protocol MN42988, Version 3 
Objectives 
Corresponding Endpoints 
Exploratory Objectives (cont.) 
 
• Note:  Immune responses to the following may be 
included: measles, mumps, rubella, tetanus, diphtheria, 
pertussis, varicella zoster, Streptococcus pneumoniae, 
HBV, and SARS-CoV-2; along with nucleocapsid and spike 
protein titers; only for those mothers who have received the 
vaccine, as per local clinical practice) 
• To measure disease activity in 
mothers during pregnancy 
and postpartum 
• Number of MS relapses during pregnancy and postpartum 
(clinical relapses) 
• Mean change from baseline in the EDSS score over the 
course of the study 
• To detect presence of 
neuroaxonal damage in the 
mother during pregnancy and 
postpartum  
• sNfL levels during pregnancy (second trimester [time frame 
of blood sampling: Week 24−30], third trimester [time frame 
of blood sampling: Week 35] and at delivery [time frame of 
blood sampling: within 24 hours after delivery]) and 
postpartum (in line with ocrelizumab administration 
timepoints) 
• To evaluate the evolution of 
B-cell levels between birth 
and the first year of life 
• Trajectory (absolute and percentage changes) of B-cell 
(CD19 + cell) levels in the infant from Week 6 of life to 
1 month after the first or second dose of MMR vaccine or 
Month 13 of age in case MMR vaccine is not planned to be 
administered 
ASQ-3 = Ages and Stages Questionnaire, version 3; EDSS = Expanded Disability Status Scale; 
HBV = hepatitis B virus; Hib = Hemophilus influenzae type b; LLN = lower limit of normal; 
MMR = measles, mumps, and rubella; MS = multiple sclerosis; PCV-13 = 13-pneumococcal 
conjugate vaccine; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
sNfL = serum neurofilament light chain; WHO = World Health Organization. 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a prospective, multicenter, open-label study in women with CIS or MS (in line with the 
locally approved indications) receiving commercial ocrelizumab up to 6 months before the LMP 
or during the first trimester (up to gestational Week 13), due to accidental exposure, or in whom 
a decision to treat with ocrelizumab was taken as part of routine clinical practice. 
Note on referral to sites:  Pregnant and lactating women with MS are often treated in a 
decentralized way between specialized and non-specialized centers.  It is difficult to predict at 
which clinical sites eligible women will be identified; and activation of new sites that identify 
potential women is not viable since it could take several months, and would not be achieved in 
time to screen the women while they still meet the protocol inclusion criteria.  By using 
established networks and pregnancy registries for referral, the study could be completed in a 
timely manner.  For these reasons, women may be referred to study sites; and study visits may 
be home-based (conducted by a mobile nurse, and by the investigator using telemedicine [i.e., 
remotely]).  Implementation of these elements will depend on local requirements as well as 
agreement by the investigator, and capacity to use telemedicine.  The investigators will be 
informed about the approach that may be used in their country. 

 
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15/Protocol MN42988, Version 3 
The study will consist of the following periods. 
• 
Screening/baseline period (between gestational Week 24 and 30):  After providing written 
informed consent, women will enter a screening period between gestational Weeks 24 
and 30, after the morphological scan (usually done at gestational Week 18−20).  Women 
fulfilling the inclusion/exclusion criteria with accidental ocrelizumab exposure, or in whom a 
decision to treat with ocrelizumab was taken as part of routine clinical practice, will be 
enrolled; some of these women should have potential fetal exposure (i.e., have received 
their last dose of ocrelizumab < 3 months before the LMP or during the first trimester [up to 
gestational Week 13]).  Exposure to ocrelizumab includes administration of an initial split 
dose of two 300 mg infusions (in 250 mL 0.9% sodium chloride) separated by 14 days for 
women initiating treatment with ocrelizumab, or a single 600 mg infusion (in 500 mL 0.9% 
sodium chloride) for women already on treatment with ocrelizumab.  The baseline visit will 
be combined with the screening visit.  To reduce the burden of visits on the mothers, results 
from physical and obstetric examinations, as well as neurological examinations, done as 
part of routine care may be used.  The scheduled obstetric blood glucose test should 
preferably be conducted at the screening/baseline visit rather than at a separate visit. 
• 
Pregnancy and early postpartum period (up to Week 6 of life):  Laboratory and clinical 
assessments during the third trimester (gestational Week 35 [± 14 days]), will be performed 
in accordance with planned prenatal care visits, whenever possible.  To reduce the burden 
of visits on the mothers, results from physical and obstetric examinations, as well as 
neurological examinations, done as part of routine care may be used.  All visit samples 
may be collected by home nurse visit.  At birth, a blood sample will be collected from the 
umbilical cord (only for live births; no collection should occur in the event of a pregnancy 
interruption [i.e., therapeutic abortion or stillbirth]).  The target time frame for collection will 
be within 1 hour after delivery; the actual time of collection after delivery will be recorded.  
At week 6 (± 7 days) of the infant’s life (or equivalent age for preterm births, i.e., gestational 
week at birth < 37 weeks).  At Week 6 (± 7 days) of the infant’s life, a blood sample will be 
collected from the infant (at an on-site visit, or by a home nurse visit) for measurement of 
B-cell levels (the primary endpoint).  Ocrelizumab must not be administered after the 
woman is enrolled in the study and until the infant’s birth.  Treatment with commercial 
ocrelizumab may be resumed at any time after birth for women who decide not to 
breastfeed.  Some women may decide to resume treatment with ocrelizumab whilst 
breastfeeding.  For those women, treatment with ocrelizumab should be restarted after 
collection of the infant blood sample at Week 6 of life (± 7 days) if possible, but the decision 
is left to the discretion of the woman and the investigator. 
If the woman switches to another DMT postpartum, the infant blood sample at Week 6 of 
life (± 7 days) will only be collected if the woman is not breastfeeding. 
• 
Vaccination period (after Week 6 of life and up to 1 month [+ 30 days] after the first or 
second dose of MMR vaccine, or at Month 13 of age [+ 30 days] if the MMR vaccine is not 
planned to be administered):  Both mother and the infant will enter an extension phase, 
which will continue approximately until the infant reaches 13 months of age.  This is 
designed to evaluate whether infants potentially exposed to ocrelizumab during pregnancy 
are able to mount humoral immune responses to clinically relevant vaccines.  Infant 
laboratory assessments will be performed 1 month (+ 30 days) after the first dose of MMR 
vaccine (if first dose is administered at 11 months of age or later), 1 month (+ 30 days) after 
the second dose of MMR vaccine (if first dose is administered before 11 months of age), or 
at Month 13 of chronological age (+ 30 days) if MMR vaccine is not planned to be 
administered (as per local clinical practice, vaccinations may include diphtheria, tetanus, 
pertussis, Hib, PCV-13, HBV, and MMR).  Additionally, infants will continue to be followed 
up for growth (age-adjusted body length, weight and head circumference) and 
developmental milestones up to 12 months of age.  Growth charts following the WHO Child 
Growth Standards, absolute values and the ASQ-3 questionnaires will be used; other 
standard measurements recorded by e.g., the pediatrician as part of routine post-natal care 
may also be used.  Post-natal timings of ocrelizumab infusions every 6 months and 
laboratory/clinical assessments in the mother may occur at different time points than infant 
assessments. 

 
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In case the mother decides to switch to another DMT or to stop DMT after birth, no 
laboratory/clinical assessments will be performed for the mother.  However, the infant blood 
sample 1 month (+ 30 days) after the first or second dose of MMR vaccine (or at Month 
13 of age [+ 30 days]) will still be collected. 
• 
A structured telephone interview will be conducted by site personnel every 3 months 
postpartum (in-between ocrelizumab infusions) for a general review, and to identify and 
collect information on any changes in the woman’s or infant’s health status (including the 
occurrence of MS relapses in the woman and use of new concomitant medications) and 
possible adverse events in both the woman and the infant (particularly infections); women 
will also be asked if the ASQ-3 form is being filled out.  No telephone contact is needed in 
weeks where the woman is performing on-site visits. 
• 
Follow-up visit after early discontinuation:  Women who decide to discontinue the study (this 
includes discontinuation of the mother or discontinuation of the infant by the mother, or 
discontinuation at the investigator’s discretion) will be invited to attend an early study 
discontinuation visit (which may be conducted virtually or by telephone) as soon as 
possible.  Depending on the timing of discontinuation, the following is recommended: 
• 
Discontinuation before birth:  Collection of pregnancy outcome and infant outcomes in the 
first year of life as per standard pharmacovigilance procedures. 
• 
Discontinuation after birth and before Week 6 of life of the infant:  
– 
Collection of pregnancy outcome and infant outcomes in the first year of life as per 
standard pharmacovigilance procedures 
– 
If the mother decides to stop participating at Week 6 of life (± 7 days), attempts to 
collect the infant sample at Week 6 of life (± 7 days) should be made, and before 
discontinuation 
– 
If the mother switches to another DMT and is breastfeeding, the infant sample at 
Week 6 of life (± 7 days) should not be collected 
• 
Discontinuation after Week 6 of life of the infant:  Collection of infant outcomes in the first 
year of life as per standard pharmacovigilance procedures. 
 
Number of Women 
This study will enroll approximately 33 pregnant women with CIS or MS (in line with the locally 
approved indications). 
End of Study 
The end of the study is defined as the date of the last assessment (vaccine response titers 
measured 1 month [+ 30 days] after the first or second dose of MMR vaccine, or at Month 13 of 
age (+ 30 days) if MMR vaccine is not planned to be administered) for the last infant. 
Length of Study 
The total length of the study, from screening of the first woman to the end of the study, is 
expected to be approximately 33 months.  This includes an enrollment period of approximately 
16 months and subject participation of approximately 17 months. 
Target Population 
Inclusion Criteria 
Women must meet the following criteria for study entry: 
• 
An informed consent form (ICF) for participation of the maternal subject and her unborn 
(for collection of blood samples, infant demographics and adverse event data) is signed and 
dated by the subject.  Where applicable, the written ICF with respect to the infant is also 
signed and dated by the holder of parental rights as designated by the maternal subject. 
• 
Able and willing to comply with the study protocol, in the Investigator’s judgment. 
• 
Age 18−40 years, inclusive, at screening. 
• 
Have a diagnosis of MS or CIS (in line with the locally approved indications). 
• 
Currently pregnant with singleton pregnancy at gestational Week ≤ 30 at enrollment. 

 
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• 
Note:  Gestational age will be determined by LMP and first trimester ultrasound so long as 
there is less than 1 week’s difference in the projected due date.  If there is over 1 week’s 
difference, then the ultrasound alone will be used.  For cases where the LMP is not known, 
then the earliest ultrasound will be used.  For cases of in vitro fertilization (IVF), the 
projected dates from the IVF procedure will be preferentially used. 
• 
Documentation that first (12-week) and second (18−20-week) obstetric ultrasound (prenatal 
screening) has been conducted before enrollment. 
• 
Documentation that the last exposure to ocrelizumab occurred up to 6 months before the 
LMP before the woman became pregnant OR during the first trimester of pregnancy (up to 
gestational Week 13 inclusive). 
Note: Exposure to ocrelizumab includes administration of an initial split dose of two 300 mg 
infusions (in 250 mL 0.9% sodium chloride) separated by 14 days for women initiating 
treatment with ocrelizumab, or a single 600 mg infusion (in 500 mL 0.9% sodium chloride) 
for women already on treatment with ocrelizumab. 
 
Exclusion Criteria 
Women who meet any of the following criteria will be excluded from study entry: 
• 
Last exposure to ocrelizumab > 6 months before the woman’s LMP or later than the first 
trimester of pregnancy (i.e., after gestational Week 13). 
• 
Gestational age at enrollment > 30 weeks. 
• 
Non-singleton pregnancy. 
• 
Received the last dose of ocrelizumab at a different posology other than per the local 
prescribing information. 
• 
Social circumstances (e.g., home relocation) that may preclude a woman from participating 
in the study. 
 
Exclusions related to obstetric and gynecological health 
• 
Lack of access to ultrasound prenatal care as part of standard clinical practice. 
• 
Women in whom aneuploid disorders or genetic disorders that cause major congenital 
malformations have been detected during first trimester prenatal screening 
(e.g., ultrasound, amniocentesis, genetic testing, nuchal translucency screening, chorionic 
villus sampling), or in whom any fetal anomalies (i.e., fetal biometry, fetal anatomy) have 
been detected during the morphology scan at around or before gestational Week 18−20. 
• 
Documented history of disorders associated with adverse pregnancy outcomes, including 
but not limited to, the following: 
– 
History of preterm birth (gestational age < 37 weeks) for any indication with or without 
fetal malformations 
– 
History of spontaneous abortion (miscarriage) after the first trimester (i.e., after 
gestational Week 13) 
– 
History of stillbirth (defined as fetal loss at gestational age > 22 weeks) 
– 
History of pre-eclampsia/eclampsia 
– 
History of a cervical pathology or intervention which may increase the risk of cervical 
incompetence (e.g., history of cervical cerclage, prior cervical conization or prior loop 
electrosurgical excision procedure [LEEP]) 
• 
Prior or current history of any other gynecological or obstetric disease considered by the 
investigator to be associated with a high risk of adverse pregnancy outcomes in the current 
pregnancy. 
 
Exclusions related to general health 
• 
Lack of peripheral venous access. 
• 
Pre-pregnancy body mass index (BMI) > 35 kg/m2. 

 
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• 
Any concomitant disease that may require chronic treatment with systemic corticosteroids 
or immunosuppressants during the course of the study. 
• 
Prior or current history of primary or secondary immunodeficiency, or woman in an 
otherwise severely immunocompromised state.  The woman may be re-screened and 
included if condition resolves. 
• 
Significant and uncontrolled disease, such as cardiovascular (including cardiac arrhythmia 
and hypertension), pulmonary (including obstructive pulmonary disease), neurological, 
psychiatric (e.g., psychosis), renal, hepatic, endocrine (e.g., diabetes, thyroid disorders), or 
gastrointestinal or any other significant disease that may preclude a woman from 
participating in the study. 
• 
Women with known active malignancies or being actively monitored for recurrence of 
malignancy including solid tumors and hematological malignancies (except basal cell and in 
situ squamous cell carcinomas of the skin).  Women with in situ carcinoma of the cervix of 
the uterus, even if excised and resolved with documented clean margins on pathology, are 
excluded from the study. 
• 
Prior or current history of alcohol or drug abuse, or current use of tobacco. 
 
Exclusions related to laboratory findings 
• 
Any abnormal screening laboratory value that is clinically relevant will be retested only once 
in order to rule out any progressive or uncontrolled underlying condition.  The last value 
before study entry must meet study criteria. 
Women with positive screening tests for hepatitis B, determined by a positive hepatitis B 
surface antigen (HBsAg) result (current infection) or positive hepatitis B core antibody 
(HBcAb) titers (previous infection) will be excluded.  Women with documented history of 
hepatitis B virus (HBV) vaccination or positive hepatitis B surface antibody (HBsAb) titers 
are eligible. 
 
Note:  based on local Ethics Committees or National Competent Authority requirements, 
additional local diagnostic testing may be required for selected women or selected centers to 
exclude tuberculosis, Lyme disease, human T-lymphotropic virus 1 associated myelopathy 
(HAM), human immunodeficiency virus (HIV), hepatitis C virus infection (HCV), severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), hereditary disorders, connective tissue 
disorders, or sarcoidosis.  Other specific diagnostic tests may be requested when deemed 
necessary by the investigator. 
Exclusions related to medications 
Absolute exclusions 
• 
Drugs known to have teratogenic effects including but not limited to certain anticonvulsants 
(even if used for pain management), antibiotics such as tetracyclines or fluoroquinolones. 
• 
Planned treatment with interferons, glatiramer acetate, or pulsed corticosteroids as a 
bridging therapy after the last ocrelizumab dose before enrollment and throughout 
pregnancy. 
 
Relative exclusions (according to medication washout period) 
• 
Treatment with one of the following agents prior to the last ocrelizumab dose or prior to the 
LMP, whichever occurred first: 
– 
Treatment with siponimod or ponesimod within 10 days 
– 
Treatment with mycophenolate within 6 weeks 
– 
Treatment with fingolimod within 2 months 
– 
Treatment with ozanimod within 3 months 
– 
Treatment with alemtuzumab within 4 months 
– 
Treatment with mitoxantrone, methotrexate, ofatumumab or cladribine within 6 months 

 
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– 
Treatment with cyclophosphamide or rituximab within 12 months 
• 
Treatment with natalizumab within 12 weeks prior to the LMP 
• 
Treatment with teriflunomide within the last two years, unless measured plasma 
concentrations are less than 0.02 mg/L.  If levels are above 0.02 mg/L or not known, an 
accelerated elimination procedure will be implemented before screening visit.  One of the 
following elimination procedures can be used:  
– 
Cholestyramine 8 g administered 3 times daily for a period of 11 days, or 
cholestyramine 4 g three times a day can be used, if cholestyramine 8 g three times a 
day is not well tolerated 
– 
Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for a 
period of 11 days 
• 
Treatment with any investigational agent within 6 months or five half-lives of the 
investigational drug (whichever is longer) prior to the last ocrelizumab dose or prior to the 
LMP, whichever occurred first. 
 
STUDIED MEDICINAL PRODUCTS 
The study treatment is commercial ocrelizumab.  Dosing and treatment duration are at the 
discretion of the physicians, in accordance with local clinical practice and local labelling (USPI; 
SmPC). 
Statistical Methods 
Primary Analysis 
The primary analysis will be performed after the last blood draw at Week 6 of life to examine 
B-cell levels in infants. 
The proportion of infants with B-cell levels below the LLN will be calculated and the 
corresponding two-sided Clopper-Pearson 95%CI will be presented. 
The B-cell levels at Week 6 of life will be analyzed using descriptive statistics.  Mean, 
corresponding 95% CI, SD, and other statistics will be presented. 
Stillbirths and abortions of any type will not be included in the primary B-cell analysis. 
Determination of Sample Size 
The study will include approximately 33 pregnant women. 
There is no formal sample size calculation, as no confirmatory hypothesis testing is planned.  
The primary analysis will be descriptive.  Considering a 10% dropout rate, approximately 
30 evaluable infants are expected.  A further investigation will be performed on the subgroup of 
infants whose mothers received the last dose of ocrelizumab 0−3 months before the LMP or 
during the first trimester. 
The precisions (width of the two-sided 95% CIs based on normal approximation) for different 
event rates (an “event” is defined as B-cell levels below the LLN) are shown in the following 
table.  If no event is observed from the 30 infants during the study, there is a 95% confidence 
that the event rate is below 0.114.   
Sample Size 
Number of Events 
Event Rate 
Precision 
30 
1 
0.033 
0.165 
30 
2 
0.067 
0.195 
30 
3 
0.100 
0.222 
30 
4 
0.133 
0.244 
30 
5 
0.167 
0.262 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AESI 
adverse events of special interest 
APGAR 
Appearance, Pulse, Grimace, Activity, and 
Respiration 
ASQ-3 
Ages and Stages Questionnaire version 3 
BMI 
body mass index 
CIS 
clinically isolated syndrome 
CRO 
contract research organization 
DMT 
disease-modifying therapy 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDSS 
Expanded Disability Status Scale 
EU 
European Union 
FAS 
full analysis set 
FDA 
(U.S.) Food and Drug Administration 
FSS 
functional systems scores 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
HAM 
human T-lymphotropic virus 1 associated myelopathy 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCP 
healthcare professional 
Hib 
Hemophilus influenzae type b 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICH 
International Council on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
ICF 
Informed Consent form 
IMP 
investigational medicinal product 
IND 
investigational new drug 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IV 
intravenous 

 
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Abbreviation 
Definition 
IVF 
in vitro fertilization 
LEEP 
loop electrosurgical excision procedure 
LLN 
lower limit of normal 
LMP 
last menstrual period 
MAH 
marketing authorization holder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
measles, mumps, and rubella 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
NCI CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NK 
natural killer (cell) 
PCV-13 
13-valent pneumococcal conjugate vaccine 
PML 
progressive multifocal leukoencephalopathy 
PPMS 
primary-progressive multiple sclerosis 
QLT 
quality tolerance limits 
RMS 
relapsing multiple sclerosis 
RRMS 
relapsing-remitting multiple sclerosis 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SmPC 
Summary of Product Characteristics 
sNfL 
serum neurofilament light chain 
SOC 
system organ class 
SPMS 
secondary progressive multiple sclerosis 
USPI 
U.S. Prescribing Information 
WHO 
World Health Organization 

 
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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 CNS that affects approximately 1 million people in the United States and 
2.8 million worldwide (Multiple Sclerosis International Federation 2020).  MS primarily 
affects young adults, with 70%−80% of patients having an age of onset (i.e., initial visit to 
a physician) between 20 and 40 years (Anderson et al. 1992; Noonan et al. 2002), and 
has a strong gender bias, with approximately 64%−70% of diagnosed patients being 
women (Goodin 2014). 
Multiple sclerosis is clinically categorized into three phenotypic disease patterns 
distinguished by the occurrence and timing of relapses as well as disability progression 
relative to disease onset: relapsing-remitting MS (RRMS), secondary progressive MS 
(SPMS), and primary-progressive MS (PPMS; Lublin et al. 2014).  RRMS is the most 
frequent disease course and develops as the initial presentation in approximately 85% of 
patients at approximately 30 years of age (Confavreux et al. 2000; Leray et al. 2015).  
If left untreated, in up to 80% of such patients, the disease advances to a secondary 
progressive stage (SPMS) within approximately 10−20 years depending on the natural 
history cohort (Koch et al. 2010; Kremenchutzky et al. 2006; Tremlett et al. 2008; 
Weinshenker et al. 1989).  PPMS is the diagnosis at disease onset in around 15% of 
patients, and is characterized by a pattern of sustained deterioration of their neurological 
function from the onset.  Around 5% of patients with PPMS will experience relapses and 
periods of remission throughout the disease course (Lublin et al. 2014).  Clinically 
isolated syndrome (CIS) is considered to be an early part of the spectrum of 
MS phenotypes and should be followed to determine subsequent disease course 
(Lublin et al. 2014). 
The clinical signs and symptoms in MS can occur in isolation or in combination, and can 
include weakness, spasticity, gait and coordination imbalances, sensory dysfunction, 
vision loss, sexual dysfunction, fatigue, depression, chronic pain, sleep disorders, and 
cognitive impairment (Tanasescu et al. 2014).  Current diagnosis of definite MS involves 
both clinical (history and neurological exam) and paraclinical evidence (for example, 
magnetic resonance imaging [MRI], lumbar puncture, or evoked potentials; 
Polman et al.2011; Thompson et al. 2018). 
The current therapeutic approach in MS involves symptomatic treatment, treatment of 
acute relapses, and disease-modifying therapies (DMTs).  Disease-modifying therapies 
are the mainstay for the pharmacological treatment of MS.  These therapies aim to 
decrease the clinical relapse rate, slow the development of MS-related neurological 
damage and disease progression, and concomitant inflammation within the CNS.  
Licensed DMTs have a range of mechanisms of action and can be immunomodulatory, 
anti-inflammatory, or immunosuppressive drugs (Reich et al. 2018). 

 
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1.2 
BACKGROUND ON OCRELIZUMAB 
Ocrelizumab is a recombinant humanized monoclonal antibody that selectively targets 
and eliminates CD20-expressing B-cells (Klein et al. 2013), which are believed to play a 
critical role in MS.  Efficacy and safety of ocrelizumab has been demonstrated in one 
Phase II and three Phase III randomized controlled clinical trials.  In two double-blind, 
double-dummy Phase III global relapsing multiple sclerosis (RMS) trials (OPERA I 
[Study WA21092] and OPERA II [Study WA21093]), ocrelizumab 600 mg administered 
every 24 weeks demonstrated superior efficacy over subcutaneous interferon beta 
(IFNβ)-1a 44 µg three times weekly (Hauser et al. 2017).  Efficacy outcomes were 
consistent between trials and across the primary and key clinical and imaging secondary 
endpoints.  Similarly, in a Phase III global PPMS trial (ORATORIO [Study WA25046]), 
ocrelizumab 600 mg demonstrated statistically significant superiority compared with 
placebo across several disability and imaging endpoints (Montalban et al. 2017). 
Based on the results from these Phase III trials, ocrelizumab was approved for use in 
patients with RMS (which includes CIS, RRMS and active SPMS) and PPMS in the 
United States, whereas in the European Union (EU) it was approved for relapsing or 
primary-progressive forms of MS.  The use of ocrelizumab in countries where it has 
been approved is governed by the applicable local label. 
1.3 
STUDY RATIONALE AND BENEFIT−RISK ASSESSMENT 
Most patients with MS are women in their reproductive years (Albor et al. 2017; 
Trojano et al. 2012).  Family planning is therefore an important consideration for women 
with MS who are receiving treatment with DMTs.  Women are usually advised to discuss 
treatment options with their healthcare professional (HCP) prior to family planning, and 
in many instances, it may be recommended, or even required, that a woman discontinue 
her treatment with DMTs during pregnancy planning or once pregnancy is confirmed 
(Hellwig et al. 2020).  However, this may lead to an increased risk of relapses during the 
period between DMT discontinuation and the start of the potential protective effects of 
pregnancy (Confavreux et al. 1998).  For example, severe rebound relapses during 
pregnancy have been reported as early as 1 month after stopping fingolimod and 
3−4 months after stopping natalizumab (Langer−Gould et al. 2019).  In addition, there is 
evidence that approximately 30% of women with MS experience a relapse in the first 
3 months after delivery (Vukusic et al. 2004). 
Ocrelizumab may be a suitable treatment option for women with MS planning to become 
pregnant because of its prolonged immunomodulatory effects.  The terminal half-life of 
ocrelizumab (26 days on average) provides a window of opportunity for a woman to 
become pregnant when B-cells remain undetectable despite the medication already 
being cleared from the body, or not being able to cross the placental barrier.  Currently, 
the ocrelizumab labeling (Summary of Product Characteristics [SmPC], U.S. Prescribing 
Information [USPI]) stipulates that contraceptives should be used during ocrelizumab 
treatment, and for 6 months (United States) or 12 months (EU) after the last dose.  

 
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The 6-month contraceptive requirement in the US label reflects the pharmacokinetic 
properties of ocrelizumab, including the lack of transfer across the placenta during the 
first trimester of pregnancy owing to its conformation as an IgG1 antibody (Kane and 
Acquah 2009). 
Available Evidence 
In an embryofetal development study in cynomolgus monkeys, there was no evidence of 
maternal toxicity, teratogenicity, or embryotoxicity following ocrelizumab treatment at 
75/100 mg/kg (loading dose/study dose).  Reductions in B-cells (the anticipated 
pharmacological effect) in maternal and fetal peripheral blood were observed.  In two 
pre- and postnatal development studies in cynomolgus monkeys, administration of 
ocrelizumab from gestational Day 20 to at least parturition was associated with 
glomerulopathy, lymphoid follicle formation in bone marrow, lymphoplasmacytic renal 
inflammation, and decreased testicular weight in offspring.  The maternal doses 
administered in these studies resulted in maximum serum concentrations (Cmax) that 
were 4.5- to 21-fold above those anticipated in the clinical setting (for a 600 mg dose).  
There were five neonatal deaths; one attributed to weakness due to premature birth 
accompanied by opportunistic bacterial infection, one due to an infective 
meningoencephalitis involving the cerebellum of the neonate from a dam with an active 
bacterial infection (mastitis), and three with evidence of jaundice and hepatic damage, 
with suspected viral etiology (possibly a polyomavirus).  The course of these five 
confirmed or suspected infections could potentially have been impacted by B-cell 
depletion.  Newborn offspring of animals exposed to ocrelizumab were noted to have 
depleted B-cell populations during the postnatal phase (Ocrelizumab Investigator’s 
Brochure, version 20.0, November 2021). 
As of 31 March 2022, 2020 MS pregnancies exposed to ocrelizumab were reported in 
the ocrelizumab global safety database which includes reports from clinical trials and 
spontaneous post-marketing (Oreja-Guevara et al. 2022).  Seven hundred five 
pregnancies were considered to have fetal ocrelizumab exposure (an embryo/fetus is 
considered exposed in utero if the last infusion of ocrelizumab was within 3 months of 
conception, during pregnancy, or if the date was unknown), 433 had no fetal exposure, 
and 882 had unknown exposure.  Among women with fetal exposure, 207 received the 
last ocrelizumab dose during the first trimester of pregnancy.  Overall, 1064 pregnancies 
had known outcomes.  Pregnancy outcomes irrespective of fetal exposure status were 
as follows:  there were 809 (76.0%) live births, 72 (6.8%) elective/therapeutic abortions, 
158 (14.8%) spontaneous abortions, 6 (0.6%) stillbirths, 2 (0.2%) intrauterine/fetal 
death, and 17 (1.6%) ectopic pregnancies.  Two hundred sixty-six pregnancies were 
ongoing, and 690 were lost to follow-up or had unknown/not reported outcomes 
(Oreja-Guevara et al. 2022).  These results remain in line with previous analyses 
(Dobson et al. 2021) and within the expected epidemiological range (CDC 2008; 
Geissbühler et al. 2015; Friend et al. 2016; Thiel et al. 2016; Lopez-Leon et al. 2020), 
suggesting no increased risk of adverse pregnancy/fetal outcomes (including 

 
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spontaneous abortions, stillbirth and malformations) with ocrelizumab use.  In a 
prospective cohort study of 88 pregnancies in 81 women with MS or other neurological 
diseases who were treated with rituximab or ocrelizumab ≤ 12 months before the last 
menstrual period (LMP; Kümpfel et al. 2021), the overall prevalence of major congenital 
abnormalities was 3.3% (n = 2; a ventricular septum defect and an atrium septum defect 
with pulmonary stenosis, both in women with RRMS who received ocrelizumab during 
pregnancy).  This rate was similar to the rate seen in pregnancies of unexposed women 
from the same registry.  Pregnancy outcomes in this study were similar between groups, 
except that there were significantly more preterm births in the group exposed after the 
LMP (45.5% [n = 5 of 13]; vs. 9.8% [n = 4 of 47] in the group with exposure < 6 months 
before the LMP and n = 0 of 8 in the group exposed > 6 months but ≤ 12 months before 
the LMP; p = 0.019). 
Reduced B-cell levels at birth have been reported in an infant born to a mother exposed 
to ocrelizumab during the second trimester of pregnancy, following relapse activity post-
alemtuzumab.  However, two months later, B-cell levels were normal 
(Ciplea et al. 2020).  The authors also reported a case where exposure to ocrelizumab 
occurred during the first trimester, in which B-cell levels in the infant returned to normal 
at 39 days postpartum (Ciplea et al. 2020).  Another case of second trimester 
ocrelizumab exposure in a patient with RRMS transitioning off natalizumab resulted in no 
neonatal B-cell depletion, no infections, and normal infant development, despite B-cell 
depletion in the mother at delivery (Rolfes et al. 2020). 
Supporting Evidence from Other Anti-CD20 Therapies 
Data from other anti-CD20 monoclonal antibodies also suggest no increased risk of 
adverse pregnancy/infant outcomes.  In fact, two classes of monoclonal antibodies, 
natalizumab and CD20-depleting agents, rituximab and ocrelizumab, are considered 
highly effective therapy options for women at a high risk of pregnancy-related 
MS relapses (Ciplea et al. 2020).  A retrospective cohort study of 74 pregnancies in 
55 women treated with rituximab for MS, of whom 9 (12%) had accidental first trimester 
exposure, found no increase in adverse pregnancy outcomes compared with expected 
rates.  Of the 38 live births, adverse pregnancy outcomes were:  3 preterm deliveries 
(including 1 set of twins), 1 neonatal death (preterm twin), and 1 perinatal stroke 
(full-term).  There were no stillbirths, chorioamnionitis, or major malformations.  Fifteen 
(27%) women had at least one first trimester miscarriage, of whom 8 (53%) had a history 
of infertility (Smith et al. 2020).  In a systematic review evaluating the safety of rituximab 
treatment before and during pregnancy in women with MS and neuromyelitis optica 
spectrum disorders, 102 pregnancies with rituximab use within 6 months of conception 
were identified, of which 78 resulted in live births and 12 in spontaneous abortions (Das 
et al. 2018).  Based on the available data, some clinicians propose that contraception 
may be discontinued as early as 4 weeks after the last dose of anti-CD20 antibodies 
(ocrelizumab or rituximab; Langer-Gould 2019). 

 
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Uncertainties and Need for Additional Evidence 
The recent report combining clinical trial and post-marketing experience (data cut-off 
31 March 2022; Oreja-Guevara et al. 2022) extends the knowledge on pregnancy 
outcomes in women with MS treated with ocrelizumab.  However, very limited systematic 
data are available to date on laboratory outcomes (particularly B-cell levels) and 
infections in infants potentially exposed to ocrelizumab during pregnancy, and no 
information on their ability to mount immune responses.  Given that 1) a large proportion 
of patients with MS are women of reproductive age, 2) ocrelizumab has a favorable 
benefit/risk profile in non-pregnant patients and a suitably prolonged pharmacodynamic 
effect and 3) to date no increased risk of adverse pregnancy outcomes is seen with 
accidental exposure to ocrelizumab during pregnancy, further investigation is required. 
While the knowledge on pregnancy outcomes upon ocrelizumab exposure will be 
extended through a dedicated pregnancy registry (Wormser et al. 2018) and a 
multi-source post-marketing study (MELODIC; Margulis et al. 2018), a dedicated 
prospective interventional study to specifically evaluate the placental transfer of 
ocrelizumab in women with MS and the corresponding pharmacodynamic effects in 
infants is required and justified.  This is part of the Sponsor’s broader research effort to 
investigate the benefit/risk of exposure to ocrelizumab during pregnancy and lactation, 
which is currently considered missing information. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the potential placental transfer of ocrelizumab in women with 
CIS or MS (in line with the locally approved indications) whose last dose of ocrelizumab 
was administered anytime from 6 months before the LMP through to the first trimester of 
pregnancy (up to gestational Week 13), and the corresponding pharmacodynamic 
effects, particularly B-cell levels, in the infants. 
Specific objectives and corresponding endpoints for the study are outlined below. 
Table 1 
Objectives and Corresponding Endpoints 
Objectives 
Corresponding Endpoints 
Primary Outcome Measure 
• To evaluate whether infants 
potentially exposed to ocrelizumab 
during pregnancy present with 
postpartum B-cell depletion 
• Proportion of infants with B-cell levels (CD19 + cells, 
absolute counts) below the LLN, measured at 
Week 6 of life 
ASQ-3  =  Ages and Stages Questionnaire, version 3; EDSS  =  Expanded Disability Status 
Scale; HBV = hepatitis B virus; Hib = Hemophilus influenzae type b; LLN = lower limit of 
normal; MMR = measles, mumps, and rubella; MS = multiple sclerosis; PCV-
13 = 13-pneumococcal conjugate vaccine; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2; sNfl = serum neurofilament light chain; WHO = World Health Organization. 
 

 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Objectives 
Corresponding Endpoints 
Secondary Outcome Measures 
• To evaluate B-cell levels in infants 
potentially exposed to ocrelizumab 
during pregnancy 
• B-cell levels (CD19 + cells, absolute counts and 
percentage of lymphocytes) measured at Week 6 
of life 
• To evaluate whether there is 
placental transfer of ocrelizumab 
from the mother to the infant 
• Serum concentration of ocrelizumab in the umbilical 
cord blood at birth (target time frame of blood 
sampling: within 1 hour after delivery) 
• Serum concentration of ocrelizumab in the infant at 
Week 6 of life 
• To evaluate whether infants 
potentially exposed to ocrelizumab 
during pregnancy are able to mount 
humoral immune responses to 
clinically relevant vaccines 
• Mean titers of antibody immune response(s) to 
common childhood vaccinations with full or partial 
doses given prior to 1 year, which include responses 
to diphtheria, tetanus, pertussis, Hib, PCV-13, MMR, 
and HBV 
• Proportion of infants with positive humoral response 
(seroprotective titers; as defined for the individual 
vaccine) to vaccines 
• To evaluate the levels of 
ocrelizumab in the mother during 
pregnancy 
• Serum concentration of ocrelizumab in the mother 
during pregnancy (time frame of blood sampling:  
Week 24−30, Week 35) and at delivery (time frame of 
blood sampling:  within 24 hours after delivery) 
Safety Objectives 
• To evaluate the safety of 
ocrelizumab in the mother, and the 
safety of infants potentially exposed 
to ocrelizumab 
• Rate and nature of adverse events in the mother 
throughout the study, including changes in clinical 
and laboratory results 
• Rate and nature of adverse events in the infant 
throughout the study, including infections and 
hospitalizations 
• To evaluate pregnancy and 
neonatal outcomes 
• Proportion of pregnancies resulting in live births (term 
and preterm, with and without congenital anomalies), 
therapeutic abortions, or stillbirths 
• Infant characteristics at birth, including but not limited 
to body weight, head circumference and length 
ASQ-3 =  Ages and Stages Questionnaire, version 3; EDSS = Expanded Disability Status 
Scale; HBV =  hepatitis B virus; Hib =  Hemophilus influenzae type b; LLN =  lower limit of 
normal; MMR =  measles, mumps, and rubella; MS =  multiple sclerosis; PCV-
13 =  13-pneumococcal conjugate vaccine; SARS-CoV-2 =  severe acute respiratory syndrome 
coronavirus 2; sNfl =  serum neurofilament light chain; WHO =  World Health Organization. 
 

 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Objectives 
Corresponding Endpoints 
Exploratory Objectives 
• To evaluate the infant’s growth 
velocity and developmental 
milestones in the first year of life 
• Assessment of growth velocity based on 
age-adjusted body length, weight and head 
circumference, using growth charts according to the 
WHO Child Growth Standards, as well as absolute 
values, at Months 2, 4, 6, 9, and 12 
• Assessment of child developmental milestones in the 
domains of communication, gross motor, fine motor, 
problem solving, and personal-social at Months 2, 4, 
6, 9, and 12, using the ASQ-3 
• To evaluate humoral immunity to 
clinically relevant pathogens in 
mothers during pregnancy 
• Mean titers of antibody immune response(s) to 
vaccinations, measured in the third trimester (time 
frame of blood sampling:  Week 35. 
• Percentage of women with positive humoral 
response (seroprotective titers; as defined for the 
individual vaccine) to vaccines (time frame of blood 
sampling:  Week 35. 
• Note:  Immune responses to the following may be 
included: measles, mumps, rubella, tetanus, 
diphtheria, pertussis, varicella zoster, Streptococcus 
pneumoniae, HBV, and SARS-CoV-2; along with 
nucleocapsid and spike protein titers; only for those 
mothers who have received the vaccine, as per local 
clinical practice) 
• To measure disease activity in 
mothers during pregnancy and 
postpartum 
• Number of MS relapses during pregnancy and 
postpartum (clinical relapses) 
• Mean change from baseline in the EDSS score over 
the course of the study 
• To detect presence of neuroaxonal 
damage in the mother during 
pregnancy and postpartum 
• sNfL levels during pregnancy (second trimester [time 
frame of blood sampling:  Week 24−30], third 
trimester [time frame of blood sampling:  Week 35] 
and at delivery [time frame of blood sampling: within 
24 hours after delivery]) and postpartum (in line with 
ocrelizumab administration timepoints) 
ASQ-3 =  Ages and Stages Questionnaire, version 3; EDSS = Expanded Disability Status 
Scale; HBV =  hepatitis B virus; Hib =  Hemophilus influenzae type b; LLN =  lower limit of 
normal; MMR =  measles, mumps, and rubella; MS =  multiple sclerosis; PCV-
13 =  13-pneumococcal conjugate vaccine; SARS-CoV-2 =  severe acute respiratory syndrome 
coronavirus 2; sNfl =  serum neurofilament light chain; WHO =  World Health Organization. 
 

 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Objectives 
Corresponding Endpoints 
Exploratory Objectives (cont.) 
• To evaluate the evolution of B-cell 
levels between birth and the first 
year of life 
• Trajectory (absolute and percentage changes) of 
B-cell (CD19 + cell) levels in the infant from Week 6 
of life to 1 month after the first or second dose of 
MMR vaccine or Month 13 of age in case MMR 
vaccine is not planned to be administered 
ASQ-3 = Ages and Stages Questionnaire, version 3; EDSS = Expanded Disability Status Scale; 
HBV = hepatitis B virus; Hib = Hemophilus influenzae type b; LLN = lower limit of normal; 
MMR = measles, mumps, and rubella; MS = multiple sclerosis; PCV-13 = 13-pneumococcal 
conjugate vaccine; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
sNfl = serum neurofilament light chain; WHO = World Health Organization. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a prospective, multicenter, open-label study in women with CIS or MS (in line with 
the locally approved indications) receiving commercial ocrelizumab up to 6 months 
before the LMP or during the first trimester of pregnancy (up to gestational Week 13), 
due to accidental exposure, or in whom a decision to treat with ocrelizumab was taken 
as part of routine clinical practice. 
Note on referral to sites:  Pregnant and lactating women with MS are often treated in a 
decentralized way between specialized and non-specialized centers.  It is difficult to 
predict at which clinical sites eligible women will be identified; and activation of new sites 
that identify potential women is not viable since it could take several months, and would 
not be achieved in time to screen the women while they still meet the protocol inclusion 
criteria.  By using established networks and pregnancy registries for referral, the study 
could be completed in a timely manner.  For these reasons, women may be referred to 
study sites; and study visits may be home-based (conducted by a mobile nurse, and by 
the investigator using telemedicine [i.e., remotely]).  Implementation of these elements 
will depend on local requirements as well as agreement by the investigator, and capacity 
to use telemedicine.  The investigators will be informed about the approach that may be 
used in their country. 
This study will enroll approximately 33 pregnant women with CIS or MS, some of whom 
should have potential fetal exposure (i.e., received their last dose of ocrelizumab 
< 3 months before the LMP or during the first trimester [up to gestational Week 13]).  
Laboratory and clinical assessments will be performed as described in the Schedule of 
Assessments presented in Appendix 1.  The study will consist of the following periods: 
• 
Screening/baseline period (between gestational Week 24 and 30) 
• 
Pregnancy and early postpartum period (up to Week 6 of life) 

 
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• 
Vaccination period (after Week 6 of life and up to 1 month [+ 30 days] after the first 
or second dose of the measles, mumps, and rubella [MMR] vaccine, or Month 13 of 
age [+ 30 days] if MMR vaccine is not planned to be administered) 
• 
Follow-up visit after early discontinuation 
 
3.1.1 
Overview of Study Design 
Figure 1 presents an overview of the study design.  A Schedule of Assessments is 
provided in Appendix 1.

 
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Figure 1 Overview of Study Design 
 
LMP = last menstrual period; MMR = measles, mumps, and rubella. 
Study description:  In this prospective, multicenter, open-label study, women with CIS or MS (in line with the locally approved indications) 
receiving commercial ocrelizumab up to 6 months before the LMP or during the first trimester of pregnancy will enter a screening/baseline period 
between gestational Weeks 24 and 30.  Women fulfilling the selection criteria with accidental ocrelizumab exposure or in whom a decision to treat 
with ocrelizumab was taken as part of routine clinical practice, will be enrolled; some of the women should have potential fetal exposure 
(i.e., received their last dose of ocrelizumab < 3 months before the LMP or during the first trimester [up to gestational Week 13]).  The baseline visit 
will be combined with the screening visit.  To reduce the burden of visits on the mothers, results from physical and obstetric examinations, as well 
as neurological examinations, done as part of routine care may be used.  In the pregnancy and early postpartum period (up to Week 6 of life), 
laboratory, and clinical assessments will be performed during the third trimester (gestational Week 35 [± 14 days]), whenever possible in 

 
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accordance with planned prenatal care visits (samples at this visit may be collected by home nurse visit).  To reduce the burden of visits on the 
mothers, results from physical and obstetric examinations, as well as neurological examinations, done as part of routine care may be used.  At 
delivery, blood samples from the mother and from the umbilical cord will be collected.  An infant blood sample for measurement of B-cell levels 
(primary endpoint) will be collected at Week 6 of life (± 7 days); or equivalent for preterm infants, i.e., gestational week at birth < 37 weeks) during a 
site visit or by home nurse visit.  Treatment with commercial ocrelizumab may be resumed at any time after birth for women who decide not to 
breastfeed.  Some women may decide to resume treatment with ocrelizumab whilst breastfeeding; for those women, treatment with ocrelizumab 
should be restarted after collection of the infant blood sample at Week 6 of life (± 7 days) if possible; but the decision is left to the discretion of the 
woman and the investigator.  If the woman switches to another DMT postpartum, the infant blood sample at Week 6 of life (± 7 days) will only be 
collected if the woman is not breastfeeding.  In the vaccination period (after Week 6 of life [± 7 days] and up to 1 month (+ 30 days) after the 
first/second dose of MMR vaccine, or Month 13 of age [+ 30 days] if the MMR vaccine is not planned to be administered), infants will receive 
vaccinations according to the local immunization schedule. 
Antibody immune response(s) to common childhood vaccinations with full or partial doses given prior to 1 year will be measured 1 month 
(+ 30 days) after the first dose of MMR vaccine (if first dose is administered at 11 months of age or later) or 1 month (+ 30 days) after second dose 
of MMR vaccine (if first dose is administered before 11 months of age) or at Month 13 of chronological age (+ 30 days) in case MMR vaccine is not 
planned to be administered; and infants will be followed up for growth and developmental milestones up to 12 months of age using appropriate 
growth charts, absolute values, and the ASQ-3 questionnaire; other standard measurements recorded by e.g., the pediatrician as part of routine 
postnatal care may also be used.  Postnatal timings of ocrelizumab infusions every 6 months and laboratory/clinical assessments in the mother 
may occur at different time points than infant assessments.  A structured telephone interview will be conducted postpartum every 3 months 
(in-between ocrelizumab infusions), except in weeks in which an on-site visit is scheduled, for a general review, and to identify and collect 
information on any changes in the woman’s or infant’s health status (including the occurrence of MS relapses in the woman and use of new 
concomitant medications) and possible adverse events in both the woman and the infant (particularly infections); women will also be asked if the 
ASQ-3 form is being filled out.  Women who decide to discontinue the study, or discontinue their infant’s participation in the study, will be invited to 
attend an early study discontinuation visit as soon as possible (this visit may be conducted virtually or by telephone).

 
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3.1.2 
Screening/Baseline Period 
After providing written informed consent, women will enter a screening period between 
gestational Weeks 24 and 30, after the morphological scan (usually done at gestational 
Week 18−20).  Women fulfilling the inclusion/exclusion criteria with accidental 
ocrelizumab exposure, or in whom a decision to treat with ocrelizumab was taken as part 
of routine clinical practice, will be enrolled.  Some of these women should have potential 
fetal exposure (i.e., have received their last dose of ocrelizumab < 3 months before the 
LMP or during the first trimester [up to gestational Week 13]).  Exposure to ocrelizumab 
includes administration of an initial split dose of two 300 mg infusions (in 250 mL 0.9% 
sodium chloride) separated by 14 days in women initiating treatment with ocrelizumab, 
or a single 600 mg infusion (in 500 mL 0.9%sodium chloride) in women already on 
treatment with ocrelizumab.  The baseline visit will be combined with the screening visit.  
To reduce the burden of visits on the mothers, results from physical and obstetric 
examinations, as well as neurological examinations, done as part of routine care may be 
used.  The scheduled obstetric blood glucose test should preferably be conducted at the 
screening/baseline visit rather than at a separate visit. 
3.1.3 
Pregnancy and Early Postpartum Period 
Mother: 
• 
Pregnancy period:  Laboratory and clinical assessments during the third trimester 
(gestational Week 35 [± 14 days]) will be performed in accordance with planned 
prenatal care visits, whenever possible.  To reduce the burden of visits on the 
mothers, results from physical and obstetric examinations, as well as neurological 
examinations, done as part of routine care may be used.  All visit samples may be 
collected by home nurse visit.  Women may be given vaccines (e.g., for Bordetella 
pertussis) as part of routine obstetric care (note: live or live-attenuated vaccines are 
not recommended during ocrelizumab treatment and until B-cells return to normal 
level).  Ocrelizumab must not be administered after the woman is enrolled in the 
study and until the infant’s birth.  Should this happen, the woman will be 
discontinued from the study. 
• 
Early postpartum period:  A blood sample will be collected from the mother within 
24 hours after delivery for assessment of serum ocrelizumab concentration.  
Treatment with commercial ocrelizumab may be resumed at any time after birth for 
women who decide not to breastfeed.  Some women may decide to resume 
treatment with ocrelizumab whilst breastfeeding.  For those women, treatment with 
ocrelizumab should be restarted after collection of the infant blood sample at 
Week 6 of life (± 7 days) if possible, but the decision is left to the discretion of the 
woman and the investigator.  If the woman switches to another DMT postpartum, 
the infant blood sample at Week 6 of life (± 7 days) will only be collected if the 
woman is not breastfeeding. 
 
Infant: 
At birth, a blood sample will be collected from the umbilical cord (only for live births; no 
collection should occur in the event of a pregnancy interruption [i.e., therapeutic abortion 

 
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or stillbirth]).  The target time frame for collection will be within 1 hour after delivery; the 
actual time of collection after delivery will be recorded.  At Week 6 (± 7 days) of the 
infant’s life, a blood sample will be collected from the infant (at an on-site visit, or by 
home nurse visit) for measurement of B-cell levels (the primary endpoint).  For preterm 
infants, blood samples will be collected at the week of life equivalent to term infants 
(e.g., if birth occurred at gestational Week 35, blood sample would be collected at 
Week 8 of life). 
Note:  If the infant’s B-cell levels are found to be below lower limit of normal (LLN), 
repeat analyses may be done at unscheduled visits at the discretion of the investigator 
(in consultation with the Sponsor). 
3.1.4 
Vaccination Period 
Both the mother and the infant will enter an extension phase, which will continue 
approximately until the infant reaches 13 months of age.  This is designed to evaluate 
whether infants potentially exposed to ocrelizumab during pregnancy are able to mount 
humoral immune responses to clinically relevant vaccines. 
Infant laboratory assessments will be performed 1 month (+ 30 days) after the first dose 
of MMR vaccine (if first dose is administered at 11 months of age or later) or 1 month 
(+ 30 days) after second dose of MMR vaccine (if first dose is administered before 
11 months of age), or at Month 13 of chronological age (+ 30 days), if MMR vaccine is 
not planned to be administered (as per local clinical practice, vaccinations may include 
diphtheria, tetanus, pertussis, Hemophilus influenzae type b [Hib], 13-valent 
pneumococcal conjugate vaccine [PCV-13], hepatitis B virus [HBV], and MMR).  
Additionally, infants will continue to be followed up for growth (age-adjusted body length, 
weight and head circumference) and developmental milestones up to 12 months of age.  
Growth charts following the World Health Organization (WHO) Child Growth Standards 
(WHO 2022), absolute values and the Ages and Stages Questionnaire, version 3 
(ASQ-3) will be used; other standard measurements recorded by e.g., the pediatrician as 
part of routine postnatal care may also be used.  The time windows for infant growth 
velocity and child developmental milestone assessments are given in Appendix 6.  
Post-natal timings of ocrelizumab infusions every 6 months and laboratory/clinical 
assessments in the mother may occur at different time points than infant assessments.  
In case the mother decides to switch to another DMT or to stop DMT after birth, no 
laboratory/clinical assessments will be performed for the mother.  However, the infant 
blood sample 1 month (+ 30 days) after the first or second dose of MMR vaccine (or at 
Month 13 of age [+ 30 days]) will still be collected. 
A structured telephone interview will be conducted by site personnel postpartum every 
3 months (in-between ocrelizumab infusions) for a general review, and to identify and 
collect information on any changes in the woman’s or infant’s health status (including the 
occurrence of MS relapses in the woman and use of new concomitant medications) and 
possible adverse events in both the woman and the infant (particularly infections); 

 
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women will also be asked if the ASQ-3 form is being filled out.  No telephone contact is 
needed in weeks where the woman is performing on-site visits. 
3.1.5 
Follow-Up Visit after Early Discontinuation 
Women who decide to discontinue the study (this includes discontinuation of the mother, 
or discontinuation of the infant by the mother, or discontinuation at the investigator’s 
discretion) are invited to attend an early study discontinuation visit (which may be 
conducted virtually or by telephone) as soon as possible.  Depending on the timing of 
discontinuation, the following is recommended: 
• 
Discontinuation before birth:  Collection of pregnancy outcome and infant 
outcomes in the first year of life as per standard pharmacovigilance procedures. 
• 
Discontinuation after birth and before Week 6 of life of the infant: 
– 
Collection of pregnancy outcome and infant outcomes in the first year of life as 
per standard pharmacovigilance procedures. 
– 
If the mother decides to stop participating at Week 6 of life (± 7 days), attempts 
to collect the infant sample at Week 6 of life (± 7 days) should be made before 
discontinuation. 
– 
If the mother switches to another DMT and is breastfeeding, the infant sample 
at Week 6 of life (± 7 days) should not be collected. 
• 
Discontinuation after Week 6 of life of the infant:  Collection of infant outcomes 
in the first year of life as per standard pharmacovigilance procedures. 
 
Further information is available in Appendix 1. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is defined as the date of the last assessment (vaccine response 
titers measured 1 month [+ 30 days] after the first or second dose of MMR vaccine, or at 
Month 13 of age (+ 30 days) if MMR is not planned to be administered for the last infant. 
The total length of the study, from screening of the first woman to the end of the study, is 
expected to be approximately 33 months.  This includes an enrollment period of 
approximately 16 months and subject participation period of approximately 17 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
This is a prospective, multicenter, open-label study evaluating placental transfer of 
ocrelizumab in women with CIS or MS receiving ocrelizumab up to 6 months before the 
LMP or during the first trimester of pregnancy (up to gestational Week 13). 
Ocrelizumab targets CD19 + B-cells, and a rapid depletion of CD19 + B-cells in blood is 
the expected pharmacologic effect of ocrelizumab treatment.  This occurs even at low 
doses (Food and Drug Administration [FDA] 2017), and is a biomarker for the 
pharmacodynamic effect of ocrelizumab.  Therefore, CD19 + B-cell levels will be 

 
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measured as the primary endpoint, to evaluate the pharmacodynamic effect in infants 
following potential in utero exposure to ocrelizumab via the placenta.  B-cell levels will be 
measured at 6 weeks of life (± 7 days) rather than in the initial postpartum weeks 
because B-cell counts have been shown to be very low in the first few days of life of 
healthy neonates (Duchamp et al. 2014).  Relative to total lymphocytes, B-cells also 
show a slightly delayed significant increase from the cord blood to the neonatal period 
and to the months 1 to 5 of life (Blanco et al. 2018), but ultimately most infants are 
reported to have B-cell levels above the LLN at a median age of 1.9 months 
(age range:  1−6 months; Duchamp et al. 2014).  For any preterm births in our cohort, 
the sampling points will be adjusted using the corrected age (i.e., adding the difference 
between the full-term age of 37 weeks and the gestational age at birth).  This approach 
is justified by data from a study of lymphocyte subsets in 338 term and preterm infants, 
where B-cell numbers increased at an approximately constant rate starting from 
gestational Week 22 (Amatuni et al. 2019). 
In addition, serum concentrations of ocrelizumab will be measured in the umbilical cord 
blood at birth and in the infant at Week 6 of life (± 7 days), to evaluate the infant’s 
potential exposure to ocrelizumab via placental transfer. 
A Phase IIIb study examining the effect of ocrelizumab treatment on the humoral 
responses in RMS patients found that patients who received ocrelizumab and were 
peripherally B-cell depleted were nevertheless able to mount humoral responses (though 
attenuated) to clinically relevant vaccines (tetanus toxoid, 23-valent pneumococcal 
polysaccharide vaccine, and influenza; Bar-Or et al. 2020).  Vaccine-induced antibody 
titers will similarly be measured in this study to check whether infants potentially 
exposed to ocrelizumab during pregnancy can mount a protective immune response to 
clinically relevant vaccines. 
Of note, the study will not be powered to investigate the effect of ocrelizumab on 
pregnancy/neonatal outcomes, however these will be captured as part of standard 
pharmacovigilance procedures.  Additionally, infant health and development outcomes 
will be assessed using growth charts according to the WHO Child Growth Standards 
(WHO 2022; as well as using absolute values) and the ASQ-3, a widely accepted tool for 
measuring development in young children (Lipkin et al. 2020; American Association of 
Pediatrics Policy Statement, 2006).  Other standard measurements recorded by e.g., the 
pediatrician as part of routine postnatal care may also be used. 
Disease activity will be measured in women with MS using the standard assessments of 
Expanded Disability Status Scale (EDSS) and number of MS relapses, which are 
commonly used in clinical trials to assess treatment efficacy and disease progression.  
Serum neurofilament light chain (sNfL), a marker of neuroaxonal injury, will be measured 
during pregnancy, at delivery and the postpartum period to explore its utility as a 
surrogate for disease activity in this population.  Several studies have demonstrated that 
sNfL is a sensitive and clinically meaningful blood biomarker to monitor tissue damage 

 
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and the effects of therapies in MS (Barro et al. 2018; Disanto et al. 2017), most recently 
also in pregnant women interrupting treatment for pregnancy (Yaldizli et al. 2020). 
3.3.1 
Rationale for Ocrelizumab Dose and Schedule 
The dosing schedule of ocrelizumab during the postpartum period is at the discretion of 
the treating physicians, in accordance with local clinical practice and local labelling. 
3.3.2 
Rationale for Patient Population 
As the aim of this study is to evaluate placental transfer of ocrelizumab and the 
corresponding pharmacodynamic effects, it will be conducted in women with CIS or MS 
(in line with the locally approved indications) aged 18−40 years who received 
ocrelizumab any time up to 6 months before the LMP or during the first trimester of 
pregnancy (up to gestational Week 13). 
Based on the average terminal half-life of 26 days (Ocrelizumab USPI), ocrelizumab is 
expected to be eliminated from the body by approximately 4.5 months, with the longest 
terminal half-life recorded as 53 days in one woman.  Considering the interpatient 
variability and the fact that ocrelizumab, as a fully humanized IgG1, is not expected to 
cross the placenta in the first trimester (Palmeira et al. 2012; Simister 2003), it is 
assumed that a potential fetal exposure is unlikely in women whose last ocrelizumab 
infusion was earlier than 3 months before conception.  Therefore, women who received 
ocrelizumab 3−6 months before conception will represent the non-exposed group.  
Women who received ocrelizumab up to 3 months before conception or during the first 
trimester of pregnancy will represent groups with potential fetal exposure.  Women who 
received ocrelizumab after the first trimester will be excluded since placental transfer of 
IgG is known to be significant after the first trimester (Palmeira et al. 2012; 
Simister 2003). 
The maximum age is set at 40 years since only a minority of pregnancies occur after this 
age (e.g., only around 3% of births of first children in the EU in 2017 were to women 
aged 40 and over [Eurostat 2019] and in the United States, the birth rate in 2018 was the 
lowest for the 40-44 age group [CDC2019]).  Additionally, advanced maternal age is 
associated with higher rates of maternal and fetal complications (Bouzaglou et al. 2020).  
Fetal complications, if they occur, may prevent the collection of the required sample or 
confound the interpretation of B-cell levels in the infants (the primary endpoint of the 
study). 
To further minimize the impact of confounding factors on the primary endpoint being 
measured at Week 6 of life (± 7 days), women with aneuploid or genetic disorders known 
to cause congenital malformations are excluded (women will be required to have a 
documented obstetric ultrasound from the first and second trimester).  Similarly, women 
with other risk factors for adverse pregnancy outcomes which would limit the ability to 
collect B-cell levels in the infants (e.g., spontaneous abortion after the first trimester and 
history of stillbirth) are also excluded. 

 
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Women with current (positive hepatitis B surface antigen [HBsAg] results) or previous 
(positive hepatitis B core antibody [HBcAb] titers) hepatitis B infection are also excluded, 
as most guidelines recommend that patients treated with anti-CD20 therapies who have 
chronic hepatitis B should receive prophylactic treatment with appropriate antiviral drugs 
(EASL 2017; Terrault et al. 2018).  Some of these drugs (e.g., entecavir) have been 
shown to have carcinogenic potential in animal studies (Aslam et al. 2018), and the 
general recommendation is that women who are or plan to become pregnant delay or 
stop treatment with prophylactic agents (EASL 2017; Terrault et al. 2018). 
4. 
MATERIALS AND METHODS 
4.1 
STUDY PARTICIPANTS 
This study will enroll approximately 33 pregnant women with CIS or MS (in line with the 
locally approved indications). 
4.1.1 
Inclusion Criteria 
Women must meet the following criteria for study entry: 
• 
An Informed Consent Form (ICF) for participation of the maternal subject and her 
unborn (for collection of blood samples, infant demographics and adverse event 
data) is signed and dated by the subject.  Where applicable, the written ICF with 
respect to the infant is also signed and dated by the holder of parental rights as 
designated by the maternal subject. 
• 
Able and willing to comply with the study protocol, in the Investigator’s judgment. 
• 
Age 18−40 years, inclusive, at screening. 
• 
Have a diagnosis of MS or CIS (in line with the locally approved indications). 
• 
Currently pregnant with singleton pregnancy at gestational Week ≤ 30 at enrollment. 
Note:  Gestational age will be determined by LMP and first trimester ultrasound so 
long as there is less than 1 week’s difference in the projected due date.  If there is 
over 1 week’s difference, then the ultrasound alone will be used.  For cases where 
the LMP is not known, then the earliest ultrasound will be used.  For cases of in vitro 
fertilization (IVF), the projected dates from the IVF procedure will be preferentially 
used. 
• 
Documentation that first (12-week) and second (18−20-week) obstetric ultrasound 
(prenatal screening) has been conducted before enrollment. 
• 
Documentation that the last exposure to ocrelizumab occurred up to 6 months 
before the LMP before the woman became pregnant OR during the first trimester of 
pregnancy (up to gestational Week 13 inclusive). 
Note:  Exposure to ocrelizumab includes administration of an initial split dose of two 
300 mg infusions (in 250 mL 0.9% sodium chloride) separated by 14 days for 
women initiating treatment with ocrelizumab, or a single 600 mg infusion (in 500 mL 
0.9% sodium chloride) for women already on treatment with ocrelizumab. 
 

 
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4.1.2 
Exclusion Criteria 
Women who meet any of the following criteria will be excluded from study entry: 
• 
Last exposure to ocrelizumab > 6 months before the woman’s LMP or later than the 
first trimester of pregnancy (i.e., after gestational Week 13). 
• 
Gestational age at enrollment > 30 weeks. 
• 
Non-singleton pregnancy. 
• 
Received the last dose of ocrelizumab at a different posology other than per the 
local prescribing information. 
• 
Social circumstances (e.g., home relocation), that may preclude a woman from 
participating in the study. 
 
Exclusions Related to Obstetric and Gynecological Health 
• 
Lack of access to ultrasound prenatal care as part of standard clinical practice. 
• 
Women in whom aneuploid disorders or genetic disorders that cause major 
congenital malformations have been detected during first trimester prenatal 
screening (e.g., ultrasound, amniocentesis, genetic testing, nuchal translucency 
screening, chorionic villus sampling), or in whom any fetal anomalies (i.e., fetal 
biometry, fetal anatomy) have been detected during the morphology scan at around 
or before gestational Week 18−20. 
• 
Documented history of disorders associated with adverse pregnancy outcomes, 
including but not limited to, the following: 
– 
History of preterm birth (gestational age < 37 weeks) for any indication with or 
without fetal malformations. 
– 
History of spontaneous abortion (miscarriage) after the first trimester (i.e., after 
gestational Week 13). 
– 
History of stillbirth (defined as fetal loss at gestational age > 22 weeks). 
– 
History of pre-eclampsia/eclampsia. 
– 
History of a cervical pathology or intervention which may increase the risk of 
cervical incompetence (e.g., history of cervical cerclage, prior cervical conization 
or prior loop electrosurgical excision procedure [LEEP]). 
• 
Prior or current history of any other gynecological or obstetric disease considered by 
the investigator to be associated with a high risk of adverse pregnancy outcomes in 
the current pregnancy. 
 
Exclusions Related to General Health 
• 
Lack of peripheral venous access. 
• 
Pre-pregnancy body mass index (BMI) > 35 kg/m2. 
• 
Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study. 

 
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• 
Prior or current history of primary or secondary immunodeficiency, or woman in an 
otherwise severely immunocompromised state.  The woman may be re-screened 
and included if condition resolves. 
• 
Significant and uncontrolled disease, such as cardiovascular (including cardiac 
arrhythmia and hypertension), pulmonary (including obstructive pulmonary disease), 
neurological, psychiatric (e.g., psychosis), renal, hepatic, endocrine (e.g., diabetes, 
thyroid disorders), or gastrointestinal or any other significant disease that may 
preclude a woman from participating in the study. 
• 
Women with known active malignancies or being actively monitored for recurrence 
of malignancy including solid tumors and hematological malignancies (except basal 
cell and in situ squamous cell carcinomas of the skin).  Women with in situ 
carcinoma of the cervix of the uterus, even if excised and resolved with documented 
clean margins on pathology, are excluded from the study. 
• 
Prior or current history of alcohol or drug abuse, or current use of tobacco. 
 
Exclusions Related to Laboratory Findings 
• 
Any abnormal screening laboratory value that is clinically relevant will be retested 
only once in order to rule out any progressive or uncontrolled underlying condition.  
The last value before study entry must meet study criteria. 
• 
Women with positive screening tests for hepatitis B, determined by a positive 
HBsAg result (current infection) or positive HBcAb titers (previous infection) will be 
excluded.  Women with documented history of HBV vaccination or positive hepatitis 
B surface antibody (HBsAb) titers are eligible. 
 
Note:  based on local Ethics Committees (ECs) or National Competent Authority 
requirements, additional local diagnostic testing may be required for selected women or 
selected centers to exclude tuberculosis, Lyme disease, human T-lymphotropic virus 1 
associated myelopathy (HAM), human immunodeficiency virus (HIV), hepatitis C virus 
infection (HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 
hereditary disorders, connective tissue disorders, or sarcoidosis.  Other specific 
diagnostic tests may be requested when deemed necessary by the investigator. 
Exclusions Related to Medications 
Absolute Exclusions 
• 
Drugs known to have teratogenic effects including but not limited to certain 
anticonvulsants (even if used for pain management), antibiotics such as 
tetracyclines or fluoroquinolones.  A more detailed, though not exclusive, list can be 
found in Appendix 2. 
• 
Planned treatment with interferons, glatiramer acetate, or pulsed corticosteroids as 
a bridging therapy after the last ocrelizumab dose before enrollment and throughout 
pregnancy. 
 

 
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Relative Exclusions (according to medication washout period) 
• 
Treatment with one of the following agents prior to the last ocrelizumab dose or prior 
to the LMP, whichever occurred first: 
– 
Treatment with siponimod or ponesimod within 10 days 
– 
Treatment with mycophenolate within 6 weeks 
– 
Treatment with fingolimod within 2 months 
– 
Treatment with ozanimod within 3 months 
– 
Treatment with alemtuzumab within 4 months 
– 
Treatment with mitoxantrone, methotrexate, ofatumumab or cladribine within 
6 months 
– 
Treatment with cyclophosphamide or rituximab within 12 months 
• 
Treatment with natalizumab within 12 weeks prior to the LMP 
• 
Treatment with teriflunomide within the last two years, unless measured plasma 
concentrations are less than 0.02 mg/L.  If levels are above 0.02 mg/l or not known, 
an accelerated elimination procedure will be implemented before screening visit.  
One of the following elimination procedures can be used: 
– 
Cholestyramine 8 g administered 3 times daily for a period of 11 days, or 
cholestyramine 4 g three times a day can be used, if cholestyramine 8 g three 
times a day is not well tolerated. 
– 
Alternatively, 50 g of activated powdered charcoal is administered every 
12 hours for a period of 11 days. 
• 
Treatment with any investigational agent within 6 months or five half-lives of the 
investigational drug (whichever is longer) prior to the last ocrelizumab dose or prior 
to the LMP, whichever occurred first. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study; therefore, no randomization or blinding is planned. 
4.3 
STUDY TREATMENT RELEVANT TO THE STUDY DESIGN 
The study treatment is commercial ocrelizumab. 
4.3.1 
Study Treatment Formulation and Packaging 
Information on formulation and packaging are available in the labeling (e.g., USPI 
[for United States] and SmPC [for EU]). 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
Dosing and treatment duration are at the discretion of the physicians, in accordance with 
local clinical practice and local labelling (USPI; SmPC).  No measures of treatment 
compliance are planned. 

 
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4.3.2.1 
Study Treatment 
Ocrelizumab must not be administered post-baseline and until the infant’s birth.  
Treatment with commercial ocrelizumab may be resumed at any time after birth for 
women who decide not to breastfeed.  Some women may decide to resume treatment 
with ocrelizumab whilst breastfeeding.  For those women, treatment with ocrelizumab 
should be restarted after collection of the infant blood sample at Week 6 of life (± 7 days) 
if possible, but the decision is left to the discretion of the woman and the investigator.  
If the woman switches to another DMT postpartum, the infant blood sample at Week 6 of 
life (± 7 days) will only be collected if the woman is not breastfeeding. 
4.3.2.2 
Premedication 
According to the label, 100 mg IV methylprednisolone (or an equivalent) and an 
antihistamine must be administered prior to administration of each ocrelizumab infusion 
to reduce the frequency and severity of infusion-related reactions (IRRs).  Premedication 
with an antipyretic (e.g., paracetamol) may also be considered prior to each ocrelizumab 
infusion. 
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 subject in addition to the study treatment.  All such medications 
taken within 6 weeks prior to the screening/baseline visit and throughout the study 
should be reported to the investigator and recorded on the Concomitant Medications 
electronic case report form (eCRF).  Folic acid (recommended daily intake 
400 micrograms per day, or as per local practice) prescribed and administered up to the 
first trimester of pregnancy (up to gestational Week 13) will be documented. 
4.4.1 
Prohibited Therapy 
Drugs known to have teratogenic effects including but not limited to anticonvulsants 
(even if used for pain management), antibiotics such as tetracyclines or fluoroquinolones 
are not permitted.  A more detailed, though not exclusive, list can be found in 
Appendix 2. 
Planned treatment with interferons, glatiramer acetate or pulsed corticosteroids as a 
bridging therapy are not permitted after the last ocrelizumab dose before enrollment and 
throughout pregnancy. 
No formal drug-drug interaction studies have been conducted with ocrelizumab, as no 
drug-drug interactions are expected via the cytochromes P450, other metabolizing 
enzymes or transporters. 
Ocrelizumab is a monotherapy and has not been studied in combination with other 
DMTs.  As with other immunomodulatory therapies, exercise caution when initiating 
ocrelizumab after an immunosuppressive therapy, and when initiating another therapy 

 
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after ocrelizumab, taking into consideration the potential for overlapping 
pharmacodynamic effects. 
More information is available in Section 4.1.2 and the ocrelizumab labeling 
(SmPC; USPI). 
4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each mother and infant. 
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).  ICFs for 
enrolled women and her unborn and for women who are not subsequently enrolled will 
be maintained at the study site.  Where applicable, the written ICF with respect to the 
infant is also signed and dated by the holder of parental rights as designated by the 
maternal subject. 
All screening evaluations must be completed and reviewed to confirm that women meet 
the eligibility criteria before enrollment.  The investigator will maintain a detailed record 
of all participants screened and document eligibility or record reasons for screening 
failure, as applicable.  Reasons for screening failure will also be captured by the sites in 
the eCRF. 
4.5.2 
Mother’s Assessments 
4.5.2.1 
Demographics, Medical and MS History 
Women’s demographics (age, self-reported ethnicity and education level) and relevant 
medical history, including clinically significant diseases, surgeries/procedures, smoking 
history and alcohol intake, will be recorded during the screening period.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the woman within 6 weeks 
prior to screening/baseline and throughout the study will be recorded. 
Obstetric and Gynecological History: 
• 
Date of LMP, documentation of obstetric ultrasounds (prenatal screening), 
gestational age at enrollment 
Note:  Gestational age will be determined by LMP and first trimester ultrasound so 
long as there is less than 1 week’s difference in the projected due date.  If there is 
over 1 week’s difference, then the ultrasound alone will be used.  For cases where 
the LMP is not known, then the earliest ultrasound will be used.  For cases of IVF, 
the projected dates from the IVF procedure will be preferentially used. 
• 
History of previous pregnancies (number, outcome, date), and clinically significant 
gynecological diseases 
 

 
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MS Disease History: 
• 
Date of MS symptom onset and MS diagnosis 
• 
Disease status (as available):  EDSS and number of relapses up to 1 year before 
LMP 
• 
History of previous DMTs:  number of DMTs ever used, last DMT before 
ocrelizumab 
• 
Treatment history with ocrelizumab:  including start of therapy, date and dose of last 
infusion prior to enrollment 
 
4.5.2.2 
Physical and Obstetric Examinations 
A complete physical examination in women should include measurement of height and 
weight, an evaluation of head, eye, ear, nose, and throat, cardiovascular, 
dermatological, musculoskeletal, respiratory, and gastrointestinal systems, as well as 
vital signs (see following section).  To reduce the burden of visits on the mothers, results 
from physical examinations done as part of routine care may be used.  The following 
assessments will also be conducted: neurological examination (see Section 4.5.2.4), 
relapse description, and EDSS (see Section 4.5.2.6).  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities not related to MS should be recorded as adverse events on the Adverse 
Event eCRF.  Height will be measured at screening only. 
An obstetric examination will be performed as per local clinical practice, at visits 
indicated in Appendix 1 (Schedule of Assessments).  To reduce the burden of visits on 
the mothers, results from obstetric examinations done as part of routine care may be 
used. 
See Appendix 1 (Schedule of Assessments) for the timing of all assessments. 
4.5.2.3 
Vital Signs 
Vital signs may be measured, in particular throughout the infusion procedure as per the 
Label and may include measurements of heart rate, systolic and diastolic blood 
pressures, and temperature.  If those measurements are performed as per clinical 
practice and are available, record any abnormalities observed on the General Medical 
History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened 
clinically significant abnormalities on the Adverse Event section of the eCRF 
(as presented in Section 5.1.2). 
4.5.2.4 
Neurological Examination 
A neurological examination will be performed at every planned visit and at unscheduled 
visit if applicable.  To reduce the burden of visits on the mothers, results from 
neurological examinations done as part of routine care may be used.  For women 
referred to the investigator, results from routine visits at the woman’s neurologist may be 

 
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used.  In the presence of newly identified or worsening neurological symptoms at any 
given time in the study, a neurological evaluation should be scheduled promptly. 
As infection is a potentially serious complication of B-cell-depleting therapy, investigators 
will also screen women for signs and symptoms of any CNS infections, and specifically 
progressive multifocal leukoencephalopathy (PML), by evaluating neurological deficits 
localized to the cerebral cortex, such as cortical symptoms/signs, behavioral and 
neuropsychological alteration, retrochiasmal visual defects, hemiparesis, cerebellar 
symptoms/signs (e.g., gait abnormalities, limb incoordination).  Women with suspected 
PML should be withheld from ocrelizumab treatment until PML is ruled out by complete 
clinical evaluation and appropriate diagnostic testing.  A woman with confirmed PML 
should be withdrawn from the study.  PML should be reported as a serious adverse 
event (SAE; with all available information) with immediate notification of the 
Medical Monitor.  Refer to Appendix 3 for guidance for diagnosis of PML. 
4.5.2.5 
Assessment of Relapses 
Potential relapses should be recorded throughout the study period after screening.  
See Appendix 1 (Schedule of Assessments) for the timing of these assessments. 
All new or worsening neurological events consistent with MS representing a “clinical 
relapse” are to be reported on the dedicated “MS relapse” form.  A clinical relapse is 
defined as a monophasic clinical episode with patient-reported symptoms and objective 
findings typical of MS, reflecting a focal or multifocal inflammatory demyelinating event in 
the CNS, developing acutely or sub-acutely, with a duration of at least 24 h, with or 
without recovery, and in the absence of fever or infection (Thompson et al. 2018).  
Multiple sclerosis relapses should not be reported as an AE, unless they are serious. 
It is recommended that women with new neurological symptoms suggestive of a relapse 
have an EDSS/Functional Systems Scores (FSS) assessment performed as soon as 
possible, ideally within 7 days of the onset of symptoms.  However, it is not mandatory to 
perform an EDSS assessment in case of a suspected relapse. 
4.5.2.6 
Assessment of Disability 
Disability in MS will be measured by the EDSS.  See Appendix 1 (Schedule of 
Assessments) for the timing of assessments. 
The EDSS is based on a standard neurological examination, incorporating seven 
functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, 
and cerebral [or mental], plus “other”) rated and scored as FSSs.  Each FSS is an 
ordinal clinical rating scale ranging from 0 to 5 or 6. These ratings are then used in 
conjunction with observations and information concerning ambulation and use of 
assistive devices to determine the EDSS score.  The EDSS is a disability scale that 
ranges in 0.5-point steps from 0 (normal) to 10 (death) (see Appendix 4).  The EDSS 

 
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assessment may also be performed by the investigator via telephone, using a specific 
licensed questionnaire (see Appendix A4–2). 
4.5.2.7 
Laboratory, Biomarker, and Other Biological Samples 
Routine laboratory assessments (performed in the central laboratory, except for 
urinalysis) are listed in the following sections.  For sampling procedures, storage 
conditions, and shipment instructions, see the laboratory manual.  For details, refer to 
Schedule of Assessments, Appendix 1. 
At Screening/Baseline (Gestational Weeks 24−30) 
• 
Hematology (hemoglobin, hematocrit, quantitative platelet count, RBC count, 
WBC count, absolute or/and differential count [neutrophils, eosinophils, 
lymphocytes, monocytes, basophils]). 
• 
Serum chemistries (AST, ALT, gamma-glutamyl transpeptidase [GGT], 
total bilirubin, creatinine, random glucose, potassium, sodium, chloride).  The 
scheduled obstetric blood glucose test should preferably be conducted at the 
screening/baseline visit (Week 24−30) rather than at a separate visit. 
• 
Urinalysis:  using urine dipstick at site (may include pH, specific gravity, glucose, 
protein, ketones, blood), and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria) at the discretion of the investigator. 
• 
Hepatitis B virus serology:  Women with positive screening tests for HBV, 
determined by a positive HBsAg result (current infection) or positive HBcAb titers 
(previous infection) will be excluded.  Women with documented history of 
HBV vaccination or positive HBsAb titers are eligible. 
• 
Lymphocyte subtypes: Blood samples will be collected to measure B-cell counts 
(CD19  +  and B-cell subsets [Table 2]), T-cell counts (CD3 +, CD4 +, CD8+ ), and 
natural killer (NK) cell counts (CD16+CD56+). 
• 
Serum immunoglobulin concentration. 
• 
Ocrelizumab concentration:  serum samples will be collected for determination of 
ocrelizumab concentration. 
• 
sNfL:  samples will be collected for determination of sNfL. 
 
During Third Trimester (Gestational Week 35 ± 14 days) 
Note:  Samples may be collected by home nurse visit. 
• 
Hematology (hemoglobin, hematocrit, quantitative platelet count, RBC count, 
WBC count, absolute or/and differential count [neutrophils, eosinophils, 
lymphocytes, monocytes, basophils]). 
• 
Serum chemistries (AST, ALT, GGT, total bilirubin, creatinine, random 
glucose, potassium, sodium, chloride). 
• 
Urinalysis: using urine dipstick at site (may include pH, specific gravity, glucose, 
protein, ketones, and blood), and microscopic examination (sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, bacteria) at the discretion of the investigator. 

 
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• 
Lymphocyte subtypes:  Blood samples will be collected to measure B-cell counts 
(CD19 +  and B-cell subsets [Table 2]), T-cell counts (CD3 +, CD4 +, CD8 + ), and NK 
cell counts (CD16+CD56+). 
• 
Serum antibody (IgG) titers to immunizations:  for measles, mumps, rubella, 
tetanus, diphtheria, pertussis, varicella zoster, Streptococcus pneumoniae, HBV and 
SARS-CoV-2 (along with nucleocapsid and spike protein titers; only for those 
mothers who have received the vaccine, as per local clinical practice) will be 
performed.  Any vaccinations received by mothers during the study will be recorded 
as concomitant medications. 
• 
Ocrelizumab concentration:  serum samples will be collected for determination of 
ocrelizumab concentration. 
• 
Serum immunoglobulin concentration. 
• 
sNfL:  samples will be collected for determination of sNfL. 
 
At Delivery (within 24 hours after delivery, only for live births) 
• 
Ocrelizumab concentration:  serum samples will be collected for determination of 
ocrelizumab concentration. 
• 
Serum immunoglobulin concentration. 
• 
sNfL:  samples will be collected for determination of sNfL. 
During the Vaccination Period (at Infusion 1 and Infusion 2) 
• 
Hematology (hemoglobin, hematocrit, quantitative platelet count, RBC count, 
WBC count, absolute or/and differential count [neutrophils, eosinophils, 
lymphocytes, monocytes, basophils]). 
• 
Serum chemistries (AST, ALT, GGT, total bilirubin, creatinine, random glucose, 
potassium, sodium, chloride). 
• 
Urinalysis:  using urine dipstick at site (may include pH, specific gravity, glucose, 
protein, ketones, and blood), and microscopic examination (sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, bacteria) at the discretion of the investigator. 
● 
Lymphocyte subtypes:  Blood samples will be collected to measure B-cell counts 
(CD19 +  and B-cell subsets [Table 2]), T-cell counts (CD3 +, CD4 +, CD8 + ), and 
NK cell counts (CD16+CD56+).  Samples will be collected prior to the ocrelizumab 
infusion. 
• 
Ocrelizumab concentration:  serum samples will be collected (before ocrelizumab 
administration) for determination of ocrelizumab concentration 
• 
Serum immunoglobulin concentration 
• 
sNfL:  On the day of the infusion, samples should be collected 5−30 minutes prior to 
the methylprednisolone infusion as it has been shown to reduce antibody reactivity 
(Quintana et al. 2012). 
• 
Any vaccinations received by mothers during the study will be recorded as 
concomitant medications. 
 

 
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The B-cell subsets that will be analyzed are described in the table below. 
Table 2 
B-Cell Subsets 
• Naive B-cells:  CD45+, CD19+, IgD+, CD27 − , CD38dim/− 
• Memory B-cells:  CD45+, CD19+, CD27+ 
• Unswitched memory B-cells:  CD45+, CD19+, IgD+, CD27+ 
• Switched memory B-cells:  CD45+, CD19+, IgD−, CD27+ 
• Double-negative B-cells:  CD45+, CD19+, IgD−, CD27− 
• IgD transitional B-cells:  CD45+, CD19+, IgD+, CD27−, CD38 bright  
• Plasmablasts or plasma cells:  CD45+, CD19+, CD27+, CD38 bright 
 
4.5.3 
Infant’s Assessments 
4.5.3.1 
Pregnancy Outcome and Infant Characteristics 
At birth: 
• 
Pregnancy and infant outcome 
• 
Mode of delivery (vaginal delivery, instrumental delivery, scheduled or urgent 
cesarean section) 
• 
Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score (1 min, 
5 min, 10 min) 
• 
Gestational age at birth 
• 
Infant vital biometrics (weight, length, head circumference) 
• 
Congenital malformations 
 
Week 6 of Life (± 7 days) 
• 
Weight measurement for safety 
• 
Feeding status: Mothers should record feeding status of the infant, i.e., whether 
exclusive breastfeeding, mixed feeding (partial breastfeeding along with infant 
formula and/or baby food), exclusive infant formula feeding, or fully weaned 
• 
Changes to concomitant medications given to the infant should be recorded 
throughout the study.  For administered vaccinations, see Section 4.5.4. 
 
Months 2, 4, 6, 9, and 12: 
• 
Growth velocity (weight, length and head circumference), using growth charts 
according to the WHO Child Growth Standards (WHO 2022); as well as absolute 
values (other standard measurements recorded by e.g., the pediatrician as part of 
routine postnatal care may also be used). 
• 
Child developmental milestones in the domains of communication, gross motor, fine 
motor, problem solving, and personal-social, using ASQ-3. 
• 
Feeding status:  Mothers should record feeding status of the infant, i.e., whether 
exclusive breastfeeding, mixed feeding (partial breastfeeding along with infant 
formula and/or baby food), exclusive infant formula feeding, or fully weaned. 

 
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• 
Changes to concomitant medications given to the infant should be recorded 
throughout the study.  For administered vaccinations, see Section 4.5.4. 
 
See Appendix 6 for time windows for infant growth velocity and child developmental 
milestone assessments. 
One month (+ 30 days) after first dose of MMR vaccine (if first dose is administered 
at 11 months of age or later) OR 1 month (+ 30 days) after second dose of 
MMR vaccine (if first dose is administered before 11 months of age) OR at 
Month 13 of chronological age (+ 30 days) if MMR vaccine is not planned to be 
administered 
• 
Weight measurement for safety 
• 
Changes to concomitant medications given to the infant should be recorded and 
throughout the study.  For administered vaccinations, see Section 4.5.4. 
 
4.5.3.2 
Laboratory, Biomarker, and Other Biological Samples 
Umbilical cord blood assessments (target collection time within one hour of birth; 
only for live births; no collection should occur in the event of a pregnancy 
interruption [i.e., therapeutic abortion or stillbirth]) 
• 
Ocrelizumab concentration: a serum sample will be collected for determination of 
ocrelizumab concentration 
 
Week 6 of Life (± 7 days) 
• 
Lymphocyte subtypes:  A blood sample will be collected to measure B-cell counts 
(CD19 + ), T-cell counts (CD3 +, CD4 +, CD8 + ), and NK cell counts 
(CD16+CD56+). 
• 
Ocrelizumab concentration:  a serum sample will be collected for determination of 
ocrelizumab concentration. 
Note:  If the infant’s B-cell levels are below LLN, repeat analyses may be done at 
unscheduled visits at the discretion of the investigator (in consultation with the 
Sponsor). 
Infant samples will be collected by venipuncture.  As per the recommendation of the 
European Commission ad hoc group (2008) the total blood volume to be collected 
from an infant in a clinical study should not exceed 0.8−0.9 mL/kg at any time point, 
or 2.4 mL/kg over any 4-week period throughout the study.  If the blood volume 
collected for an infant (as a result of these limits) is insufficient to carry out all 
planned assessments, Table 3 shows the order of priority for assessments. 
 

 
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Table 3 
Prioritization Order for Infant Blood Sample Assessments at 
Week 6 of Life (± 7 days) 
Order of Priority 
Assessment 
1 
Any safety laboratory samples (scheduled or unscheduled and performed at 
the discretion of the Investigator) 
2 
Lymphocyte subtypes blood sample a 
3 
Serum ocrelizumab concentration 
NK = natural killer. 
a Blood samples will be collected to measure B-cell counts (CD19 + ), T-cell counts (CD3 +, 
CD4 +, and CD8 + ), and NK cell counts (CD16+CD56+). 
 
One month (+ 30 days) after first dose of MMR vaccine (if first dose is 
administered at 11 months of age or later) OR 1 month (+ 30 days) after second 
dose of MMR vaccine (if first dose is administered before 11 months of age) OR at 
Month 13 of chronological age (+ 30 days) if MMR vaccine is not planned to be 
administered 
• 
Lymphocyte subtypes: A blood sample will be collected to measure B-cell counts 
(CD19 + ), T-cell counts (CD3 +, CD4 +, CD8 +) and NK cell counts (CD16+CD56+). 
Note:  If the infant’s B-cell levels are below LLN, repeat analyses may be done at 
unscheduled visits at the discretion of the investigator (in consultation with the 
Sponsor). 
• 
Serum antibody titers to vaccines administered as per local practice (e.g., 
diphtheria, tetanus, pertussis, Hib, PCV-13, HBV, and MMR) 
Note:  While vaccination schedules are not exactly the same from country to 
country, all participating countries are expected to provide the specific vaccines for 
the planned titer assessments 
Infant samples will be collected by venipuncture.  As per the recommendation of the 
European Commission ad hoc group (2008) the total blood volume to be collected 
from an infant in a clinical study should not exceed 0.8−0.9 mL/kg at any time point, 
or 2.4 mL/kg over any 4-week period throughout the study.  If the blood volume 
collected for an infant (as a result of these limits) is insufficient to carry out all 
planned assessments, Table 4 shows the order of priority for assessments. 
 

 
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Table 4 
Prioritization Order for Infant Blood Sample Assessments 
1 Month (+ 30 days) after First/Second Dose of MMR Vaccine OR 
at Month 13 of Age (+ 30 Days) 
Order of Priority 
Assessment 
1 
Any safety laboratory samples (scheduled or unscheduled and performed at 
the discretion of the Investigator) 
2 
Serum titers of antibody responses to vaccines a 
3 
Lymphocyte subtypes blood sample b 
Ab = antibody; IgG  =  immunoglobulin G; MMR = measles, mumps, and rubella; NK  =  natural 
killer; PCV-13 = 13-valent pneumococcal conjugate vaccine. 
a Titers of responses to vaccines administered as per local practice may include the following:  
anti-measles Ab IgG, anti-rubella Ab IgG, anti-mumps Ab IgG, PCV-13 Ab (all serotypes), 
anti-tetanus toxoid IgG, anti-diphtheria IgG, Bordetella pertussis Ab IgG, hepatitis B 
surface Ab, and Hemophilus influenzae B IgG. 
b Blood samples will be collected to measure B-cell counts (CD19 + ), T-cell counts (CD3 +, 
CD4 +, and CD8 + ), and NK cell counts (CD16+CD56+). 
 
4.5.4 
Infant Vaccination Schedule 
Infants will receive vaccinations according to the immunization schedule recommended 
in each participating country.  The safety and timing of vaccination of the infant should 
still be discussed with the mother, in particular the vaccination with live-attenuated 
vaccines (e.g., MMR) for which the results on B-cell levels at Week 6 of life may be 
informative.  Vaccines administered from birth throughout the end of the study, should 
be recorded at Months 2, 4, 6, 9, and 12 as well as at 1 month (+ 30 days) after first or 
second MMR dose/Month 13 of age (+ 30 days) and may include diphtheria, tetanus, 
pertussis, Hib, PCV-13, HBV, and MMR. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
The decision to discontinue a woman from treatment lies with the treating physician, in 
agreement with the woman’s wishes, and is not regulated by this protocol. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF page.  In case the woman switches to another treatment for MS, the 
DMT should also be documented on the appropriate eCRF page. 
4.6.2 
Discontinuation from the Study 
Women and their unborns/infants 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 woman 
from the study at any time.  Women who decide to discontinue the study (this includes 
discontinuation of either the mother or the infant) are invited to attend an early study 
discontinuation visit (which may be conducted virtually or by telephone) as soon as 
possible (further details in Section 3.1.5). 

 
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Reasons for woman discontinuation from the study may include, but are not limited to, 
the following: 
• 
Woman withdrawal of consent. 
• 
Study termination or site closure. 
• 
Adverse event. 
• 
Loss to follow-up. 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the safety of the woman, unborn or infant if he or she continues in the study. 
• 
Woman’s non-compliance, defined as failure to comply with protocol requirements 
as determined by the investigator or Sponsor. 
 
Every effort should be made to obtain a reason for woman discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF (see Section 3.1.5).  Women who withdraw from the study will not 
be replaced. 
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 women in the study. 
• 
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 on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline 
for GCP. 
• 
No study activity (i.e., all women and their infants have completed the study and all 
obligations have been fulfilled). 
 

 
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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY REPORTING REQUIREMENTS FOR STUDIED 
MEDICINAL PRODUCTS 
5.1.1 
Safety Parameters and Definitions 
The reporting requirements in this section apply to ocrelizumab and any other treatments 
used as co-administered products (i.e., premedication), according to the label.  For a list 
of products, see Section 4.3. 
For safety reporting requirements for non-studied medicinal products, see Section 5.2. 
Safety assessments will consist of monitoring and recording serious adverse events and 
non-serious adverse events (including adverse events of special interest), performing 
safety laboratory assessments, measuring vital signs, and conducting other tests that 
are deemed critical to the safety evaluation of the study as per standard medical 
practice. 
5.1.1.1 
Adverse Events 
According to the ICH, an adverse event is any untoward medical occurrence in a patient 
or clinical investigation patient administered a pharmaceutical product, regardless of 
causal attribution.  An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Appendix 5. 
• 
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 medicine. 
 
Adverse events and serious adverse events related to MS are not considered for 
recording in the eCRF, unless they meet specific criteria.  For more details, refer to 
Section 5.1.1.2. 
5.1.1.2 
Assessment of Serious Adverse Events and Non-Serious 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) and Other Non-Serious Adverse Events 
Serious Adverse Events 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death). 

 
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• 
Is life-threatening.  (NOTE:  The term “life-threatening” refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more severe.) 
• 
Requires or prolongs inpatient hospitalization. 
• 
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 medicine. 
• 
Is a significant medical event in the physician’s judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria; 
see Appendix 5); 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 (for detailed instructions, see Appendix 5). 
Non-Serious Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) for this study include the following: 
• 
Cases of potential medicine-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 Appendix 5). 
• 
Suspected transmission of an infectious agent by the study medicine, 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 only applies when a 
contamination of the study medicine is suspected. 
 
A. Non-Serious Adverse Events other than Adverse Events of Special Interest 
All non-serious adverse events (in addition to adverse events of special interest) must be 
collected for this study, and coded according to the appropriate level of Medical 
Dictionary for Regulatory Activities (MedDRA) classification. 

 
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B. Specific Adverse Events that are exempt from collection 
Adverse events and serious adverse events related to MS are not considered for 
recording in the eCRF.  Medical occurrences or symptoms of deterioration that are 
anticipated as part of MS or which are expected in the patient population studied should 
be recorded as an adverse event only if judged by the physician to have unexpectedly 
worsened in severity or frequency or changed in nature at any time during the study. 
Following the above rationale, the following events will not be considered as adverse 
events for this study: 
1. 
MS relapses. 
2. 
Disability progression (increase in EDSS or other scales performed by the 
physician). 
3. 
MRI activity (new/enlarged T2 or T1 gadolinium-enhancing lesion in spinal or brain 
MRI), unless the activity is suggestive of a serious adverse event such as PML.  
In this case, information should be recorded in the section “PML” of the eCRF. 
4. 
MS signs and symptoms. 
 
Although these adverse events are not being actively solicited, the investigator/patients 
are reminded of the possibility to report any adverse reactions (for which they suspect a 
causal role of a medicinal product) that come to their attention to the Sponsor of the 
suspected medicinal product, or to the concerned competent authorities via the national 
spontaneous reporting system. 
5.1.2 
Methods and Timing for Capturing/Assessing 
Safety Parameters 
The investigator is accountable for ensuring that all adverse events collected as per 
protocol (see Section 5.1.1 for definition) are recorded in the Adverse Event eCRF and 
reported to the Sponsor in accordance with instructions provided in this section and in 
Section 5.1.3. 
For each adverse event recorded in the adverse event section of the eCRF, the 
investigator will make an assessment of seriousness (see Section 5.1.1.2), severity (see 
Appendix 5), and causality (see Appendix 5). 
5.1.2.1 
Adverse Event Reporting Period 
Investigator will seek information on adverse events at each patient contact.  All adverse 
events subject to the collecting and reporting requirements outlined in this protocol, 
whether reported by the patient or noted by study personnel, will be recorded in the 
patient’s medical record and in the Adverse Event eCRF. 
Adverse events will be reported throughout the study and until the last study visit for both 
mother and infant.  After this period, the investigator should report any serious adverse 
events that are believed to be related to prior study drug treatment.  Adverse events that 

 
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occur in a pregnant woman pre- and post- study should be reported to the marketing 
authorization holder (MAH), as a follow up spontaneous pregnancy report to the initially 
spontaneously reported pregnancy, by following the standard pharmacovigilance 
reporting process for post-marketing pregnancy cases. 
5.1.2.2 
Procedures for Recording Adverse Events 
Investigator should use correct medical terminology/concepts when recording adverse 
events in the Adverse Event eCRF.  Colloquialisms and abbreviations should be 
avoided. 
Only one adverse event term should be recorded in the event field of the eCRF. 
See Appendix 5 for further specific instructions regarding: 
• 
IRRs 
• 
Diagnosis versus signs and symptoms 
• 
Adverse events occurring secondary to other adverse events 
• 
Persistent or recurrent adverse events 
• 
Abnormal laboratory values 
• 
Abnormal vital sign values 
• 
Abnormal liver function tests 
• 
Deaths 
– 
All events with an outcome or consequence of death should be classified as 
serious adverse events and reported to the Sponsor immediately.  In certain 
circumstances, however, suspected adverse reactions with fatal outcome may 
not be subject to expedited reporting (see Section 5.4).  All deaths that occur 
during the protocol-specified adverse event reporting period, regardless of 
relationship to study medicine, must be recorded in the Adverse Event eCRF 
and immediately reported to the Sponsor. 
• 
Worsening of pre-existing medical conditions 
• 
Lack of therapeutic efficacy 
• 
Hospitalization or prolonged hospitalization 
• 
Overdoses, misuses, abuses, off-label use, occupational exposure, or medication 
error 
• 
Quality defects, falsified medicinal products and product complaints 
• 
Drug interactions 
 
5.1.3 
Reporting Requirements from HCP to Sponsor 
5.1.3.1 
Immediate Reporting Requirements from HCP to Sponsor 
Certain events require immediate reporting to allow the Sponsor and the regulatory 
authorities to take appropriate measures to address potential new risks associated with 

 
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the use of the medicine.  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 medicine: 
• 
Serious adverse events 
• 
Non-serious adverse events of special interest 
• 
Accidental pregnancy occurred during the study (for additional information 
see Section 5.1.3.5) 
 
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 
 
For reports of serious adverse events and non-serious adverse events of special 
interest, including follow-up, investigator should record all case details that can be 
gathered immediately (i.e., within 24 hours) in the Adverse Event eCRF and submit the 
report via the electronic data capture (EDC) system.  A report will be generated and sent 
to Roche Drug Safety by the EDC system. In the event that the EDC system is 
temporarily unavailable, refer to Section 5.1.3.4. 
Investigator must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.1.3.2 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitor is available 
24 hours per day, 7 days per week.  An Emergency Medical Call Center will also be 
available 24 hours per day, 7 days per week.  Details will be provided separately.  The 
Emergency Medical Call Center will connect the investigator with an Emergency 
Medical Contact, provide medical translation service if necessary, and track all calls.  
Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators. 
5.1.3.3 
Reporting Requirements for Non-Serious Adverse Events 
For all non-serious adverse events, including follow-up reports, the investigator must 
record all case details that can be gathered within 30 calendar days of learning of the 
event on the adverse event section of the eCRF. 

 
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5.1.3.4 
If EDC System Is Temporarily Unavailable 
In the event that the EDC system is temporarily unavailable, a completed paper 
reporting form and fax coversheet should be faxed/scanned to Roche Drug Safety or its 
designee immediately (i.e., no more than 24 hours after learning of the event) or within 
30 calendar days for non-serious adverse events if not adverse events of special 
interest, using the fax number or email address provided to investigator. 
Once the system is available again, all information should additionally be entered and 
submitted via the EDC system. 
5.1.3.5 
Reporting Requirements for Pregnancies, 
Abortions/Congenital Anomalies/Birth Defects 
Pregnancies 
All pregnancies in women enrolled in this study should have been previously reported to 
the Sponsor as spontaneous pregnancy reports by following the standard 
pharmacovigilance reporting process for post-marketing pregnancy cases.  This should 
be done by a neurologist at the time of learning of the patient's pregnancy.  In case a 
pregnant woman enrolled in the study becomes accidentally pregnant again during the 
study, she will remain on study and discontinue treatment with commercial ocrelizumab 
until pregnancy completion.  She and her subject infant should continue with all study 
assessments.  The investigator should complete the Global Clinical Trial Pregnancy 
Form and submit it to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the accidental pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator will 
submit to the Sponsor a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
Any serious adverse events associated with the accidental pregnancy during the study 
(e.g., an event in the fetus, an event in the mother during or after the pregnancy, or a 
congenital anomaly/birth defect in the child) should be reported on the Adverse Event 
section of the eCRF. 
Abortions 
Pregnant women who experienced a spontaneous abortion will be excluded from the 
study at enrollment, scheduled at gestational Week 24−30; see Section 4.1.2, exclusions 
related to obstetric and gynecological health.  Thus, the reporting of spontaneous 
abortion as serious adverse event is exempted in this study, while it should be reported 
as medical history on the study eCRF Medical History page, if a spontaneous abortion 
occurred in previous pregnancy. 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as an SAE, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.1.3.1).  A therapeutic or elective 

 
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abortion performed for reasons other than an underlying maternal or embryofetal toxicity 
is not considered an AE. 
In addition, therapeutic or elective abortion should be reported as pregnancy outcomes 
on the study eCRF Pregnancy page and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.1.3.1). 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to the 
medicine should be classified as a serious adverse event, recorded in the adverse event 
section of the eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.1.3.1). 
5.1.4 
Follow-Up of Patients after Adverse Events 
5.1.4.1 
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 studied medicinal product 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
in the adverse event section of the eCRF and in the patient’s medical record to facilitate 
source data verification. 
5.1.4.2 
Sponsor Follow-Up 
For all adverse events, the Sponsor or a designee may follow up by telephone, fax, 
electronic mail, and/or a monitoring visit to obtain additional case details and outcome 
information (e.g., from hospital discharge summaries, consultant reports, autopsy 
reports) in order to perform an independent medical assessment of the reported case.  
Adverse event follow-up should be documented in the adverse event section of the 
eCRF. 
5.2 
SAFETY REPORTING REQUIREMENTS FOR NON-STUDIED 
MEDICINAL PRODUCTS 
Although adverse event information is not being actively solicited for non-studied 
medicinal products, the investigator/patients are reminded to report any adverse 
reactions (for which they suspect a causal role of a medicinal product) that come to their 
attention to the MAH of the suspected medicinal product, or to the concerned competent 
authorities via the national spontaneous reporting system. 
In addition, the following should also be reported if occurring during exposure to a 
marketed medicinal product, even in the absence of an adverse event: 
• 
Pregnancy 

 
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• 
Abnormal laboratory findings 
• 
Overdose, abuse, misuse, off-label use, medication error or occupational exposure 
• 
Reports of lack of efficacy 
• 
Product quality defects and falsified medicinal products 
• 
Data related to a suspected transmission of an infectious agent via a medicinal 
product 
• 
Drug interactions (including drug/drug, drug/food, drug/device, and drug/alcohol) 
 
When a patient is not exposed to a marketed medicinal product, but the 
physician/consumer becomes aware of the potential for a medication error, or an 
intercepted medication error, this should also be reported. 
5.3 
REPORTING OF PRODUCT COMPLAINTS WITHOUT ADVERSE 
EVENTS 
Report Roche product complaints without adverse events, where a product complaint is 
any written or oral information received from a complainant that alleges deficiencies 
related to identity, quality, safety, strength, purity, reliability, durability, effectiveness, or 
performance of a product after it has been released and distributed to the commercial 
market, to basel.complaint_manager_pharma@roche.com.  Report non-Roche product 
complaints as per local regulation. 
5.4 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
PHYSICIANS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious AESI 
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: 
• 
Local prescribing information for ocrelizumab (SmPC). 
 
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 physician’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 

 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of this open-label study will be primarily based on descriptive statistical 
methods.  Unless otherwise specified, no statistical tests are planned.  Corresponding 
95%CIs will be presented as appropriate. 
The primary analysis will be performed after the last blood draw at Week 6 to examine 
B-cell levels in infants.  The full analysis, including the analysis of growth velocity of the 
infants in the first year, will be conducted at the end of the study. 
Full details of all statistical aspects and planned statistical analyses will be specified in a 
separate statistical analysis plan (SAP), which will be finalized prior to the locking of the 
study database and may include further exploratory analyses not explicitly described in 
this section. 
Analysis Populations 
Full analysis set (FAS) 
Two separate FAS populations will be considered: 
• 
Women’s FAS:  this will include all pregnant women defined through the inclusion 
and exclusion criteria in the study who were exposed to ocrelizumab either 
0−6 months before the last menstrual period or in the first trimester of pregnancy 
(i.e., up to gestational Week 13 [inclusive]). 
• 
Infants’ FAS:  includes all infants born to women in the FAS who were potentially 
exposed to ocrelizumab during pregnancy. 
 
Safety Population 
The safety population for the women is the same as the FAS.  The safety population for 
infants will include all infants of mothers in the FAS population. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The study will include approximately 33 pregnant women. 
There is no formal sample size calculation, as no confirmatory hypothesis testing is 
planned.  The primary analysis will be descriptive.  Considering a 10% dropout rate, 
approximately 30 evaluable infants are expected.  A further investigation will be 
performed on the subgroup of infants whose mothers received the last dose of 
ocrelizumab 0−3 months before the LMP or during the first trimester. 
The precisions (width of the two-sided 95% CIs based on normal approximation) for 
different event rates (an “event” is defined as B-cell levels below LLN) are shown in the 
following table.  If no event is observed from the 30 infants during the study, there is a 
95% confidence that the event rate is below 0.114.   

 
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Table 5 Precision at Different Event Rates 
Sample Size 
Number of Events 
Event Rate 
Precision 
30 
1 
0.033 
0.165 
30 
2 
0.067 
0.195 
30 
3 
0.100 
0.222 
30 
4 
0.133 
0.244 
30 
5 
0.167 
0.262 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, screening failures, ocrelizumab administration, and discontinuations from the 
study will be summarized using descriptive statistics (frequency tables for categorical 
endpoints and mean, median, range, SD, and 25th−75th quartiles for the continuous 
endpoints).  Subject disposition and the incidence of treatment discontinuation for 
different reasons will be tabulated.  Major protocol violations, including violations of 
inclusion/exclusion criteria, will also be summarized.  All analyses will be performed for 
overall population. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
For women, demographics (age, self-reported ethnicity and educational level), medical 
history, and neurological examination will be summarized.  The following will also be 
summarized: MS disease history (duration since first MS symptoms, duration of MS 
since diagnosis, relapses in the past year), baseline measures of EDSS and other 
important variables. 
Characteristics of infants at birth will also be summarized (gender, weight, gestational 
age at birth and other endpoints collected). 
6.4 
PRIMARY ANALYSES 
6.4.1 
Primary Endpoint 
The primary analysis will occur once the last infant enrolled has completed the Week 6 
of life visit (or equivalent if preterm birth) for B-cell measurement.  A sensitivity analysis 
may be performed; details will be specified in the SAP. 
The B-cell levels at Week 6 of life will be analyzed using descriptive statistics.  Mean, 
corresponding 95% CI, SD, and other statistics will be presented.  Stillbirths and 
abortions of any type will not be included in the primary B-cell analysis. 
The primary estimand is defined as follows: 
• 
Population:  Infants exposed to ocrelizumab up to 6 months before the mother’s 
LMP or during the first trimester (up to gestational Week 13) of pregnancy and 
not exposed after the first trimester (Infants’ FAS). 

 
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• 
Variable:  Binary endpoint if the B-cell level is below LLN.   
Note:  B-cell reference ranges by week of life (absolute and percentage 
counts) can be found in Appendix 7. 
• 
Intercurrent events: 
– 
Withdrawal from the study prior to infant’s Week 6 visit – missing data will 
not be imputed 
– 
Interrupted pregnancy (elective or therapeutic abortion or stillbirth) – missing 
data will not be imputed 
– 
Fetal complications, or other issues, that render the sample not suitable for 
measurement of B-cell levels at Week 6 of life:  missing data will not be 
imputed 
– 
Breastfeeding before sample at Week 6 is taken:  
o No DMT postpartum while breastfeeding: B-cell data will be included 
o Received any DMT postpartum whilst breastfeeding: B-cell data will be 
excluded because sample will not be collected 
o Resume OCR postpartum while breastfeeding: B-cell data will be 
included 
– 
Infants that were born preterm and whose intervals of assessment were not 
adjusted (i.e., a baby was born at Week 35, the blood sample needs to be taken 
at Week 8 (± 14 weeks), gestational weeks that would sum up to a full-term 
baby): B-cell data will be included.   
• 
Population-level summary:  Proportion of infants with B-cell below LLN and the 
two-sided 95% CI will be reported; no formal statistical testing will be done. 
• 
Handling of missing data:  No data will be imputed.  Every effort will be made to 
ensure all samples with all supporting information are collected for B-cell 
measurement. 
 
6.4.2 
Secondary Endpoints 
Serum concentration of ocrelizumab in the pregnant women/mothers during pregnancy 
and at delivery, and the serum concentration of ocrelizumab in infants at birth (umbilical 
cord blood) and at Week 6 of life (or equivalent if preterm birth) will be summarized 
descriptively. 
Mean titers of antibody immune response(s) to vaccinations will be summarized 
descriptively.  The proportion of infants with a positive response (seroprotective titers; as 
defined for the individual vaccine) to different vaccinations will be calculated and the 
corresponding two-sided Clopper-Pearson 95% CIs will be presented overall. 
Continuous variables at each visit, as well as change from baseline (if applicable) will be 
analyzed primarily using descriptive statistics.  Mean, corresponding 95% CIs, SD, and 
other statistics will be presented. 

 
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6.4.3 
Exploratory Endpoints 
The exploratory endpoints listed in Section 2 will be summarized descriptively.  
Full details of the derivations and analyses of exploratory endpoints will be provided in 
the SAP. 
6.4.4 
Subgroup Analyses 
The subgroup of infants with potential fetal exposure (infants of mothers with 
ocrelizumab exposure 0-3 months before the LMP or first trimester exposure) will be 
analyzed. 
The following subgroups, based on timing of ocrelizumab exposure relative to the LMP, 
may be analyzed, depending on how many women/infants are enrolled in each group: 
(1) exposure to ocrelizumab 3−6 months prior to the LMP; (2) exposure to ocrelizumab 
in the 3 months prior to the LMP; (3) exposure to ocrelizumab during the first trimester of 
pregnancy (up to gestational Week 13). 
6.5 
SAFETY ANALYSES 
The safety analyses will be performed on the safety populations for the women and for 
the infants separately.  The analyses will be conducted on data collected from 
enrollment until the end of the study. 
The safety outcome measures will comprise the following: incidence and nature of all 
adverse events, including findings on vital sign measurements, neurological 
examinations, clinical laboratory tests, locally-reviewed MRIs conducted for safety 
reasons (non-MS CNS pathology), and concomitant medications. 
Safety will be assessed through summaries of adverse events (including rates/incidence 
rates and corresponding 95% CIs) and clinical laboratory abnormalities. 
All adverse events will be summarized by mapped term, appropriate thesaurus level and 
toxicity grade, and tabulated by MedDRA system organ class (SOC) and preferred term 
for individual adverse events within each SOC.  Grade 3−5 adverse events, serious 
adverse event, adverse events leading to treatment discontinuation, and time to 
withdrawal from the study due to an adverse event will be summarized.  In addition, all 
serious adverse events and deaths will be listed. 
Associated laboratory parameters, such as hepatic function, renal function, and 
hematology values will be grouped and presented together. 
The proportion of pregnancy outcomes including live births (term and preterm), 
therapeutic abortions and stillbirths will be calculated, and the corresponding two-sided 
Clopper-Pearson 95% CIs will be presented overall. 

 
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Concomitant medications recorded during the study will be summarized using frequency 
tables. 
6.6 
INTERIM ANALYSIS 
No formal effectiveness and safety interim analyses are planned.  Interim analyses for 
administrative or scientific purposes may be conducted during the course of the study. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data.  Data entered manually will be 
collected via EDC through use of eCRFs.  Sites will be responsible for data entry into the 
EDC system.  In the event of discrepant data, the CRO will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system. 
The Sponsor will perform oversight of the data management of this study.  The CRO will 
produce eCRF specifications for the study based on Sponsor’s templates including 
quality checking to be performed on the data. 
The 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  
The eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  The 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.  The eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 

 
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clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification 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 
investigational medicinal product (IMP), including eCRFs, ICFs, laboratory test results, 
and medication inventory records, must be retained by the Principal Investigator for 
15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 

 
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Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the applicable laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to 
the individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).  
Studies conducted in the US or under a US Investigational New Drug (IND).  Application 
will comply with U.S. FDA regulations and applicable local, state, and federal laws.  
Studies conducted in the EU or European Economic Area will comply with the 
EU Clinical Trials Directive (2001/20/EC) or Clinical Trials Regulation (536/2014) and 
applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample ICF (and ancillary sample ICFs such as a Mobile Nursing ICF, 
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 ICFs 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 ICF will contain separate sections for any optional procedures.  
The investigator or authorized designee will explain to each woman the objectives, 
methods, and potential risks associated with each optional procedure.  Women 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 woman's 
agreement to participate in optional procedures.  Women who decline to participate will 
not provide a separate signature. 
The Consent Forms must be signed and dated by the woman or the woman's legally 
authorized representative before her participation in the study.  Where applicable, the 
written ICF with respect to the infant will also be signed and dated by the holder of 
parental rights as designated by the maternal subject.  The case history or clinical 
records for each woman 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 

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

 
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8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the ICF (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 Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 

 
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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, ICFs, 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 GCP guidelines and require reporting 
to health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) prior to study initiation.  Due to the 
small sample size and the lack of reference quality tolerance limits (QTLs), no QTLs will 
be established or monitored.  A Quality Tolerance Limit Management Plan is therefore 
not applicable to the study. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Roche and will be managed by Roche and CROs.  
The CROs will provide clinical operations management, data management, and 
biostatistics. 
Patient data will be recorded via an EDC system using eCRFs. 

 
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9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to HCPs and to the public, at scientific congresses, in clinical 
trial registries and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  Study data may be shared with others who 
are not participating in this study (see Section 8.4 for details), and redacted Clinical 
Study Reports and/or other summaries of clinical study results may be available in 
health authority databases for public assess, as required by local regulation, and will be 
made available upon request.  For more information, refer to the Roche Global Policy on 
Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 

 
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9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
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Appendix 1:  Schedule of Assessments:  Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
84/Protocol MN42988, Version 3 
APGAR = Appearance, Pulse, Grimace, Activity, and Respiration; ASQ-3 = Ages and Stages Questionnaire version 3; CIS = Clinically isolated 
syndrome; DMT = Disease-modifying therapy; eCRF = electronic case report form; EDSS = Expanded Disability Status Scale; 
GGT = Gamma-glutamyl transpeptidase; HBcAb = Hepatitis B core antibody; HBsAb = Hepatitis B surface antibody; HBsAg = Hepatitis B surface 
antigen; HBV = Hepatitis B virus; Hib = Hemophilus influenzae type b; ICF = Informed consent form; IVF  =  in vitro fertilization; LEEP = loop 
electrosurgical excision procedure; LLN = Lower limit of normal; LMP  =  last menstrual period; MMR = Measles, mumps, and rubella; MS = Multiple 
sclerosis; NK  =  natural killer; PCV-13 = 13-pneumococcal conjugate vaccine; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
SmPC =  Summary of Product Characteristics; sNfL =  serum neurofilament light chain; USPI =  U.S. Prescribing Information; WHO = World 
Health Organization. 
Note:  ‘x’ indicates an assessment or procedure is to be done at that visit, and ‘(x)’ indicates that depending on the situation, the assessment or 
procedure may or may not be done at that visit (e.g., the pertussis vaccine would not be administered if the mother has already received it, and the 
telephone interview will not be conducted in a week where there will be an on-site visit). 
a The length of the screening/baseline period between gestational 
Week 24 and 30 is variable and depends on local timings for 
performing some of the eligibility assessments and associated 
preterm screenings performed during the first and second 
trimester.  The baseline and screening visits will be combined. 
b Depending on the timing of postpartum ocrelizumab infusion, 
postnatal assessments in the infant and the mother may occur at 
different time points.  Visit 4 and 7 timings are related to infant 
assessments, and Visits 5 and 6 to the mother’s ocrelizumab 
infusion and assessments. 
c Women who decide to discontinue the study (this includes 
discontinuation of the mother or discontinuation of the infant by the 
mother, or discontinuation at the investigator’s discretion) will be 
invited to attend an early study discontinuation visit (which may be 
conducted virtually or by telephone) as soon as possible. 
d For the umbilical cord sample, the target time of collection is within 
1 hour after birth.  The actual time of collection after delivery 
should be recorded.  The umbilical cord blood sample should only 
be collected if the mother delivered a live birth; no collection 
should occur in the event of a pregnancy interruption 
(i.e., therapeutic abortion or stillbirth). 
e Dosing and treatment duration are at the discretion of the 
physicians, in accordance with local clinical practice and local 
labelling (USPI; SmPC).  The first postpartum ocrelizumab dose 
can also be administered as 2 × 300 mg infusions separated by 
14 days.  However, all clinical and laboratory assessments related 
to Visit 5 (except for documentation of ocrelizumab and 
premedication administration) will occur only at the first 300 mg 
infusion. 
f All women must receive prophylactic treatment with 100 mg 
methylprednisolone (or an equivalent), administered by slow 
IV infusion, to be completed approximately 30 minutes prior to 
each ocrelizumab infusion and an antihistamine by oral or IV route, 
to be completed approximately 30–60 minutes prior to each 
infusion of ocrelizumab.  The antihistamine should be the first 
premedication to be administered.  The addition of an antipyretic 
(e.g., acetaminophen/paracetamol) may also be considered 
approximately 30−60 minutes prior to each infusion of 
ocrelizumab. 

Appendix 1:  Schedule of Assessments:  Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
85/Protocol MN42988, Version 3 
g Treatment with ocrelizumab may be resumed at any time after 
birth in women who decide not to breastfeed.  Some women may 
decide to resume ocrelizumab whilst breastfeeding; in those 
women, treatment with ocrelizumab should be restarted after 
collection of the infant blood sample at Week 6 of life (± 7 days) 
if possible (however, the decision is left to the discretion of the 
woman and the investigator).  If the woman switches to another 
DMT postpartum, the infant blood sample at Week 6 of life 
(± 7 days) will only be collected if the woman is not breastfeeding. 
h Samples at this visit will be collected 1 month (+ 30 days) after the 
first dose of MMR vaccine (if first dose is administered at 
11 months of age or later) OR 1 month (+ 30 days) after the 
second dose of MMR vaccine (if first dose is administered before 
11 months of age) OR at Month 13 of chronological age 
(+ 30 days) if MMR vaccine is not planned to be administered. 
i The following diagnoses are accepted: MS or CIS (in line with the 
locally approved indications). 
j Written informed consent will be obtained from all women at 
screening in order to be eligible for the study.  Where applicable, 
the written ICF with respect to the infant is also signed and dated 
by the holder of parental rights as designated by the maternal 
subject. 
k Medical history includes clinically significant diseases, 
surgeries/procedures, smoking history, alcohol intake and all 
medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, and nutritional 
supplements) used by the woman within 6 weeks prior to the 
screening/baseline visit.  Demographic data will include age, 
educational level and self-reported ethnicity.  Clinically significant 
diseases and/or surgeries/procedures, and concomitant 
medication should also be recorded throughout the study. 
l Documentation whether folic acid (recommended daily intake 
400 micrograms per day, or as per local practice) was prescribed 
and administered up to the first trimester of pregnancy (up to 
gestational Week 13). 
m Documentation of start of ocrelizumab therapy and date and dose 
of last ocrelizumab infusion prior to enrollment. 
n Gestational age will be determined by LMP and first trimester 
ultrasound so long as there is less than 1 week’s difference in the 
projected due date.  If there is over 1 week’s difference, then the 
ultrasound alone will be used.  For cases where the LMP is not 
known, then the earliest ultrasound will be used.  For cases of IVF, 
the projected dates from the IVF procedure will be preferentially 
used. 
o History of previous pregnancy outcomes and disorders associated 
with adverse pregnancy outcomes includes, but is not limited to 
history of the following:  preterm birth (gestational age < 37 weeks) 
for any indication with or without fetal malformations; spontaneous 
abortion (miscarriage) after the first trimester (i.e., after gestational 
Week 13); stillbirth (defined as fetal loss at gestational age 
> 22 weeks); pre-eclampsia/eclampsia; and cervical pathology or 
intervention which may increase the risk of cervical incompetence 
(e.g., history of cervical cerclage, prior cervical conization or prior 
LEEP). 
p Prior or current history of any other gynecological disease 
considered by the investigator to be associated with a high risk of 
adverse pregnancy outcomes in the current pregnancy. 
q The first (12-week) and second (18−20-week) obstetric 
ultrasounds have to be documented and should confirm the 
absence of abnormalities described in the exclusion criteria.  
The third trimester ultrasound may be performed in countries 
where this is part of routine obstetric care. 

Appendix 1:  Schedule of Assessments:  Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
86/Protocol MN42988, Version 3 
r A complete physical examination should be performed at the 
screening/baseline visit and at all subsequent visits (results from 
examinations done as part of routine care may be used).  Any 
abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.  Changes 
from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities not related to 
MS should be recorded as adverse events on the Adverse Event 
eCRF.  An obstetric examination will also be performed as per 
local clinical practice. 
s Neurological examinations will be used to distinguish relapse in 
MS from another neurological (non-MS) disorder.  Potential 
relapses should be recorded throughout the study period after 
screening.  To reduce the burden of visits to mothers, results from 
neurological examinations done as part of routine care may be 
used.  For patients referred to the investigator, results from routine 
visits at the woman’s neurologist may be used. 
t In women who undergo vaccination as part of routine care.  
Information on vaccinations administered during the study will be 
collected under concomitant medications. 
u Samples at third trimester (Week 35 [± 14 days]) may be collected 
by home nurse visit. 
v Hematology will include hemoglobin, hematocrit, RBCs, WBC 
absolute or/and differential count (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils), and quantitative platelet 
count.  Chemistry will include AST, ALT, GGT, creatinine, total 
bilirubin, random glucose, potassium, sodium, chloride.  The 
scheduled obstetric blood glucose test should preferably be 
conducted at the screening/baseline visit rather than at a separate 
visit.  Urine dipstick (pH, specific gravity, glucose, protein, ketones, 
blood) and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria) will be done at site locally 
at the discretion of the investigator. 
w Women with positive screening tests for HBV, determined by a 
positive HBsAg result (current infection) or positive HBcAb titers 
(previous infection) will be excluded.  Women with documented 
history of HBV vaccination or positive HBsAb titers are eligible. 
x Postpartum, lymphocyte subtype samples should be collected 
(fresh whole blood) prior to ocrelizumab infusion to screen for 
B-cell counts (CD19 +  and B-cell subsets [Table 2]), T-cell counts 
(CD3 +, CD4 +, CD8 + ), and NK cell counts (CD16+CD56+) 
analysis by flow cytometry. 
y At delivery, the serum sample should be collected within 24 hours 
after delivery.  Postpartum, serum samples should be collected 
5−30 minutes prior to the methylprednisolone infusion on the day 
of sampling.  The maternal blood sample at delivery should only 
be collected if the mother delivered a live birth; no collection 
should occur in the event of a pregnancy interruption (i.e., 
therapeutic abortion or stillbirth). 
z Serum titers of antibody responses to vaccinations for measles, 
mumps, rubella, tetanus toxoid, diphtheria, pertussis, varicella 
zoster, Streptococcus pneumoniae, HBV, and SARS-CoV-2 (along 
with nucleocapsid and spike protein titers; only for those mothers 
who have received the vaccine, as per local clinical practice) will 
be performed during the third trimester (Week 35 ± 14 days). 
aa These will include:  mode of delivery (vaginal delivery, instrumental 
delivery, scheduled or urgent cesarean section); APGAR score 
(1 min, 5 min, 30 min); gestational age at birth; infant’s 
measurements (weight, length, head circumference); and 
congenital malformations. 
bb Mothers should record feeding status of the infant, i.e., whether 
exclusive breastfeeding, mixed feeding (partial breastfeeding 

Appendix 1:  Schedule of Assessments:  Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
87/Protocol MN42988, Version 3 
along with infant formula and/or baby food), exclusive infant 
formula feeding, or fully weaned. 
cc Growth charts (according to the WHO Child Growth Standards 
[WHO 2022]) as well as other standard questionnaires may be 
used.  In addition, absolute values will be recorded 
(measurements recorded by e.g., the pediatrician as part of routine 
postnatal care may be used.  Infant growth will be captured at 
Months 2, 4, 6, 9, and 12 (see Appendix 6 for time windows for 
infant growth velocity and child developmental milestone 
assessments). 
dd Assessment of child developmental milestones in the domains of 
communication, gross motor, fine motor, problem solving, and 
personal-social will be captured at Months 2, 4, 6, 9, and 12 using 
the ASQ-3 (see  Appendix 6 for time windows for infant growth 
velocity and child developmental milestone assessments). 
ee Changes to concomitant medication given to the infant should be 
recorded throughout the study. 
ff Vaccines administered from birth throughout the end of the study 
should be recorded at Months 2, 4, 6, 9, and 12 as well as at 
Month 13 of age (+ 30 days)/1 month (+ 30 days) after first or 
second MMR dose. 
gg As per the recommendation of the EC ad hoc group (2008) the 
total blood volume to be collected from an infant in a clinical study 
should not exceed 0.8−0.9 mL/kg at any timepoint, or 2.4 mL/kg 
over any 4 week period throughout the study.  If the blood volume 
collected for an infant (as a result of these limits) is insufficient to 
carry out all planned assessments, the order of priority for 
assessments is as follows: for the Week 6 sample, (1) safety 
laboratory samples [scheduled or unscheduled and performed at 
the discretion of the Investigator] (2) lymphocyte subtypes sample 
for B-cell counts (CD19 + ), T-cell counts (CD3 +, CD4 +, and 
CD8 + ), and NK cell counts (CD16+CD56+) (3) serum 
ocrelizumab concentration; for the Month 13 of age 
(+ 30 days)/1 month (+ 30 days) after first or second MMR vaccine 
dose sample, (1) safety laboratory samples [scheduled or 
unscheduled and performed at the discretion of the Investigator] 
(2) serum titers of antibody response to immunizations (3) 
lymphocyte subtypes sample for B-cell counts (CD19 + ), T-cell 
counts (CD3 +, CD4 +, and CD8 + ), and NK cell counts 
(CD16+CD56 + ). 
hh For preterm infants (gestational age < 37 weeks), blood samples 
will be collected at the week of life equivalent to term infants 
(e.g., if birth occurred at gestational Week 35, blood sample would 
be collected at Week 8 of life). 
ii If the infant’s B-cell levels are below LLN, repeat analyses may be 
done at unscheduled visits, at the discretion of the investigator (in 
consultation with the Sponsor). 
jj Note that this sample will be taken from umbilical cord blood. 
kk Infant samples at Week 6 of life (± 7 days) may be collected during 
a site visit, or by home nurse visit. 
ll For Month 13 of age (+ 30 days)/1 month (+ 30 days) after the first 
or second dose of MMR:  all efforts will be made to collect 
samples.  However, if they cannot be collected, this will not be 
considered a protocol deviation. 
mm Vaccinations may include the following, in line with clinical 
practice:  diphtheria, tetanus, pertussis, Hib, PCV-13, HBV, and 
MMR.  Antibody responses to vaccinations will be measured 
1 month (+ 30 days) after the first dose of MMR vaccine (if first 
dose is administered at 11  months of age or later), or 1 month 
(+ 30 days) after second dose of MMR vaccine (if first dose is 
administered before 11 months of age), or at Month 13 of 
chronological age (+ 30 days) if MMR vaccine is not planned to be 
administered. 

Appendix 1:  Schedule of Assessments:  Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
88/Protocol MN42988, Version 3 
nn A structured telephone interview will be conducted by site 
personnel postpartum every 3 months (in-between ocrelizumab 
infusions) for a general review, and to identify and collect 
information on any changes in the woman’s or infant’s health 
status (including the occurrence of MS relapses in the woman and 
use of new concomitant medications) and possible adverse events 
in both the woman and the infant (particularly infections); women 
will also be asked if the ASQ-3 form is being filled out.  No 
telephone contact is needed in weeks where the woman is 
performing on-site visits. 
oo Adverse events in both the mother and the infant will be reported 
throughout the study as per standard pharmacovigilance 
procedures. 
 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
89/Protocol MN42988, Version 3 
  
Potentially Teratogenic Drugs 
Table A2-1 List of Potentially Teratogenic Drugs a 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Anti-infective and Anti-parasitic agents 
Albendazole 
P02CA03 
D 
n.a. 
C 
Amikacin 
J01GB06 
D 
D 
D 
Artemether 
P01BE52 
D 
n.a. 
C 
Artemether 
P01BE02 
D 
n.a. 
C 
Chloroquine 
P01BA01 
D 
B3 
n.a. 
Cidofovir 
J05AB12 
D 
D 
C 
Demeclocycline 
J01AA01 
D 
n.a. 
D 
Doxycycline 
A01AB22 
D 
n.a. 
D 
Doxycycline 
J01AA02 
D 
D 
D 
Efavirenz 
J05AG03 
D 
D 
D 
Fluconazole 
J02AC01 
D 
B3 
C 
Ganciclovir 
J05AB06 
D 
D 
C 
Gentamicine 
J01GB03 
D 
D 
D 
Hydroxychloroquine 
P01BA02 
D 
B3 
n.a. 
Minocycline 
J01AA08 
D 
n.a. 
D 
Netilmicin 
J01GB07 
D 
D 
D 
Oxytetracycline 
J01AA06 
D 
D 
n.a. 
Primaquine 
P01BA03 
D 
n.a. 
n.a. 
Quinine 
P01BC01 
D 
D 
C 
Ribavirin 
J05AB04 
D 
D 
X 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
90/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Streptomycine 
J01GA01 
n.a. 
n.a. 
D 
Tetracycline 
A01AB13 
D 
n.a. 
D 
Tetracycline 
J01AA07 
D 
D 
D 
Tigecycline 
J01AA12 
D 
D 
D 
Tobramycin 
J01GB01 
D 
B3 
D 
Valganciclovir 
J05AB14 
D 
D 
C 
Zalcitabine 
J05AF03 
D 
n.a. 
C 
Agents acting on the renin-angiotensin 
system 
Benazepril 
C09AA07 
n.a. 
n.a. 
D 
Candesartan 
C09CA06 
D 
D 
D 
Captopril 
C09AA01 
D 
D 
D 
Cilazapril 
C09AA08 
D 
n.a. 
n.a. 
Enalapril 
C09AA02 
D 
D 
D 
Eprosartan 
C09CA02 
D 
D 
D 
Exforge 
C09DB01 
D 
D 
D 
Fosinopril 
C09AA09 
D 
n.a. 
C 
Irbesartan 
C09CA04 
D 
D 
C 
Lisinopril 
C09AA03 
D 
D 
D 
Losartan 
C09CA01 
D 
D 
C 
Olmesartan 
C09CA08 
D 
n.a. 
C 
Perindopril 
C09AA04 
D 
D 
D 
Quinapril 
C09AA06 
D 
D 
D 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
91/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Ramipril 
C09AA05 
D 
D 
D 
Telmisartan 
C09CA07 
D 
D 
C 
Trandolapril 
C09AA10 
D 
n.a. 
C 
Valsartan 
C09CA03 
D 
D 
D 
Anti-thrombotic agents 
Acenocoumarol 
B01AA07 
n.a. 
n.a. 
n.a. 
Fenprocoumon 
B01AA04 
n.a. 
n.a. 
n.a. 
Warfarin 
B01AA03 
D 
D 
X 
Statins 
Atorvastatin 
C10AA05 
D 
D 
X 
Fluvastatin 
C10AA04 
D 
B3 
X 
Pravastatin 
C10AA03 
D 
B3 
X 
Rosuvastatin 
C10AA07 
D 
D 
X 
Simvastatin 
C10AA01 
D 
B3 
X 
Dermatologicals 
Aciretin 
D05BB02 
X 
D 
X 
Adapalene 
D10AD03 
D 
B3 
C 
Finasteride 
D11AX10 
X 
D 
X 
Isotretinoin 
D10BA01 
X 
n.a. 
X 
Tazaroteen 
D05AX05 
D 
n.a. 
X 
Tetracycline 
D06AA04 
D 
n.a. 
B 
Tretinoin 
D10AD01 
D 
B3 
C 
Pituitary, hypothalamic and sex 
hormones 
Carboprost 
G02AD04 
D 
n.a. 
C 
Cetrorelix 
H01CC02 
D 
C 
X 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
92/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Danazol 
G03XA01 
D 
n.a. 
X 
Dutasteride 
G04CB02 
D 
n.a. 
X 
Dydrogesteron 
G03DB01 
D 
n.a. 
n.a. 
Estrogens, esterified 
G03CA57 
D 
n.a. 
X 
Finasteride 
G04CB01 
D 
D 
X 
Follitropin alpha 
G03GA05 
D 
B1 
n.a. 
Ganirelix 
H01CC01 
D 
C 
X 
Gestrinon 
G03XA02 
D 
n.a. 
n.a. 
Levonorgestrel 
G02AC03 
B3 
n.a. 
X 
Lynestrenol 
G03DC03 
D 
D 
n.a. 
Medrogestron – IM 
G03DA02 
D 
D 
n.a. 
Medroxyprogesterone and 
estrogen 
G03FA12 
D 
B3 
X 
Medroxyprogesterone and 
estrogen 
G03FB06 
D 
B3 
X 
Mesterolon 
G03BB01 
D 
n.a. 
n.a. 
Nafarelin 
H01CA02 
D 
B3 
X 
Nomegestrol 
G03DB04 
D 
n.a. 
n.a. 
Norethisterone 
G03DC02 
D 
D 
X 
Progesterone 
G03DA04 
D 
n.a. 
n.a. 
Raloxifene 
G03XC01 
D 
D 
X 
Testosterone 
G03BA03 
D 
D 
X 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
93/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Tetracosactide 
H01AA02 
D 
C 
n.a. 
Tibolon 
G03CX01 
D 
B3 
n.a. 
Anti-neoplastic agents 
Alitretinoin 
L01XX22 
n.a. 
n.a. 
D 
Altretamine 
L01XX03 
D 
n.a. 
D 
Amsacrine 
L01XX01 
D 
D 
n.a. 
Bevacizumab 
L01XC07 
D 
D 
C 
Bleomycin 
L01DC01 
D 
D 
n.a. 
Bortezomib 
L01XX32 
C 
D 
D 
Busulfan 
L01AB01 
D 
D 
D 
Capecitabine 
L01BC06 
D 
D 
D 
Carboplatin 
L01XA02 
D 
D 
D 
Carmustine 
L01AD01 
D 
n.a. 
D 
Cetuximab 
L01XC06 
D 
B2 
C 
Chlorambucil 
L01AA02 
D 
D 
D 
Cisplatin 
L01XA01 
D 
D 
D 
Cladribine 
L01BB04 
D 
D 
D 
Clofarabine 
L01BB06 
n.a. 
D 
D 
Cyclophosphamide 
L01AA01 
D 
D 
D 
Cytarabine 
L01BC01 
D 
D 
D 
Dacarbazine 
L01AX04 
D 
D 
C 
Dactinomycin 
L01DA01 
D 
n.a. 
C 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
94/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Dasatinib 
L01XE06 
D 
B3 
D 
Daunorubicin 
L01DB02 
D 
D 
D 
Docetaxel 
L01CD02 
D 
D 
D 
Doxorubicin 
L01DB01 
D 
D 
D 
Epirubicin 
L01DB03 
D 
D 
D 
Erlotinib 
L01XE03 
C 
B3 
D 
Estramustine 
L01XX11 
D 
n.a. 
n.a. 
Etoposide 
L01CB01 
D 
D 
D 
Fludarabine 
L01BB05 
D 
D 
D 
Fluorouracil 
L01BC02 
D 
D 
D 
Gemcitabine 
L01BC05 
D 
D 
D 
Hydroxycarbamide 
L01XX05 
n.a. 
D 
n.a. 
Idarubicin 
L01DB06 
D 
D 
D 
Ifosfamide 
L01AA06 
D 
D 
D 
Imatinib 
L01XE01 
D 
B3 
D 
Irinotecan 
L01XX19 
D 
B3 
D 
Lapatinib 
L01XE07 
n.a. 
B3 
D 
Lomustine 
L01AD02 
D 
D 
D 
Melphalan 
L01AA03 
D 
D 
D 
Mercaptopurine 
L01BB02 
D 
D 
D 
Methotrexate 
L01BA01 
D 
D 
X 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
95/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Mitomycine 
L01DC03 
D 
D 
D 
Mitoxantrone 
L01DB07 
D 
D 
D 
Nelaribine 
L01BB07 
n.a. 
D 
D 
Oxaliplatin 
L01XA03 
D 
D 
D 
Paclitaxel 
L01CD01 
D 
D 
D 
Pemetrexed 
L01BA04 
D 
D 
D 
Pentostatin 
L01XX08 
n.a. 
n.a. 
D 
Procarbazine 
L01XB01 
D 
n.a. 
D 
Raltitrexed 
L01BA03 
D 
n.a. 
n.a. 
Sorafenib 
L01XE05 
D 
C 
D 
Streptozocine 
L01AD04 
n.a. 
n.a. 
D 
Sunitinib 
L01XE04 
D 
B3 
D 
Tegafur 
L01BC03 
D 
n.a. 
n.a. 
Temozolomide 
L01AX03 
D 
D 
D 
Teniposide 
L01CB02 
D 
n.a. 
D 
Thioguanine 
L01BB03 
D 
D 
D 
Thiotepa 
L01AC01 
D 
n.a. 
D 
Topotecan 
L01XX17 
D 
D 
D 
Tretinoin 
L01XX14 
X 
n.a. 
D 
Vinblastine 
L01CA01 
D 
D 
D 
Vincristine 
L01CA02 
D 
D 
D 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
96/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Vindesine 
L01CA03 
D 
D 
n.a. 
Vinorelbine 
L01CA04 
D 
D 
D 
Immunomodulating agents 
Aminoglutethimide 
L02BG01 
D 
n.a. 
D 
Azathioprine 
L04AX01 
D 
D 
D 
Basiliximab 
L04AC02 
D 
B2 
B 
Daclizumab 
L04AC01 
D 
n.a. 
C 
Fulvestrant 
L02BA03 
D 
D 
D 
Goserelin 
L02AE03 
D 
D 
D 
Interferon Beta 1a 
L03AB07 
D 
D 
C 
Interferon Beta 1b 
L03AB08 
D 
D 
C 
Leflunomide 
L04AA13 
D 
D 
X 
Lenalilomide 
L04AX04 
n.a. 
D 
X 
Letrozole 
L02BG04 
D 
B3 
D 
Leuprorelin 
L02AE02 
D 
C 
n.a. 
Medrogestron IM 
L02AB02 
D 
D 
n.a. 
Megestrol 
L02AB01 
D 
B3 
X 
Mycophenolic acid 
L04AA06 
D 
D 
D 
Penicillamine 
M01CC01 
D 
n.a. 
D 
Tamoxifen 
L02BA01 
B3 
D 
D 
Tasonermine 
L03AX11 
D 
B2 
n.a. 
Thalidomide 
L04AX02 
D 
D 
X 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
97/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Toremifene 
L02BA02 
B3 
B3 
D 
Triptorelin 
L02AE04 
D 
B3 
X 
Anti-epileptic agents 
Carbamazepine 
N03AF01 
D 
D 
C 
Ethosuximide 
N03AD01 
D 
D 
n.a. 
Lamotrigine 
N03AX09 
D 
B3 
C 
Methylfenobarbital 
N03AA01 
D 
n.a. 
n.a. 
Oxcarbazepine 
N03AF02 
D 
D 
C 
Phenobarbital 
N03AA02 
D 
D 
D 
Phenytoin 
N03AB02 
D 
D 
n.a. 
Primidone 
N03AA03 
D 
n.a. 
n.a. 
Sultiam 
N03AX03 
D 
n.a. 
n.a. 
Valproic acid 
N03AG01 
D 
D 
D 
Vigabatrin 
N03AG04 
D 
D 
C 
Psycholeptic and psychoanaleptic 
agents 
Amobarbital 
N05CA02 
n.a. 
n.a. 
D 
Butabarbital 
N05CA03 
n.a. 
n.a. 
D 
Lithium 
N05AN01 
D 
n.a. 
n.a. 
Paroxetine 
N06AB05 
D 
C 
D 
Pentobarbital 
N05CA01 
n.a. 
n.a. 
D 
Secobarbital 
N05CA06 
n.a. 
n.a. 
D 
Miscellaneous agents 
Acetohydroxac acid 
G04BX03 
n.a. 
n.a. 
X 
Ambrisentan 
C02KX02 
X 
D 
X 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
98/Protocol MN42988, Version 3 
Group 
Name 
ATC-
Code 
The Former 
ADEC 
The 
FASS 
Pregnancy Classification of 
the FDA 
Bosentan 
C02KX01 
D 
D 
X 
Deferipron 
V03AC02 
D 
n.a. 
n.a. 
Dihydroergotamine 
N02CA01 
C 
C 
X 
Ergotamine 
N02CA02 
C 
n.a. 
X 
Hydrokinine 
M09AA01 
D 
n.a. 
n.a. 
Ivrabradine 
C01EB17 
D 
D 
n.a. 
Misoprostol 
A02BB01 
X 
D 
X 
Nandrolone 
A14AB01 
D 
n.a. 
X 
Nicotine 
N07BA01 
D 
C 
C 
Oxandrolone 
A14AA08 
D 
n.a. 
X 
Prasteron 
A14AA07 
D 
n.a. 
n.a. 
Retinol 
A11CA01 
D 
n.a. 
n.a. 
Tretinoin 
A01AD11 
D 
n.a. 
D 
ADEC = Australian Drug Evaluation Committee; ATC = anatomical therapeutic chemical; FASS = Swedish catalogue of approved drugs; 
FDA = Food and Drug Authority. 
a See definitions of the pregnancy classifications in the following table. 
Source:  Zomerdijk et al. 2015. 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
99/Protocol MN42988, Version 3 
Table A2-2 Overview of the Definitions of the Pregnancy Classifications of the ADEC, FASS, and FDA 
Category 
The Former ADEC 
The FASS 
Pregnancy Classification of the FDA 
A 
Drugs which have been taken by a 
large number of pregnant women and 
women of childbearing age without 
any proven increase in the frequency 
of malformations or other direct or 
indirect harmful effects on the fetus 
having been observed. 
Medicinal products which may be assumed to have 
been used by a large number of pregnant women and 
women of childbearing age without any identified 
disturbance in the reproductive process, e.g., an 
increased incidence of malformations or other direct or 
indirect harmful effect on the fetus. 
Adequate and well-controlled studies in pregnant 
women have failed to demonstrate a risk to the 
fetus in the first trimester of pregnancy (and there 
is no evidence of risk in later trimesters). 
B 
Drugs which have been taken by only 
a limited number of pregnant women 
and women of childbearing age, 
without an increase in the frequency 
of malformation or other direct or 
indirect harmful effects on the human 
fetus having been observed.  B1 
Studies in animals have not shown 
evidence of an increased occurrence 
of fetal damage. 
B2 Studies in animals are inadequate 
or may be lacking, but available data 
show no evidence of an increased 
occurrence of fetal damage. 
B3 Studies in animals have shown 
evidence of an increased occurrence 
of fetal damage, the significance of 
which is considered uncertain in 
humans. 
Medicinal products which may be assumed to have 
been used by only a limited number of pregnant 
women and women of childbearing age, without any 
identified disturbance in the reproductive process 
having been noted so far, e.g., an increased incidence 
of malformations or other direct or indirect harmful 
effect on the fetus.  B1 reproduction toxicity studies 
have not given evidence of an increased incidence of 
fetal damage or other deleterious effects on the 
reproductive process. 
B2 reproduction toxicity studies are inadequate or 
lacking, but available data do not indicate an 
increased incidence of fetal damage or other 
deleterious effects on the reproductive process. 
B3 reproduction toxicity studies in animals have 
revealed an increased incidence of fetal damage or 
other deleterious effects on the reproductive process, 
the significance of which is considered uncertain in 
man. 
Animal reproduction studies have failed to 
demonstrate a risk to the fetus and there are no 
adequate and well-controlled studies in pregnant 
women OR Animal reproduction studies have 
shown an adverse effect, but adequate and well- 
controlled studies in pregnant women have failed 
to demonstrate a risk to the fetus during the first 
trimester of pregnancy (and there is no evidence 
of a risk in later trimesters) 

Appendix 2:  Potentially Teratogenic Drug 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
100/Protocol MN42988, Version 3 
Category 
The Former ADEC 
The FASS 
Pregnancy Classification of the FDA 
C 
Drugs which, owing to their 
pharmacological effects, have caused 
or may be suspected of causing, 
harmful effects on the human fetus or 
neonate without causing 
malformations. 
These effects may be reversible.  
Accompanying texts should be 
consulted for further details. 
Medicinal products which by their pharmacological 
effects have caused, or must be suspected of causing, 
disturbances in the reproductive process that may 
involve risk to the fetus without being directly 
teratogenic.  If experimental studies in animals have 
indicated an increased occurrence of fetal injuries or 
other injurious effects on the reproductive process of 
uncertain significance in humans, these findings are to 
be stated in this category. 
Animal reproduction studies have shown an 
adverse effect on the fetus and there are no 
adequate and well-controlled studies in humans, 
but potential benefits from the use of the drug in 
pregnant women may be acceptable despite its 
potential risk. 
D 
Drugs which have caused, are 
suspected to have caused or may be 
expected to cause, an increased 
incidence of human fetal 
malformations or irreversible 
damage.  These drugs may also have 
adverse pharmacological effects. 
Accompanying texts should be 
consulted for further details. 
Medicinal products which have caused an increased 
incidence of fetal malformations or other permanent 
damage in man or which, on the basis of e.g., 
reproduction toxicity studies, must be suspected of 
doing so.  This category comprises drugs with primary 
teratogenic effects.  If the product also has 
pharmacological effects that may directly or indirectly 
have a harmful effect on the fetus, this must also be 
stated. 
There is positive evidence of human fetal risk 
based on adverse reaction data from 
investigational or marketing experience or 
studies in humans, but potential benefits from the 
use of the drug in pregnant women may be 
acceptable despite its potential risks (for 
example, if the drug is needed in a life-
threatening situation or serious disease for which 
safer drugs cannot be used or are ineffective). 
X 
Drugs which have such a high risk of 
causing permanent damage to the 
fetus that they should not be used in 
pregnancy or when there is a 
possibility of pregnancy. 
Not applicable 
Studies in animals or humans have 
demonstrated fetal abnormalities and/or there is 
positive evidence of human fetal risk based on 
adverse reaction data from investigational or 
marketing experience, and the risks of the use of 
the drug in pregnant women clearly outweighs 
any 
ADEC = Australian Drug Evaluation Committee; FASS = Swedish catalogue of approved drugs; FDA = Food and Drug Authority. 
Source:  Zomerdijk et al. 2015. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
101/Protocol MN42988, Version 3 
  
Guidance for Diagnosis of Progressive 
Multifocal Leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) is a rare infection of the CNS caused 
by reactivation of a latent JC virus (JCV), and develops almost exclusively in patients 
with a compromised immune system (i.e., opportunistic).  It is pathologically 
characterized by lytic infection of oligodendrocytes and astrocytes by the JCV. 1,2 
Most confirmed cases of PML in patients with MS have been associated with and 
described in those treated with natalizumab, but cases associated with fingolimod and 
dimethyl fumarate have also been reported.3 
A3–1 
CLINICAL PRESENTATION 
Cognitive changes are the most common clinical feature of PML, but presentation is 
often heterogeneous with neurobehavioral, motor, language, and visual symptoms, as 
well as other clinical signs and symptoms that often resemble those observed with an 
MS relapse (see Table A3-1).  However, in PML these tend to follow a slow and 
persistently progressive course.1,2,4 No distinguishing clinical features appear to exist 
between PML associated with natalizumab, fingolimod, or DMF.3,5 
Acute or subacute cognitive changes, language disturbances, and seizures should serve 
as “red flags” for the possibility of PML, whereas optic neuritis and myelopathy should be 
considered as unlikely clinical manifestations of PML. 
Table A3-1 Clinical Features of MS and PML 
Parameters 
MS 
PML 
Onset 
Acute 
Subacute 
Evolution 
Hours to days 
Over weeks 
Normally stabilize.  May resolve 
spontaneously even without 
therapy 
Progressive 
Clinical Presentation 
Diplopia 
Paranesthesia 
Paraparesis 
Optic neuritis 
Myelopathy 
Aphasia 
Behavioral/neuropsychiatric 
changes 
Hemiparesis 
Retrochiasmal visual changes 
(e.g., hemianopia) 
Seizures 
MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy. 
 

Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
102/Protocol MN42988, Version 3 
A3–2 
MRI PRESENTATION 
MRI scans offer a sensitive tool in the diagnosis of PML but detection, particularly of pre-
symptomatic PML, can be difficult owing to the overlap of imaging findings with 
MS lesions.  However, the four most distinguishing imaging features of a PML lesion are 
(Figure A3-1 and Figure A3-2): 
• 
Subcortical location (involvement of U-fibers) 
• 
T1 hypointensity 
• 
Diffusion weighted imaging hyperintensity 
• 
Presence of punctate T2-hyperintense lesions (Table A3-2) 2 
 
No unique or pathognomonic radiographic features appear to exist for NTZ-, fingolimod- 
or DMF-associated PML.3,5 
Figure A3-1 
Imaging characteristics of MS and PML 
 
IRIS = immune reconstitution inflammatory syndrome; MS = multiple sclerosis; PMS = progressive 
multifocal leukoencephalopathy. 
T2- and T1-weighted images (with contrast administration) at the time of PML diagnosis (top row) 
and at the time of PML-IRIS stage (bottom row).  The images at diagnosis (‘inflammatory PML’) 
show a subcortical lesion and multiple cortical lesions in the right frontal lobe showing contrast 
enhancement (C and D) in addition to punctuate T2 lesions following a perivascular distribution 
that also enhance on T1 after contrast administration (A and B).  These inflammatory PML 
lesions show different enhancement pattern such as punctuate (B) and patchy (D).  At the time of 
PML-IRIS manifestation, the PML lesions have increased in size, and the contrast enhancement 
of the main PML lesion (H and I) as well as in and around the perivascular T2 lesions (F and G) 
has also markedly increased.  In addition, there are now signs of edema with mass effect around 
the PML lesions (F and H).  Adapted Wattjes 2018.8 
 

Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
103/Protocol MN42988, Version 3 
Figure A3-2 
Imaging Characteristics of MS and PML 
 
DWI = diffusion weighted imaging; FLAIR = fluid attenuated inversion recovery; MS = multiple 
sclerosis; PMS = progressive multifocal leukoencephalopathy. 
FLAIR (left) and DWI (right) images.  DWI can help determine new lesions (hyperintense) on a 
background of older diffuse MS lesions (right).  Adapted from MS-PML.org. 
 
Table A3-2 Imaging Characteristics of MS and PML1,6,7 
 
Parameters 
MS 
PML 
Location 
• Unilateral or bilateral 
• Mostly located in periventricular, 
deep white matter, cerebellum, 
spinal cord areas 
• Also cortical and deep grey 
matter 
• U-fibers may be involved 
• Often bilateral 
• a Subcortical frontal (+ + +), parietal 
(+ +), occipital (+) white matter 
(involving U-fibers) is the prime site 
• Cortex and basal ganglia are often 
involved 
• Can involve corpus callosum but 
unusual; rarely brainstem and posterior 
fossa 
Appearance 
and Borders 
• Focal (mostly) 
• Well-defined lesions with sharp 
edges; mostly round or finger-
like in shape (especially 
periventricular lesions) 
• Multifocal 
• Ill-defined lesions with sharp border 
towards grey matter, and ill-defined 
border towards white matter 
Size 
• Usually < 3cm 
• Usually > 3cm 
Mode of 
extension 
• Initially focal, lesions enlarge 
within days or weeks and later 
decrease in size within months  
• Lesions increase in size and new 
lesions appear 
• Confluence with other lesions is 
common 
 

Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
104/Protocol MN42988, Version 3 
Table A3-2 Imaging Characteristics of MS and PML1,6,7 (cont.) 
 
Parameters 
MS 
PML 
Mass effect 
Acute lesions, in particular large 
lesions, show some mass effect 
Not typical in neither small nor large 
lesions.  PML-IRIS may show mass effect 
T2W 
Acute lesions:  hyperintense 
center, isointense ring, discrete 
hyperintensity outside the ring 
structure 
Subacute and chronic lesions: 
hyperintense, with no ring 
structure 
Always hyperintense 
a Small, punctate T2-hyperintense lesions 
in the immediate vicinity of the main 
lesion are often present 
FLAIR 
Hyperintense equal to T2; sharply 
delineated 
Always hyperintense (better appreciated 
than on T2W images making it more 
sensitive for detection of PML in 
subcortical structures) 
T1W 
Isointense or hypointense 
a Typically hypointense; no reversion of 
signal intensity (hyperintensity suggestive 
of PML-IRIS) 
DWI 
It can be hyperintense or 
non-hyperintense 
a Always hyperintense; in larger lesions 
there is a hyperintense rim at the lesion’s 
edge b 
Contrast 
enhancement 
Acute lesions enhancenodular 
or incomplete ring 
40%–50% enhancement−linear, nodular, 
punctate or peripheral pattern (variable) 
Atrophy 
Focal atrophy possible, due to 
focal degeneration 
No atrophy in the early phase 
DWI = diffusion weighted imaging; FLAIR = fluid attenuated inversion recovery; IRIS = immune 
reconstitution inflammatory syndrome; MS = multiple sclerosis; PML = progressive multifocal 
leukoencephalopathy; T1W = T1-weighted; T2W = T2-weighted. 
a Features especially helpful in the identification of small PML lesions. 
b In the early stages of disease, DWI shows high signal owing to swollen and dying 
oligodendrocytes.  Treatment commencement results in the lesion rim losing its DWI 
hyperintensity, and over time the lesion becomes hypointense owing to tissue destruction.  
Apparent diffusion coefficient values rise with progressive white matter injury, in keeping with 
more irreversible damage.  This evolution of DWI signal changes is essential in monitoring 
disease progression and treatment response. 
 
A3–3 
PML DIAGNOSIS 
American Academy of Neurology consensus statements mandate that diagnosis is made 
from brain biopsy, or more commonly from clinical findings combined with JCV DNA in 
CSF, typically supported by typical imaging findings.9 
Verification of a PML diagnosis without symptoms is challenging.  At a very early stage, 
CSF viral load might be low or undetectable and the dynamic nature of PML 
cannot be confirmed by a single MRI scan.  PML lesions usually evolve on repeated 

Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
105/Protocol MN42988, Version 3 
imaging, either because the JCV-induced disease progresses or because the 
inflammatory response (IRIS) controlling the infection results in evolution of the image 
characteristics.  Thus, stable appearances on repeated MRI may help to rule out PML, 
whereas evolving lesions are consistent with a PML diagnosis.2 
PML BRAIN MRI PROTOCOL: 
Although recommendations on specific protocols are provided by different groups 
(e.g., MAGNIMS, CMSC), an optimal protocol would include the following sequences: 
• 
FLAIR 
• 
T2-weighted 
• 
T1-weighted with and without gadolinium 
• 
DWI (diffusion weighted imaging) 
 
Table A3-3 Establishing the diagnosis with Clinical, Radiographic and 
Laboratory Data (Modified from AAN Criteria9) 
Certainty of 
PML Diagnosis 
Compatible Clinical 
Features 
Compatible Imaging 
Findings 
CSF PCR for 
JC Virus 
Definite 
+ 
+ 
+ 
Probable 
+ 
− 
+ 
− 
+ 
+ 
Possible 
+ 
+ 
−/ND 
− 
− 
+ 
− 
(+) a 
− 
Not PML 
+ 
− 
− 
− 
− 
− 
AAN = American Academy of Neurology; JCV = John Cunningham virus; MRI = magnetic 
resonance imaging; ND = not done or equivocal result; NTZ = natalizumab; PML = progressive 
multifocal leukoencephalopathy; + = positive; − = negative. 
a Note:  according to current AAN criteria, no diagnosis of PML can be made if only 
compatible imaging findings are present.  However, recent evidence has shown that 
asymptomatic patients treated with NTZ, who have negative CSF JCV PCR results but 
PML compatible MRI changes, may later develop symptoms or have JCV detected in the 
CSF.10 
 

Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
106/Protocol MN42988, Version 3 
A3–3.1 
ACTION STEPS IF PML IS SUSPECTED (CLINICAL, IMAGING 
OR CSF SUSPICION): 
• 
If the patient has clinical features that are suggestive of PML (see Table A3-1), 
further investigations should include brain MRI with a specific protocol, and/or 
CSF analysis for JCV DNA (using a validated ultrasensitive PCR assay). 
• 
If the patient is asymptomatic but has imaging features that are suggestive of PML 
(see Table A3-2), further investigations should include CSF analysis for JCV DNA 
(using a validated ultrasensitive PCR assay). 
• 
If the patient is asymptomatic but has detectable copies of JCV DNA in the CSF 
using a validated and ultrasensitive PCR assay (in cases where this method is used 
for PML surveillance), further investigations should include brain MRI with specific 
protocol. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
107/Protocol MN42988, Version 3 
Figure A3-3 
Suggested Algorithm for Diagnosis of Progressive Multifocal Leukoencephalopathy 
 
CSF = cerebrospinal fluid; DWI = diffusion weighted imaging; FLAIR = fluid attenuated inversion recovery; IRIS = immune reconstitution inflammatory 
syndrome; JCV = John Cunningham virus; LLOQ = lower limit of quantification; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
PMS = progressive multifocal leukoencephalopathy; RT = reverse transcription; T1W = T1-weighted; T2W = T2-weighted. 
* Optimal MRI assessment would include the following sequences:  FLAIR, T2W, T1W with and without gadolinium, DWI. 
** An ultrasensitive RT-PCR assay with a LLOQ of 10 genome copies/mL is recommended (further details on UNILABS assay 
https://stratifyjcv.unilabsweb.com/csfjcvdnatest.aspx or QUEST assay https://testdirectory.questdiagnostics.com/test/test-detail/18939/?cc=SJC) 

Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
108/Protocol MN42988, Version 3 
A3–4 
TREATMENT SWITCHING CONSIDERATIONS 
Treatment with natalizumab is associated with the highest risk of PML in 
anti-JCV antibody positive patients (risk further varies with anti-JCV antibody index 
levels in serum) and treatment duration > 2 years (class I according to a recent 
classification), while dimethyl fumarate (DMF) and fingolimod are deemed as class II 
agents with a low, but real, risk of PML.3 
NATALIZUMAB (NTZ) 
• 
Natalizumab has pharmacodynamic effects for approximately 12 weeks following 
the last dose, but the risk of PML persists for 6 months after discontinuing treatment 
with natalizumab, and has been reported in patients who did not have findings 
suggestive of PML at the time of discontinuation.  Physicians should therefore 
remain vigilant for clinical and radiological features of PML for approximately 
6 months after NTZ discontinuation (Natalizumab USPI and SmPC) 
• 
It is important to follow the natalizumab prescribing information which outlines the 
need for continued monitoring of natalizumab patients following discontinuation of 
the drug and potential switch to another treatment.  The following recommendations 
apply to patients treated with natalizumab who are being considered for switching to 
ocrelizumab: 
1. 
To determine the optimal washout period when switching from natalizumab to 
ocrelizumab, physicians should consider balancing the risk of return of 
MS disease activity with possible additive immunosuppressive effects of each 
drug 
2. 
In patients with new or recent worsening of neurological signs/symptoms and/or 
a new or evolving lesion on brain MRI, PML must be ruled out (see suggested 
algorithm in Figure A3-3) 
3. 
In asymptomatic patients who carry a higher risk of PML as per established risk 
stratification factors according to natalizumab labels, rule out PML as far as 
possible, by excluding new or evolving lesions on brain MRI.  A repeat MRI 
assessment that includes at least FLAIR/T2 and DWI sequences is 
recommended 3 and 6 months after discontinuing natalizumab in patients at 
high risk of PML who initiated ocrelizumab.2 
 
FINGOLIMOD (FNG) AND DIMETHYL FUMARATE (DMF) 
• 
For patients switching from fingolimod to ocrelizumab, there is no definite risk-
mitigation strategy.  Based on available data, there appear to be no clinically or 
radiographically unique features of FNG-associated PML.  In these patients there 
appears to be no correlation with profound lymphopenia and lymphocyte subsets 
(CD4, CD8, and CD4/8 ratios), and this is not believed to be informative of PML 
risk.5 

Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
109/Protocol MN42988, Version 3 
• 
For patients switching from DMF to ocrelizumab, there is no definite risk-
mitigation strategy.  Prolonged lymphopenia with absolute lymphocyte counts of less 
than 750 lymphocytes/mL accounts for most cases of DMF-associated PML, 
although the risk might reside particularly in the loss of CD8+ cells that are crucial to 
control of JCV.2  
• 
In patients switching from fingolimod or dimethyl fumarate with new or recent 
worsening of neurological signs/symptoms and/or a new or evolving lesion on brain 
MRI suggestive of PML, PML must be ruled out (see Figure A3-3) 
 
REFERENCES: 
1. 
Igra MS, Paling D., Wattjes MP, et al. Multiple sclerosis update: Use of MRI for early 
diagnosis, disease monitoring and assessment of treatment related complications. 
Br J Radiol 2017;90:20160721. 
2. 
Major EO, Yousry TA., Clifford DB. Pathogenesis of progressive multifocal 
leukoencephalopathy and risks associated with treatments for multiple sclerosis: a 
decade of lessons learned. Lancet Neurol 2018;17:467–80. 
3. 
Berger, JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat 
Disord 2017;12:59–63. 
4. 
Clifford DB, De Luca A, Simpson DM, et al. Natalizumab-associated progressive 
multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 
cases. Lancet Neurol 2010;9: 438–46. 
5. 
Berger JR, Cree BA., Greenberg B, et al. Progressive multifocal 
leukoencephalopathy after fingolimod treatment. Neurology 2018;90: e1815–1821. 
6. 
Yousry TA, Pelletier D, Cadavid D, Gass A, et al. Magnetic resonance imaging 
pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann 
Neurol 2012;72:779–87. 
7. 
Yousry, TA, Habil M, Major EO, et al. Evaluation of Patients Treated with 
Natalizumab for Progressive Multifocal Leukoencephalopathy. N Engl J Med 
2006;354: 924–33. 
8. 
Wattjes MP, Wijburg MT, van Eijk J, et al. Inflammatory natalizumab-associated 
PML: baseline characteristics, lesion evolution and relation with PML-IRIS. J Neurol 
Neurosurg Psychiatry 2018;89:535–41. 
9. 
Berger JR, Aksamith A, Clifford DB. PML diagnostic criteria: consensus statement 
from the AAN Neuroinfectious Disease Section. Neurology 2013;80:1430–38. 
10. Wattjes MP, Vennegoor A, Mostert J, et al. Diagnosis of asymptomatic natalizumab-
associated PML: are we between a rock and a hard place? J Neurol 
2014;261:1139–43. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
110/Protocol MN42988, Version 3 
  
Expanded Disability Status Scale (EDSS) 
A4–1 
EDSS STEPS 
0 
Normal neurological exam (all FS Grade 0) 
1.0 
No disability, minimal signs in one FS (one FS Grade 1) 
1.5 
No disability, minimal signs in more than one FS (more than one FS Grade 1) 
2.0 
Minimal disability in one FS (one FS Grade 2, others 0 or 1) 
2.5 
Minimal disability in two FS (two FS Grade 2, others 0 or 1) 
3.0 
Fully ambulatory but with moderate disability in one FS (one FS Grade 3, others 0 or 1) 
OR 
Fully ambulatory but with mild disability in three or four FS (three/four FS Grade 2, others 
0 or 1) 
3.5 
Fully ambulatory but with moderate disability in one FS (one FS Grade 3) and mild 
disability in one or two FS (one / two FS Grade 2) and others 0 or 1; OR 
Fully ambulatory with two FS Grade 3 (others 0 or 1); OR 
Fully ambulatory with five FS Grade 2 (others 0 or 1) 
4.0 
Fully ambulatory for ≥ 500 meters without aid or rest; up and about some 12 hours a 
day characterized by relatively severe disability consisting of one FS Grade 4 (others 0 or 
1) or combinations of lesser grades exceeding limits of previous steps 
4.5 
Ambulatory for 300−500 meters without aid or rest; up and about much of the day, 
characterized by relatively severe disability usually consisting of one FS Grade 4 and 
combination of lesser grades exceeding limits of previous steps 
5.0 
Ambulatory for 200−300 meters without aid or rest (usual FS equivalents include at 
least one FS Grade 5, or combinations of lesser grades usually exceeding specifications 
for step 4.5) 
5.5 
Ambulatory for 100−200 meters without aid or rest  
6.0 
Ambulatory for at least 100 meters with intermittent or constant unilateral 
assistance (cane or crutch) with or without rest OR 
Ambulatory < 100 meters without help or assistance OR 
Ambulatory ≥ 50 meters with unilateral assistance OR 
Ambulatory ≥ 120 meters with bilateral assistance  
6.5 
Ambulatory for at least 20 meters with constant bilateral assistance (canes or 
crutches) without rest OR 
Ambulatory for < 50 meters with unilateral assistance (cane or crutch) OR 
Ambulatory 5 to 120 meters with constant bilateral assistance (canes or crutches) 
7.0 
Unable to walk 5 meters even with aid, essentially restricted to wheelchair; wheels 
self and transfers alone; up and about in wheelchair some 12 hours a day 
7.5 
Unable to take more than a few steps; restricted to wheelchair; may need some help 
in transferring and in wheeling self 
8.0 
Essentially restricted to bed or chair or perambulated in wheelchair, but out of bed 
most of day; retains many self-care functions; generally has effective use of arms 
8.5 
Essentially restricted to bed much of the day; has some effective use of arm(s); 
retains some self-care functions 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
111/Protocol MN42988, Version 3 
9.0 
Helpless bed patient; can communicate and eat 
9.5 
Totally helpless bed patient; unable to communicate effectively or eat/swallow 
10 
Death due to MS 
Standardized Neurological Examination and Assessment of Kurtzke’s Functional Systems and 
Expanded Disability Status Scale 
Slightly modified from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an 
expanded disability status scale (EDSS). Neurology 1983:33,1444−52. 
2011 Ludwig Kappos, MD, Neurology, University Hospital Basel, 4031 Basel, Switzerland; 
Version 04/10.2 
 
FUNCTIONAL SYSTEM SCORES 
1. VISUAL FSS 
0 
normal 
1 
disc pallor and/or small scotoma and/or visual acuity (corrected) of worse eye less than 
20/20 (1.0) but better than 20/30 (0.67) 
2 
worse eye with maximal visual acuity (corrected) of 20/30 to 20/59 (0.67−0.34) 
3 
worse eye with large scotoma and/or moderate decrease in fields and/or maximal visual 
acuity (corrected) of 20/60 to 20/99 (0.33−0.21) 
4 
worse eye with marked decrease of fields and/or maximal visual acuity (corrected) of 20/100 
to 20/200 (0.2−0.1); Grade 3 plus maximal acuity of better eye of 20/60 (0.33) or less 
5 
worse eye with maximal visual acuity (corrected) less than 20/200 (0.1); Grade 4 plus 
maximal acuity of better eye of 20/60 (0.33) or less 
6 
Grade 5 plus maximal visual acuity of better eye of 20/60 (0.33) or less 
 
2. BRAINSTEM FSS 
0 
normal 
1 
signs only 
2 
moderate nystagmus and/or moderate EOM impairment and/or other mild disability 
3 
severe nystagmus and/or marked EOM impairment and/or moderate disability of other 
cranial nerves 
4 
marked dysarthria and/or other marked disability 
5 
inability to swallow or speak 
 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
112/Protocol MN42988, Version 3 
3. PYRAMIDAL FSS 
0 
normal 
1 
abnormal signs without disability 
2 
minimal disability: patient complains of motor-fatigability or reduced performance in 
strenuous motor tasks (motor performance Grade 1) and/or BMRC Grade 4 in one or two 
muscle groups 
3 
mild to moderate paraparesis or hemiparesis: BMRC Grade 4 in > two muscle groups; 
and/or 
BMRC Grade 3 in one or two muscle groups (movements against gravity are possible); 
and/or 
Severe monoparesis: BMRC Grade 2 or less in one muscle group 
4 
marked paraparesis or hemiparesis: usually BMRC Grade 2 in two limbs and/or 
monoplegia: BMRC Grade 0 or 1 in one limb; and/or 
moderate tetraparesis: BMRC Grade 3 in ≥ three limbs 
5 
paraplegia:  BMRC Grade 0 or 1 in all muscle groups of the lower limbs; and/or 
marked tetraparesis: BMRC Grade 2 or less in ≥ three limbs; and/or 
hemiplegia 
6 
tetraplegia:  BMRC Grade 0 or 1 in all muscle groups of the upper and lower limbs 
 
4. CEREBELLAR FSS 
0 
normal 
1 
abnormal signs without disability 
2 
mild ataxia and/or moderate station ataxia (Romberg) and/or tandem walking not possible 
3 
moderate limb ataxia and/or moderate or severe gait/truncal ataxia 
4 
severe gait/truncal ataxia and severe ataxia in three or four limbs 
5 
unable to perform coordinated movements due to ataxia 
X pyramidal weakness (BMRC Grade ≤ 3) or sensory deficits interfere with cerebellar testing 
 
5. SENSORY FSS 
0 
normal 
1 
mild vibration or figure-writing or temperature decrease only in 1 or 2 limbs 
2 
mild decrease in touch / pain / position sense or moderate decrease in vibration in 1 or 2 
limbs 
and/or 
mild vibration or figure-writing or temperature decrease alone in more than 2 limbs 
3 
moderate decrease in touch / pain / position sense or marked reduction in vibration in 1 or 
2 limbs 
and/or 
mild decrease in touch or pain or moderate decrease in all proprioceptive tests in > 2 limbs 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
113/Protocol MN42988, Version 3 
4 
marked decrease in touch or pain in 1 or 2 limbs 
and/or 
moderate decrease in touch or pain and/or marked reduction of proprioception > 2 limbs 
5 
loss (essentially) of sensation in one or two limbs 
and/or 
moderate decrease in touch or pain and/or marked reduction of proprioception for most of 
the body below the head 
6 
sensation essentially lost below the head 
 
6. BOWEL/BLADDER FSS 
0 
normal 
1 
mild urinary hesitancy, urgency and/or constipation 
2 
moderate urinary hesitancy/retention and/or moderate urinary urgency/incontinence 
and/or moderate bowel dysfunction 
3 
frequent urinary incontinence or intermittent self-catheterization; needs enema or manual 
measures to evacuate bowels 
4 
in need of almost constant catheterization 
5 
loss of bladder or bowel function; external or indwelling catheter 
6 
loss of bowel and bladder function 
 
7. CEREBRAL FSS 
0 
normal 
1 
signs only in decrease in mentation; mild fatigue 
2 
mild decrease in mentation; moderate or severe fatigue 
3 
moderate decrease in mentation 
4 
marked decrease in mentation 
6 
dementia 
 
8. AMBULATION SCORE 
0 
unrestricted 
1 
Fully ambulatory ≥ 500 meters without help or assistance but not unrestricted (pyramidal or 
cerebellar FS ≥ 2) 
2 
Ambulatory ≥ 300 meters, but < 500 meters, without help or assistance (EDSS 4.5 or 5.0, 
defined by FSS) 
3 
Ambulatory ≥ 200 meters, but < 300 meters, without help or assistance (EDSS 5.0) 
4 
Ambulatory ≥ 100 meters, but < 200 meters, without help or assistance (EDSS 5.5) 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
114/Protocol MN42988, Version 3 
5 
Ambulatory < 100 meters without help or assistance (EDSS 6.0) 
6 
Ambulatory ≥ 50 meters with unilateral assistance (EDSS 6.0) 
7 
Ambulatory ≥ 120 meters with bilateral assistance (EDSS 6.0) 
8 
Ambulatory < 50 meters with unilateral assistance (EDSS 6.5) 
9 
Ambulatory ≥ 5 meters, but < 120 meters with bilateral assistance, (EDSS 6.5) 
10 Uses wheelchair without help; unable to walk 5 meters even with aid, essentially restricted to 
wheelchair; wheels self and transfers alone; up and about in wheelchair some 12 hours a 
day (EDSS 7.0) 
11 Uses wheelchair with help; unable to take more than a few steps; restricted to wheelchair; 
may need some help in transferring and in wheeling self (EDSS 7.5) 
12 essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most of 
day; retains many self-care functions; generally has effective use of arms (EDSS 8.0) 
Standardized Neurological Examination and Assessment of Kurtzke’s Functional Systems and 
Expanded Disability Status Scale 
Slightly modified from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an 
expanded disability status scale (EDSS). Neurology 1983:33,1444−52. 
2011 Ludwig Kappos, MD, Neurology, University Hospital Basel, 4031 Basel, Switzerland; 
Version 04/10.2 
 
 
 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
115/Protocol MN42988, Version 3 
A4–2 
EDSS BY TELEPHONE 
 
 
 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
116/Protocol MN42988, Version 3 
 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
117/Protocol MN42988, Version 3 
 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
118/Protocol MN42988, Version 3 
 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
119/Protocol MN42988, Version 3 
 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
120/Protocol MN42988, Version 3 
 

Appendix 4:  Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
121/Protocol MN42988, Version 3 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
122/Protocol MN42988, Version 3 
  
Methods for Assessing and Recording Adverse Events 
A5–1 
Assessment of Severity of Adverse Events ........................................ 123 
A5–2 
Assessment of Causality of Adverse Events ...................................... 123 
A5–3 
Procedures for recording Adverse Events .......................................... 124 
A5–3.1 
Infusion-Related Reactions ................................................................ 124 
A5–3.2 
Diagnosis versus Signs and Symptoms ............................................. 124 
A5–3.3 
Adverse Events Occurring Secondary to Other Events ...................... 124 
A5–3.4 
Persistent or Recurrent Adverse Events ............................................. 125 
A5–3.5 
Abnormal Laboratory Values .............................................................. 125 
A5–3.6 
Abnormal Vital Sign Values ................................................................ 126 
A5–3.7 
Abnormal Liver Function Tests ........................................................... 127 
A5–3.8 
Deaths ............................................................................................... 127 
A5–3.9 
Pre-existing Medical Conditions ......................................................... 128 
A5–3.10 
Lack of Therapeutic Efficacy .............................................................. 128 
A5–3.11 
Hospitalisation or Prolonged Hospitalisation ...................................... 128 
A5–3.12 
Overdoses, Misuses, Abuses, Off-Label Use, Occupational 
Exposure, or Medication Error ............................................................ 129 
A5–3.13 
Quality Defects, Falsified Products and Product Complaints .............. 129 
A5–3.14 
Drug Interactions ................................................................................ 129 
 

Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
123/Protocol MN42988, Version 3 
A5–1 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  The table below will be used for assessing severity 
for adverse events that are not specifically listed in the NCI CTCAE. 
Table A5-1 Adverse Event Severity Grading Scale 
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 NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a “significant medical event,” it must be reported as a serious 
adverse event (see Section 5.1.1.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.1.1.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.1.1.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.1.1. 
 
A5–2 
ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS 
For patients receiving combination therapy, causality will be assessed individually for 
each of the medicinal products. 
Physicians should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether or not 
an adverse event is considered to be related to the study medicine, indicating “yes” or 
“no” accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study medicine 

Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
124/Protocol MN42988, Version 3 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study medicine, or reintroduction of study medicine (when 
applicable) 
• 
Known association of the event with the study medicine or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
A5–3 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
A5–3.1 
INFUSION-RELATED REACTIONS 
Adverse events that occur during or within 24 hours after study medicine administration 
and are judged to be related to studied medicinal product infusion should be captured as 
a diagnosis (e.g., "infusion-related reaction [IRR]") in the adverse event section of the 
eCRF.  If possible, avoid ambiguous terms such as "systemic reaction." Associated 
signs and symptoms should be recorded on the dedicated IRR section of the eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of studied 
medicinal product, each reaction should be recorded separately in the adverse event 
section of the eCRF, with signs and symptoms also recorded separately on the 
dedicated IRR section of the eCRF. 
A5–3.2 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
For adverse events other than IRR (see Section A5–3.1 above), a diagnosis (if known) 
should be recorded in the adverse event section of the CRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded in the adverse event section of the 
CRF.  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. 
A5–3.3 
ADVERSE EVENTS OCCURRING 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 

Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
125/Protocol MN42988, Version 3 
that is separated in time from the initiating event should be recorded as an independent 
event in the adverse event section of the CRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the CRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the CRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the CRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the CRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the CRF. 
 
All adverse events should be recorded separately in the adverse event section of the 
eCRF if it is unclear as to whether the events are associated. 
A5–3.4 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation time points.  Such events should only be recorded once in the adverse 
event section of the CRF.  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 in the adverse event 
section of the CRF.  If the event becomes serious, it should be reported to the marketing 
authorization holder (MAH) immediately (i.e., no more than 24 hours after learning that 
the event became serious; see Section 5.1.3.1 for reporting instructions).  The adverse 
event section of the CRF 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’s evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately in the adverse event section of the CRF. 
A5–3.5 
ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an AE.  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) 

Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
126/Protocol MN42988, Version 3 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the physician’s judgment 
 
It is the physician’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 AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × the upper limit of normal [ULN] associated 
with cholestasis), only the diagnosis (i.e., cholestasis) should be recorded in the adverse 
event section of the eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded in the adverse event section of the eCRF, 
along with a descriptor indicating if the test result is above or below the normal range 
(e.g., “elevated potassium,” as opposed to “abnormal potassium”).  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the AE.  For example, an elevated serum potassium 
level of 7.0 mEq/L should be recorded as “hyperkaliemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once in the adverse event section of the eCRF 
(see Section A5–3.4 for details on recording persistent adverse events). 
A5–3.6 
ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an AE.  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 physician’s judgment 
 
It is the physician’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 AE. 
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 in 
the adverse event section of the eCRF. 

Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
127/Protocol MN42988, Version 3 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once in the adverse event section of the eCRF (see 
Section A5–3.4 for details on recording persistent adverse events). 
A5–3.7 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST (> 3 × the baseline value) in combination with 
either an elevated total bilirubin (> 2 × the ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered to be an indicator of 
severe liver injury.  Therefore, physicians must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × the baseline value in combination with total 
bilirubin > 2 × the ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × the baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded in the adverse event section of the CRF 
(see Section A5–3.5) and reported to the MAH immediately (i.e., no more than 24 hours 
after learning of the event) either as a serious adverse event or a non-serious AESI 
(see Section 5.1.3.1). 
A5–3.8 
DEATHS 
All events with an outcome or consequence of death should be classified as serious 
adverse events and reported to the MAH immediately.  In certain circumstances, 
however, suspected adverse reactions with fatal outcome may not be subject to 
expedited reporting (see Section A5–3.10). 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.1.2.1), regardless of relationship to study medicine, must be recorded in 
the adverse event section of the eCRF and immediately reported to the MAH 
(see Section 5.1.3.1). 
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 section of the eCRF.  Generally, only one such event 
should be reported.  The term “sudden death” should only be used for the occurrence 
of an abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without pre-existing heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the adverse event section of the 

Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
128/Protocol MN42988, Version 3 
CRF.  If the cause of death later becomes available (e.g., after autopsy), “unexplained 
death” should be replaced by the established cause of death. 
A5–3.9 
PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing medical condition is one that is present at the baseline visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions in the eCRF. 
A pre-existing 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 in the adverse event section of the eCRF, it is important to convey 
the concept that the pre-existing condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
A5–3.10 
LACK OF THERAPEUTIC EFFICACY 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as effectiveness assessment data only.  In most cases, the expected pattern of 
progression will be based on EDSS score.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an AE.  This exception from reporting includes events of disease progression with a 
fatal outcome which are clearly attributable to disease progression. 
A5–3.11 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.1.1), except as outlined below. 
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
Hospitalization for giving birth 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
• 
Elective hospitalizations or surgical procedures that are a result of a patient’s 
pre-existing condition(s) that have not worsened since receiving trial medication.  
Examples may include, but are not limited to, cholecystectomy for gallstones, and 
diagnostic testing.  Such events should still be recorded as medical procedures in 
the concomitant procedures/treatments eCRF 
• 
Hospitalization to receive trial medication such as infusions of ocrelizumab unless 
this is prolonged (more than 24 hours) 

Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
129/Protocol MN42988, Version 3 
• 
Hospitalization following an MS relapse as long as the reason for hospitalization is 
to receive standard treatment with IV methylprednisolone 
 
A5–3.12 
OVERDOSES, MISUSES, ABUSES, OFF-LABEL USE, 
OCCUPATIONAL EXPOSURE, OR MEDICATION ERROR 
Any overdose, misuse, abuse, off-label use, occupational exposure, medication error 
(including intercepted or potential), or any other incorrect administration of medicine 
under observation should be noted in the Drug Administration section of the eCRF.  Any 
overdose, abuse, misuse, inadvertent/erroneous administration, medication error 
(including intercepted or potential), or occupational exposure reports must be forwarded 
to the MAH with or without an AE. 
Reports with or without an adverse event should be forwarded to the MAH as per non-
serious timelines.  If the associated adverse event fulfils the seriousness criteria, the 
event should be reported to the MAH immediately (i.e., no more than 24 hours after 
learning of the event, see Section 5.1.3.1). 
For the purpose of reporting cases of suspected adverse reactions, an occupational 
exposure to a medicine means an exposure to a medicine as a result of one’s 
professional or non-professional occupation. 
A5–3.13 
QUALITY DEFECTS, FALSIFIED PRODUCTS AND PRODUCT 
COMPLAINTS  
Reports of suspected or confirmed falsified product or quality defect of a product, with or 
without an associated AE, should be forwarded to the MAH as per non-serious timelines.  
If the associated adverse event fulfils the seriousness criteria, the event should be 
reported to the MAH immediately (i.e., no more than 24 hours after learning of the event, 
see Section 5.1.3.1). 
A5–3.14 
DRUG INTERACTIONS 
Reports of suspected or confirmed drug interactions, including drug/drug, drug/food, 
drug/device and drug/alcohol, should be forwarded to the MAH as per non-serious 
timelines.  If the associated adverse event fulfils the seriousness criteria, the event 
should be reported to MAH immediately (i.e., no more than 24 hours after learning of the 
event, see Section 5.1.3.1). 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
130/Protocol MN42988, Version 3 
  
Time Windows for Infant Growth Velocity and Child 
Developmental Milestone Assessments 
The following time windows must be applied for the assessment of growth velocity and 
child developmental milestones at Months 2, 4, 6, 9, and 12: 
Timepoint 
Associated time window 
Month 2a 
1 month 0 days through 2 months 30 days 
Month 4 
3 months 0 days through 4 months 30 days 
Month 6 
5 months 0 days through 6 months 30 days 
Month 9 
9 months 0 days through 9 months 30 days 
Month 12 
11 months 0 days through 12 months 30 days 
a Where possible, the month 2 assessment can be combined with Visit 4 (Week 6 of life 
[± 7 days]). 
 
The following visualization depicts the timepoints and corresponding time windows 
based on the infant’s month of age: 
 
 
To calculate whether the infant falls under the respective assessment window based 
on its date of birth and weeks premature, the ASQ-3 age calculator can be used: 
https://agesandstages.com/free-resources/asq-calculator/.  Note that an adjustment 
for premature birth will need to be made either manually or by using the calculator. 
Assessment of growth velocity at Months 2, 4, 6, 9, and 12 must fall under the 
corresponding time windows of the ASQ-3; however, the date of assessment or data 
collection does not need to correspond to the same date of ASQ-3 assessment.  
Whenever possible, assessment of growth velocity may be collected as part of the 
infant’s routine postnatal care visits performed by e.g., the pediatrician. 
 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
131/Protocol MN42988, Version 3 
  
B-cell Reference Ranges by Week of Life:  Absolute and 
Percentage Counts 
 
REFERENCE 
Borriello F, Pasquarelli N, Law L, et al. Normal B-cell ranges in infants: a systematic 
review and meta-analysis. J Allergy Clin Immunol. 2022; 150:1216−24. 
 

Signature Page for Protocol - MN42988 - OCREVUS - v3 - Global/Core - Published
System identifier: RIM-CLIN-489480
Approval Task
Yusuf Tanrikulu (tanrikuy)
Deputy EU QPPV
05-Jun-2023 08:55:19 GMT+0000
Approval Task
Company Signatory
05-Jun-2023 12:58:50 GMT+0000