Conditions: Multiple Sclerosis Clinically Isolated Syndrome
Keywords: ocrelizumab, OCREVUS, breastmilk transfer, breast milk transfer, lactation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
This study will evaluate the pharmacokinetics of ocrelizumab in the breastmilk of lactating women with clinically isolated syndrome (CIS) or multiple sclerosis (MS) \[in line with the locally approved indications\] treated with ocrelizumab, by assessing the concentration of ocrelizumab in mature breastmilk, as well as the corresponding exposure and pharmacodynamic effects (blood B cell levels) in the infants.

Detailed description:

Arms:
arm 1: Lactating women with CIS or MS (in line with the locally approved indications) who decided together with their treating physician to continue on, or start treatment with, OCREVUS (ocrelizumab) post-partum. Women resuming treatment with ocrelizumab post-partum will be included only if the last exposure to ocrelizumab occurred more than 3 months before the last menstrual period to exclude any interference between fetal exposure and exposure via lactation.

Interventions: intervention 1: Ocrelizumab
Intervention descriptions: intervention 1: Women will receive the ocrelizumab dose regimen as per the locally-approved label. The ocrelizumab dose will be administered as an initial split dose of two 300 mg infusions separated by 14 days or a single 600 mg infusion according to the local prescribing information.

Protocol document:
Prot_002.pdf: 


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  The information contained in this document, especially any unpublished data, 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 MN42989, Version 4 (United States) 
PROTOCOL 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL
STUDY EVALUATING B-CELL LEVELS IN
INFANTS OF LACTATING WOMEN WITH CIS OR
MS RECEIVING OCRELIZUMAB – THE
SOPRANINO STUDY 
PROTOCOL NUMBER: 
MN42989 
VERSION NUMBER: 
4 (United States) 
EUDRACT NUMBER: 
2021-000063-79 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998851 
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 MN42989, Version 4 (United States) 
PROTOCOL HISTORY 
Protocol 
Associated Parent Protocol 
Country or Region 
Version 
Date Final 
Version 
Date Final 
United States 
4 
See electronic date 
stamp on final page 
of this document 
3 
5 June 2023 
 
 
 
2 
1 April 2022 
 
 
- 
1 
15 March 2021 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
3/Protocol MN42989, Version 4 (United States) 
PROTOCOL AMENDMENT, VERSION 4 (United States): 
RATIONALE 
Protocol MN42989 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 infant postpartum exposure to ocrelizumab via breastmilk 
has been updated to present data from an analysis performed with a cut-off date of 
31 March 2022, replacing data from an analysis performed up to 31 March 2021 
(Section 1.3). 
 
The secondary objectives have been amended to include the evaluation of the 
relative exposure to ocrelizumab in infants of lactating women with clinically isolated 
syndrome (CIS) or multiple sclerosis (MS) receiving ocrelizumab postpartum.  The 
average relative infant dose will be assessed over 60 days, calculated as the 
average oral daily infant dosage (mg/kg/day) divided by the maternal dosage 
(mg/kg/day), multiplied by 100 (Sections 2 [Table 1] and 6.5.2). 
 
In the endpoint for the exploratory objective “to evaluate the evolution of B-cell 
levels over the first year of life in infants of lactating women with CIS or MS 
receiving ocrelizumab postpartum”, language has been clarified that trajectory 
(absolute and percentage changes) of B-cells (CD19  cell) in the infant will be 
measured from Day 30 after the mother’s first ocrelizumab postpartum infusion to 
1 month after the first or second dose of 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 sample size has been reduced from at least 20 to at least 10 women with CIS 
or MS.  Given that women with CIS or MS are not routinely treated with ocrelizumab 
during breastfeeding 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 6.2). 
 
The telephone interview has been further expanded to include that women using the 
lactational amenorrhea method as contraception will be asked whether the three 
necessary criteria outlined in Section 4.1.1 to ensure adequate protection from an 
unplanned pregnancy are applied (Figure 1 [footnotes]; Sections 3.1.3, 3.1.4, and 
4.1.1, and Appendix 1 [footnote “bb”]). 
 
Additional guidance on infant B-cell monitoring in case levels are found to be below 
the lower limit of normal (LLN) has been added (Sections 3.1.3 and 4.5.3.3, and 
Appendix 1 [footnote “y”]). 
 
It has been clarified throughout the protocol that dosing and treatment duration are 
at the discretion of the physicians, in accordance with local clinical practice and local 
labeling (U.S. Prescribing Information and the Summary of Product Characteristics) 
(Section 3.1.3; Appendix 1). 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
4/Protocol MN42989, Version 4 (United States) 
 
The total length of the study has been increased from approximately 2 years to 
approximately 3 years, due to the extension of the enrolment period from 
approximately 8 months to approximately 21 months (Section 3.2). 
 
Language has been added to clarify that, based on the ocrelizumab average 
terminal half-life of 26 days, it is assumed that a potential fetal exposure is unlikely 
in women whose last ocrelizumab infusion was earlier than 3 months before last 
menstrual period (Section 3.3.2). 
 
To reduce the burden of visits on the mothers, it has been detailed that 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 used (Section 4.5.2.4; Appendix 1 [footnote “i"]). 
 
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 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 
4.5.2.7 and 4.5.3.3 [Tables 3 and 4]; Appendix 1). 
 
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 provide further details on how infant’s non-laboratory 
assessments are to be collected (Sections 4.5.3.1 and 4.5.3.2). 
 
It has been clarified that all laboratory samples for the infant within one visit are to 
be collected at one timepoint (Section 4.5.3.3). 
 
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 4.5.3.3). 
 
The list of antibody (Ab) titers of responses to vaccines administered as per local 
practice, has been updated to detail that the following will be included:  anti-measles 
Ab IgG, anti-rubella Ab IgG, anti-mumps Ab IgG, 13-pneumococcal conjugate 
vaccine (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 4.5.3.3 [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). 
 
The full analysis set (FAS) population of infants has been amended to remove the 
requirement to only include infants of the FAS population of women whose B-cell 
level data at Day 30 post-infusion 1 are available; the FAS population of infants will 
include all the infants of the FAS population of women (Section 6.1). 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
5/Protocol MN42989, Version 4 (United States) 
 
Due to a reduction in sample size, the precision (width of the two-sided 95% CIs) for 
event rates (an event is defined as B-cells below the LLN) have been amended 
(Section 6.2). 
 
A reference to Appendix 7 (B-cell reference ranges by week of life [absolute and 
percentage counts]) has been added (Section 6.5.1). 
 
The handling of intercurrent events of the estimand of the proportion of infants with 
B-cell levels below the LLN (Section 6.5.1) have been amended to include the 
following: 
– 
If an infant does not receive any breastmilk before B-cell measurement during 
the entire 30-day period after the mother’s first ocrelizumab postpartum 
infusion, B-cell data will be excluded from the analysis. 
– 
If an infant’s blood sample is collected before the assessment window 
(i.e., before Day 28), the data will be excluded from the analysis. 
– 
If an infant’s blood sample is collected while the infant has an illness, the B-cell 
data will be excluded on a case-by-case basis if the illness is likely to confound 
the B-cell data. 
 
Further details on the statistical considerations for the PCV-13 serotypes have been 
added (Section 6.5.2). 
 
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). 
 
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 following changes have been made to the Schedule of Assessments 
(Appendix 1): 
– 
The requirement to measure breastmilk ocrelizumab concentration at screening 
has been removed. 
– 
The requirement to collect documentation of collection of second postpartum 
ocrelizumab administration at Visit 7 has been included, with a corresponding 
footnote (footnote “dd”) detailing that documentation of premedication is not 
required. 
– 
The corresponding footnote to the assessment “Whole blood sample for 
lymphocyte subtype sample” in infant laboratory assessments has been 
corrected to footnote “x”. 
– 
It has been clarified that breastmilk samples that are to be collected on Day 0 
(baseline) should be taken before the infusion (footnote “j”). 
 
The EDSS by telephone questionnaire has been included in the protocol 
(Appendix 4 [Appendix A42]). 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
6/Protocol MN42989, Version 4 (United States) 
 
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 
7/Protocol MN42989, Version 4 (United States) 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND ............................................................................ 23 
1.1 
Background on Multiple Sclerosis ............................................ 23 
1.2 
Background on Ocrelizumab.................................................... 24 
1.3 
Study Rationale and BenefitRisk Assessment ....................... 24 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 27 
3. 
STUDY DESIGN ........................................................................... 29 
3.1 
Description of the Study ........................................................... 29 
3.1.1 
Overview of Study Design........................................................ 30 
3.1.2 
Screening Period ..................................................................... 33 
3.1.3 
Treatment and Sampling Period .............................................. 33 
3.1.4 
Vaccination Period ................................................................... 34 
3.1.5 
Discontinuation ........................................................................ 35 
3.2 
End of Study and Length of Study ........................................... 35 
3.3 
Rationale for Study Design ...................................................... 36 
3.3.1 
Rationale for Ocrelizumab Dose and Schedule ....................... 37 
3.3.2 
Rationale for Subject Population .............................................. 38 
4. 
MATERIALS AND METHODS ...................................................... 39 
4.1 
Study Participants .................................................................... 39 
4.1.1 
Inclusion Criteria ...................................................................... 39 
4.1.2 
Exclusion Criteria ..................................................................... 40 
4.2 
Method of Treatment Assignment and Blinding ....................... 42 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 42 
4.3.1 
Study Treatment Formulation and Packaging .......................... 42 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 42 
4.3.2.1 
Study Treatment ...................................................................... 42 
4.3.2.2 
Premedication .......................................................................... 43 
4.4 
Concomitant Therapy .............................................................. 43 
4.4.1 
Prohibited Therapy .................................................................. 43 


 
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4.5 
Study Assessments ................................................................. 43 
4.5.1 
Informed Consent Forms and Screening Log .......................... 44 
4.5.2 
Mother’s Assessments ............................................................. 44 
4.5.2.1 
Demographics, Medical and MS History, and Disease 
Characteristics ......................................................................... 44 
4.5.2.2 
Physical Examinations and Related Assessments .................. 44 
4.5.2.3 
Vital Signs ................................................................................ 45 
4.5.2.4 
Neurological Examinations ...................................................... 45 
4.5.2.5 
Assessment of Relapses ......................................................... 46 
4.5.2.6 
Assessment of Disability .......................................................... 46 
4.5.2.7 
Laboratory, Biomarker, and Other Biological Samples ............ 46 
4.5.3 
Infant’s Assessments ............................................................... 47 
4.5.3.1 
Medical History, Biometrics and Concomitant Medications ..... 47 
4.5.3.2 
Physical Examinations and Related Assessments .................. 48 
4.5.3.3 
Laboratory, Biomarker, and Other Biological Samples ............ 49 
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 ......................................................... 52 
5.1 
Safety Reporting Requirements for Studied Medicinal 
Products .................................................................................. 52 
5.1.1 
Safety Parameters and Definitions .......................................... 52 
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 and Assessing 
Safety Parameters ................................................................... 55 
5.1.2.1 
Adverse Event Reporting Period .............................................. 55 
5.1.2.2 
Procedures for Recording Adverse Events .............................. 55 
5.1.3 
Reporting Requirements from Investigator to Sponsor ............ 56 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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5.1.3.1 
Immediate Reporting Requirements from Investigator 
to Sponsor ............................................................................... 56 
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 Electronic Data Capture System Is Temporarily 
Unavailable .............................................................................. 57 
5.1.3.5 
Reporting Requirements for Pregnancies, 
Abortions/Congenital Anomalies/Birth Defects ........................ 57 
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 ......... 60 
6.1 
Analysis Populations ................................................................ 61 
6.2 
Determination of Sample Size ................................................. 61 
6.3 
Summaries of Conduct of Study .............................................. 61 
6.4 
Summaries of Demographic and Baseline Characteristics ...... 61 
6.5 
Primary Analyses ..................................................................... 62 
6.5.1 
Primary Endpoint ..................................................................... 62 
6.5.2 
Secondary Endpoints ............................................................... 63 
6.5.3 
Exploratory Endpoints .............................................................. 64 
6.6 
Safety Analyses ....................................................................... 64 
6.6.1 
Analyses of Exposure, Adverse Event, Laboratory, and 
Vital Signs Data ....................................................................... 64 
6.7 
Interim analysis ........................................................................ 64 
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 


 
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7.5 
Retention of Records ............................................................... 66 
8. 
ETHICAL CONSIDERATIONS ...................................................... 67 
8.1 
Compliance with Laws and Regulations .................................. 67 
8.2 
Informed Consent .................................................................... 67 
8.3 
Institutional Review Board or Ethics Committee ...................... 68 
8.4 
Confidentiality .......................................................................... 68 
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 ................................... 27 
Table 2 
B-Cell Subsets ............................................................................ 47 
Table 3 
Prioritization Order for Infant Blood Sample Assessments at 
Day 30 (2 days) Post-Infusion 1 ................................................ 49 
Table 4 
Prioritization Order for Infant Blood Sample Assessments 
1 Month ( 30 days) After the First/Second Dose of MMR 
Vaccine or at Month 13 of Age ( 30 Days) if MMR Vaccine 
Is Not Planned to Be Administered ............................................. 50 
 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design ........................................................... 31 
 


 
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LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments: Screening through the End of 
Treatment Period ........................................................................ 79 
Appendix 2 
Compatibility of Common Medications with Breastfeeding ......... 89 
Appendix 3 
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy ............................................................... 100 
Appendix 4 
Expanded Disability Status Scale (EDSS) ................................ 109 
Appendix 5 
Methods for Assessing and Recording Adverse Events ........... 121 
Appendix 6 
Time Windows for Infant Growth Velocity and Child 
Developmental Milestone Assessments ................................... 129 
Appendix 7 
B-Cell Reference Ranges by Week of Life:  Absolute and 
Percentage Counts .................................................................... 130 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
12/Protocol MN42989, Version 4 (United States) 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY 
EVALUATING B-CELL LEVELS IN INFANTS OF 
LACTATING WOMEN WITH CIS OR MS RECEIVING 
OCRELIZUMAB – THE SOPRANINO STUDY 
PROTOCOL NUMBER: 
MN42989 
VERSION NUMBER: 
4 (United States) 
EUDRACT NUMBER: 
2021-000063-79 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998851 
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 
13/Protocol MN42989, Version 4 (United States) 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY EVALUATING 
B-CELL LEVELS IN INFANTS OF LACTATING WOMEN WITH CIS 
OR MS RECEIVING OCRELIZUMAB – THE SOPRANINO STUDY 
PROTOCOL NUMBER: 
MN42989 
VERSION NUMBER: 
4 (United States) 
EUDRACT NUMBER: 
2021-000063-79 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998851 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
Phase IV 
INDICATION: 
Multiple Sclerosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics of ocrelizumab in the breastmilk of lactating 
women with clinically isolated syndrome (CIS) or multiple sclerosis (MS) [in line with the locally 
approved indications] treated with ocrelizumab, by assessing the concentration of ocrelizumab 
in mature breastmilk, as well as the corresponding exposure and pharmacodynamic effects 
(blood B-cell levels) in the infants.  Specific objectives and corresponding endpoints for the 
study are outlined below. 
Objectives 
Corresponding Endpoints 
Co-Primary Outcome Measure 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum present with B-cell 
depletion 
 
Proportion of infants with B-cell levels 
(CD19  cells, absolute counts in blood) below 
the LLN, measured at Day 30 after the mother’s 
first ocrelizumab postpartum infusion 
 
To evaluate the exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated ADID, calculated as the ocrelizumab 
average milk concentration over 60 days 
post-ocrelizumab infusion 1 multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
Secondary Outcome Measures 
 
To evaluate B-cell levels in 
infants of lactating women with 
CIS or MS receiving 
ocrelizumab postpartum 
 
B-cell levels (CD19  cells, absolute counts and 
percentage of lymphocytes) measured at 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 


 
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Objectives 
Corresponding Endpoints 
 
 
Secondary Outcome Measures (cont.) 
 
To evaluate transfer of 
ocrelizumab into breastmilk of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
AUC of ocrelizumab in mature breastmilk 
(i.e., milk produced after Day 14 postpartum) 
over 60 days after the first postpartum 
ocrelizumab infusion using the following time 
points: 
– 
If receiving 1  600 mg: before infusion and 
at 24 hours (Day 1), Day 7, Day 30 and Day 
60 post-infusion 
– 
If receiving 2  300 mg: before infusion 1 
and at 24 hours (Day 1), Day 7, Day 14, 
Day 15 (24 hours after infusion 2), Day 21, 
Day 30, and Day 60 post-infusion 1 
 
Average and peak ocrelizumab milk 
concentration as well as time to reach peak milk 
concentration, measured over 60 days after the 
mother’s first postpartum ocrelizumab infusion 
 
To evaluate the relative and 
maximum exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated MDID calculated as the peak 
ocrelizumab milk concentration multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
measured over 60 days after the mother’s first 
postpartum ocrelizumab infusion 
 
Average RID over 60 days, calculated as the 
ADID (mg/kg/day) divided by the maternal 
dosage (mg/kg/day) multiplied by 100 
Note:  Other pharmacokinetic and exposure 
parameters may be calculated as appropriate, 
based on the data obtained 
 
To evaluate whether there is 
transfer of ocrelizumab from the 
mother to the infant via 
breastmilk  
 
Serum concentration of ocrelizumab in the 
infant measured at Day 30 after the mother’s 
first ocrelizumab postpartum infusion 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 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 MMR, diphtheria, tetanus, 
pertussis, Hib, HBV, and PCV-13 
 
Proportion of infants with positive humoral 
response (seroprotective titers; as defined for 
the individual vaccine) to vaccines 
Safety Objectives 
 
To evaluate the safety of 
ocrelizumab in lactating women 
with CIS or MS receiving 
ocrelizumab postpartum and in 
their respective infants 
 
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 
 


 
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Objectives 
Corresponding Endpoints 
Exploratory Objectives 
 
To evaluate infant’s growth 
velocity and developmental 
milestones in the first year of life 
 
Assessment of growth velocity based on 
age-adjusted length, weight, head 
circumference, using monthly 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 measure disease activity in 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Number of MS relapses during the postpartum 
period (clinical relapses) 
 
Mean change in the EDSS score from last 
pre-baseline measurement (up to 1 year before 
LMP) to baseline 
 
To evaluate the evolution of 
B-cell levels over the first year 
of life in infants of lactating 
women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Trajectory (absolute and percentage changes) 
of B-cells (CD19  cells) in the infant from 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 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 
ADID  average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire version 3; 
AUC  area under the milk concentration-time curve; CIS  clinically isolated syndrome; 
EDSS  Expanded Disability Status Scale; HBV  hepatitis B virus; Hib  Hemophilus influenzae 
type b; LLN  lower limit of normal; LMP  last menstrual period; MDID  maximum oral daily 
infant dosage; MMR  measles, mumps, and rubella MS  multiple sclerosis; PCV-
13  13-pneumococcal conjugate vaccine; RID    relative infant dose; WHO  World Health 
Organization. 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a prospective, multicenter, open-label study in lactating women with CIS or MS (in line 
with the locally approved indications) who decided together with their treating physician to 
continue on, or start treatment with, OCREVUS (ocrelizumab) postpartum despite ocrelizumab 
currently not being recommended during lactation. 
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 at least 10 women with CIS or MS who are breastfeeding or planning to 
breastfeed. 


 
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The study will consist of the following periods: 
 
Screening period:  After providing written informed consent, women will enter a screening 
period for eligibility assessments.  Considering that decisions on initiating or resuming 
treatment with a disease-modifying therapy (DMT) in the postpartum period are usually 
taken before or during pregnancy, screening may be conducted at any time from the third 
trimester until 24 weeks postpartum.  Final inclusion will only take place for women who 
have delivered a healthy term infant and have made a decision to breastfeed their infant 
despite ongoing ocrelizumab treatment.  General health and medical history of the infant 
will also be reviewed for eligibility. 
Women resuming treatment with ocrelizumab postpartum will be included only if the last 
exposure to ocrelizumab occurred more than 3 months before the last menstrual period 
(LMP) (i.e., women without potential fetal exposure) to exclude any interference between 
fetal exposure and exposure via lactation. 
 
Treatment and sampling period:  Women fulfilling the inclusion/exclusion criteria will receive 
the ocrelizumab dose regimen as per the locally approved label.  The first dose of 
ocrelizumab may be administered at any point between Week 2 and Week 24 postpartum, 
as an initial split dose of two 300 mg infusions (in 250 mL 0.9% sodium chloride) separated 
by 14 days or as a single 600 mg infusion (in 500 mL 0.9% sodium chloride) according to 
the local prescribing information.  For women where a decision not to administer a second 
300 mg infusion is taken after enrolment, continuation in the study will be allowed.  Dosing 
and treatment duration are at the discretion of the physicians, in accordance wit h local 
clinical practice and local labeling (U.S. Prescribing Information [USPI]; Summary of 
Product Characteristics [SmPC]).  If women did not experience a serious infusion-related 
reaction (IRR) with any previous ocrelizumab infusion, a shorter (2-hour) infusion can be 
administered for subsequent 600 mg doses (Summary of Product Characteristics [SmPC], 
United States Prescribing Information [USPI]).  Women referred by healthcare professionals 
(HCPs) to participate in the trial may receive ocrelizumab treatment at their neurologist’s 
site as part of their standard of care treatment. 
Maternal breastmilk samples will be collected over several time points up to 60 ( 2) days 
after the first postpartum ocrelizumab infusion at approximately the same time of day, 
although flexibility is allowed on collection timings to accommodate the mother and infant 
feeding schedule.  The only exception is the first (Day 1) post-infusion breastmilk sample 
and, in women who received a 2  300 mg dose, the second (Day 15) post-infusion 
breastmilk sample, which should be collected 24 hours after the midpoint of the infusion.  
On days of collection, milk should be expressed from both breasts until completely emptied 
using an electric breast pump.  The milk from each breast is then mixed and a sample 
(volume  5 mL) is removed for analysis.  The infant can be bottle-fed the remaining 
expressed milk.  If the infant is not usually fed using a bottle, milk may be expressed from 
one breast only.  If the mother presents with unilateral mastitis, milk should only be 
expressed from the unaffected breast, until the infection resolves.  If mastitis presents 
bilaterally (rare), breastmilk collection should be stopped until the infection resolves. 
The infant blood sample will be collected at Day 30 ( 2 days) of lactation after the first 
ocrelizumab infusion administered postpartum, i.e., regardless of whether women receive a 
600 mg or a 2  300 mg dose.  Blood samples may be collected at home by a visiting nurse, 
or at the hospital as part of study visits.  Note:  If the infant’s B-cell levels are found to be 
below lower limit of normal (LLN), analyses of B-, T-, and natural killer cells will be 
repeated every 4 weeks until B-cell levels are found to be above the age-adequate LLN (in 
consultation with the Sponsor).  The first repeat analysis will also include a complete 
blood count  and immunoglobulin levels.  
A structured telephone interview will be conducted by site personnel every 2 weeks in the 
treatment and sampling period, for a general review, and to identify and collect information 
on any changes in the woman’s and infant’s health status (including the occurrence of 
MS relapses in the mother and use of and 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 using the lactational amenorrhea 
method as contraception will also be asked whether the three necessary criteria to ensure 


 
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adequate protection from an unplanned pregnancy are applied.  No telephone contact is 
needed in weeks where the woman is performing on-site visits. 
 Vaccination period:  After the 60-day ( 2 days) treatment and sampling period, infants will 
continue to be followed-up for growth (age-adjusted length, weight, head circumference) 
and developmental milestones up to 12 months of age.  Growth charts (following the World 
Health Organization 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 post-natal care, may also be used. 
Infant laboratory assessments will be performed 1 month ( 30 days) after the first or 
second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13 of age 
( 30 days), in case MMR vaccine is not planned to be administered, to evaluate whether 
infants are able to mount humoral immune responses to clinically relevant vaccines, and for 
measurement of B-cell levels.  In case the mother decides to switch to another DMT or to 
stop DMT after the 60-day treatment and sampling period, the infant blood sample will still 
be collected. 
A structured telephone interview will be conducted by site personnel postpartum every 
3 months in the vaccination period (in-between ocrelizumab infusions) for a general review, 
and to identify and collect information on any changes in the woman’s and infant’s health 
status (including the occurrence of MS relapses in the mother and use of and 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 using the lactational amenorrhea method as contraception will also be asked 
whether the three necessary criteria to ensure adequate protection from an unplanned 
pregnancy are applied.  No telephone contact is needed in weeks where the woman is 
performing on-site visit. 
 
Discontinuation:  Women who decide to discontinue the study (this includes discontinuation 
of either the mother or the infant; this does not apply to treatment discontinuation) will be 
invited to attend an early study discontinuation visit (which may be conducted remotely, 
i.e., virtually or by telephone) as soon as possible.  Depending on the timing of 
discontinuation, the following is recommended: 
Discontinuation before the infant blood draw at 30 ( 2) days post-infusion 1:  Collection 
of infant outcomes in the first year of life as per standard pharmacovigilance procedures 
– 
If the mother remains on treatment with ocrelizumab and decides to stop 
participating at 30 ( 2) days after the first postpartum ocrelizumab infusion, 
attempts to collect the infant sample at 30 ( 2) days should be made before 
discontinuation. 
– 
If the mother switches to another DMT, the infant sample at 30 ( 2) days should 
not be collected. 
Discontinuation after the infant blood draw at 30 ( 2) days post-infusion 1:  Collection 
of infant outcomes in the first year of life as per standard pharmacovigilance 
procedures. 
 
NUMBER OF WOMEN 
This study will enroll at least 10 women with CIS or MS (in line with the locally approved 
indications) who are breastfeeding or planning to breastfeed. 
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.  
The primary analysis will be conducted at the end of the Treatment and Sampling Period 
(Day 60 [ 2 days]). 
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 3 years.  This includes an enrolment period of approximately 
21 months and a woman’s participation period of 16 months. 


 
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TARGET POPULATION 
INCLUSION CRITERIA 
The following criteria must be met for study entry: 
 
An Informed Consent Form (ICF) for participation of the maternal subject and her infant 
(for collection of blood, infant demographic 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 
 
Woman is able and willing to comply with the study protocol, according to the judgment of 
the investigator, in particular: 
– 
Woman is willing to breastfeed (either exclusively, or with formula supplementation) for 
at least 60 days after the first postpartum ocrelizumab infusion (this decision is to be 
taken prior to and independent from study participation) 
– 
Woman is willing to provide breastmilk samples before and after their first and, 
if applicable, second postpartum ocrelizumab infusion 
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. 
 
Woman is between 18 and 40 years of age at screening 
 
Woman has a diagnosis of MS or CIS (in line with the locally approved indications) 
 
Woman has delivered a healthy term singleton infant ( 37 weeks gestation)  
 
Infant is between 224 weeks of age at the time of the mother’s first postpartum dose of 
ocrelizumab 
 
For women who received commercial ocrelizumab (OCREVUS) before enrolment: 
documentation that last exposure to ocrelizumab occurred more than 3 months before the 
LMP (i.e., excluded a potential fetal exposure) and was given at the approved dose of 
2  300 mg or 1  600 mg 
 
Woman agrees to use acceptable contraceptive methods or alternative methods during the 
study as described below and, if applicable, upon study treatment discontinuation, as 
defined by the local prescribing information 
– 
The following contraceptive methods are considered acceptable (failure rate  1% 
[Clinical Trial Facilitation Group (CTFG)]):  progestogen-only oral hormonal 
contraception, where inhibition of ovulation is not the primary mode of action; male or 
female condom with or without spermicide; cap, diaphragm, or sponge with spermicide; 
combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier method). 
Birth control methods that are highly effective (i.e., failure rate  1% [CTFG]) may also be 
used but are not required, and include: oral, intravaginal or transdermal combined hormonal 
contraception associated with inhibition of ovulation [unless not recommended or 
contraindicated during breastfeeding];  oral, injectable or implantable progestogen-only 
hormonal contraception associated with inhibition of ovulation; intrauterine device; 
intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; 
sexual abstinence. 
Note:  lactational amenorrhea method can be used to ensure adequate protection from an 
unplanned pregnancy, and the following three criteria must be met: 1) amenorrhea; 2) fully 
or nearly fully breastfeeding (no interval of  46 hours between breastfeeds); and 
3)  6 months postpartum.  If any of the three listed criteria change at any stage during the 
study, an alternative or additional method of acceptable contraception is required.  During 
the structured telephone interview, occurring every 2 weeks during the treatment and 
sampling period and every 3 months during the vaccination period, women will also be 
asked whether the three criteria are applied. 
 


 
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EXCLUSION CRITERIA 
Mothers/infants who meet any of the following criteria will be excluded from study entry: 
Exclusions related to the mother 
 
Hypersensitivity to ocrelizumab or to any of its excipients 
 
Woman received last dose of ocrelizumab  3 months before the LMP or during pregnancy 
(i.e., there was a potential fetal exposure to ocrelizumab) 
 
Active infections (note: the woman may be included once the infection is treated and is 
resolved; women with bilateral mastitis infection should not have samples collected until the 
infection is completely resolved) 
 
Prior or current history of primary or secondary immunodeficiency, or woman in an 
otherwise severely immunocompromised state.  Woman may be re-screened and included 
if condition resolves 
 
Woman 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 high risk of breast malignancies 
undergoing prophylactic treatment with drugs such as tamoxifen are excluded  
 
Woman has history of breast implants, breast augmentation, breast reduction surgery or 
mastectomy 
 
Woman has prior or current history of chronic alcohol abuse or drug abuse 
 
Woman has any medical, obstetrical or psychiatric condition that, in the opinion of the 
investigator, would compromise the woman's ability to participate in this study 
 
Treatment with a DMT for CIS or MS during pregnancy and/or first weeks postpartum, with 
the exception of formulations of interferon-beta, glatiramer acetate or pulsed corticosteroids 
 
Drugs known to transfer to the breastmilk and with established or potential deleterious 
effects for the infant, including but not limited to aspirin (risk of Reye’s syndrome), 
tetracyclines or fluoroquinolones 
 
Treatment with any investigational agent within 6 months or five half-lives of the 
investigational drug (whichever is longer) prior to the LMP, unless the investigational agent 
is ocrelizumab administered  3 months prior to the LMP in the context of a study or registry 
sponsored by Roche 
 
Exclusions related to the infant 
 
Infant is  24 weeks of age at the time of the mother’s first postpartum dose of ocrelizumab 
 
Infant has any abnormality that may interfere with breastfeeding or milk absorption, 
including but not limited to cleft palate and/or lip, congenital diaphragmatic hernia and 
esophageal atresia 
 
Infant has an active infection.  Infant may be included once the infection resolves 
 
Infant has any other medical condition or abnormality that, in the opinion of the investigator, 
could compromise the infant’s ability to participate in this study, including interference with 
the interpretation of study results 
 
Infant has any other medical condition or abnormality that, in the opinion of the investigator, 
could compromise the infant’s ability to participate in this study, including interference with 
the interpretation of study results 
 
Infant has at least one documented brief resolved unexplained event (BRUE), as defined by 
the 2016 Guidelines of the American Academy of Pediatrics 
 
Exclusions related to laboratory findings 
 
Mother with any abnormal screening laboratory value that is clinically relevant should 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. 


 
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 
Mother 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 (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. 
 
STUDY TREATMENT 
The study treatment is commercial ocrelizumab. 
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 IRRs.  Premedication with an antipyretic (e.g., paracetamol) may also 
be considered prior to each ocrelizumab infusion 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary analysis will be conducted on the full analysis set (all women who meet the 
eligibility criteria and received any postpartum dose of ocrelizumab) and infants of women in the 
full analysis set.  The analysis will be performed after the last breastmilk sample collection at the 
end of the 60-day treatment and sampling period. 
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 estimated average 
oral daily infant dosage will be analyzed using descriptive statistics.  Mean, corresponding 
95% CI, standard deviation, and other statistics will be presented. 
More details about missing data handling, as well as sensitivity analyses based on alternative 
imputation approaches, will be specified in the statistical analysis plan. 
DETERMINATION OF SAMPLE SIZE 
The study will include at least 10 women with CIS or MS (in line with the locally approved 
indications) who are breastfeeding or planning to breastfeed.   
With 10 infants, a precision (width of the two-sided 95% CI) of 0.443 is expected if one event is 
observed (defined as B-cells below the LLN) and a precision of 0.531 if two events are 
observed in the study.  If no event is observed during the study, there is a 95% confidence that 
the event rate is below 0.31. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
definition 
ADID 
average (oral) daily infant dosage 
AE 
adverse event 
AESI 
adverse events of special interest 
ASQ-3 
Ages And Stages Questionnaire, version 3 
AUC 
area under the milk concentration-time curve 
BRUE 
brief resolved unexplained event 
CBC 
complete blood count 
CIS 
clinically isolated syndrome 
CRO 
contract research organization 
CTFG 
clinical trial facilitation group 
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 
Food and Drug Administration 
FSS 
functional systems score 
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 
HCV 
hepatitis c virus infection 
Hib 
Hemophilus influenzae type b 
HIPAA 
health insurance portability and accountability act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 


 
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Abbreviation 
definition 
IMP 
investigational medicinal product 
IND 
investigational new drug 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
LLN 
lower limit of normal 
LMP 
last menstrual period 
mAb 
monoclonal antibody 
MAH 
marketing authorization holder 
MDID 
maximum (oral) daily infant dosage 
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-pneumococcal conjugate vaccine 
PML 
progressive multifocal leukoencephalopathy 
PPMS 
primary-progressive multiple sclerosis 
QTL 
quality tolerance limit 
RID 
relative infant dose 
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 
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).  Multiple 
sclerosis 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 multiple sclerosis (RRMS), secondary 
progressive multiple sclerosis (SPMS), and primary-progressive multiple sclerosis 
(PPMS; Lublin et al. 2014).  Relapsing-remitting multiple sclerosis 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, Zhao, and 
Devonshire 2008; Weinshenker et al. 1989).  Primary-progressive multiple sclerosis 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 (for example, magnetic 
resonance imaging [MRI], lumbar puncture, evoked potentials) evidence 
(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 (mAb) 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-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).  The appropriate treatment strategy during pregnancy and after 
birth remains uncertain, since none of the many DMTs available for MS are 
recommended during pregnancy or breastfeeding (LaHue et al. 2019).  There is no 
consensus on how soon after birth may DMTs be safely resumed.  Women often have to 
choose between breastfeeding and early resumption of a disease-modifying therapy 
(DMT) postpartum.  This can have a significant impact on disease management since 
the risk of postpartum relapse is high.  About 30% of women experience a relapse in the 
first 3 months postpartum (Vukusic et al. 2004).  Such relapses may in turn worsen 
disability (Portaccio et al. 2014). 
The general benefits of breastfeeding are well established, both for mothers as well as 
for infants.  Infants who are exclusively breastfed have a lower risk of gastrointestinal as 
well as respiratory infections (Kramer and Kakuma 2012), and mothers who breastfeed 
have a reduced risk of breast, ovarian, and endometrial cancer (Ip et al. 2007; Kramer 
and Kakuma 2012; Jordan et al. 2017; Collaborative Group on Hormonal Factors in 
Breast Cancer, 2002).  In addition, there is good evidence that exclusive breastfeeding 
may reduce the risk of postpartum relapses.  A systematic literature 
review/meta-analysis of 24 studies exploring the association between breastfeeding and 
MS relapse reported a pooled adjusted hazard ratio (HR) for the association of 
breastfeeding and postpartum relapses of 0.57 (95% CI:  0.38 to 0.85; p  0.006) vs. 
non-breastfeeding (Krysko et al. 2020); and a study of a cohort of 466 pregnancies in 


 
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375 women with MS (based on electronic health records) found that exclusive 
breastfeeding reduced the risk of early postpartum relapses (adjusted HR  0.37, 
p  0.009; Langer-Gould et al. 2020).  Despite reduction in postpartum relapses with 
breastfeeding, annual relapse rates remain fairly high after birth, highlighting the need 
for additional strategies to prevent such relapses (Krysko et al. 2020).  An efficacious 
mAb therapy that could safely be resumed soon after birth would significantly reduce the 
risk of postpartum relapses (LaHue et al. 2020). 
Available Evidence 
In a pre- and post-natal development study in cynomolgus monkeys, administration of 
ocrelizumab from gestation day 20 to approximately 5 weeks postpartum was associated 
with glomerulopathy, lymphoid follicle formation in bone marrow, lymphoplasmacytic 
renal inflammation, and decreased testicular weight in offspring.  There were two cases 
of moribundity, one attributed to weakness due to premature birth accompanied by 
opportunistic infection and the other to an infective meningoencephalitis involving the 
cerebellum of the neonate from a maternal dam with an active infection (mastitis).  The 
course of both neonatal infections could have potentially been impacted by B-cell 
depletion.  Newborn offspring of maternal animals exposed to ocrelizumab were noted to 
have depleted B-cell populations during the post-natal phase.  Measurable levels of 
ocrelizumab were detected in milk (approximated 0.2% of steady state through serum 
levels) during the lactation period.  Overall, it has to be taken into account that 
ocrelizumab was administered as 15/20 and 75/100 mg/kg loading/study doses, which 
correspond to human equivalent doses of approximately 3000 mg (approximately 
5  clinical dose) and 15,000 mg (approximately 25  clinical dose), respectively.  
Maternal doses administered in this study resulted in mean maximum serum 
concentrations (Cmax) that were 4.5- and 21-fold above those anticipated in the clinical 
setting.  Moreover, preclinical studies studying ocrelizumab exposure through lactation 
only (i.e., administering ocrelizumab only postpartum) have not been conducted. 
Clinical studies of the effects on infants associated with the use of ocrelizumab during 
lactation have not been performed.  A few cases of exposure through breastmilk have 
been reported.  Reduced B-cell levels at birth were reported in an infant born to a mother 
exposed to ocrelizumab during the second trimester of pregnancy (following relapse 
activity post-alemtuzumab), who also received a single 300-mg dose postpartum.  
Two months after this dose, the infant’s B-cell levels were normal.  The authors also 
reported an infant who was exposed through breastmilk to a single 600-mg dose 
postpartum, in whom B-cell levels were normal 39 days afterwards.  Neither infant had 
hospitalizations or infections requiring antibiotic or hospitalization, during the period of 
exposure through breastfeeding (Ciplea et al. 2020). 
As of 31 March 2022, 40 cases of infant postpartum exposure to ocrelizumab via 
breastmilk have been reported in the Roche global safety database (Oreja-Guevara et 
al. 2022).  Thirty-three infants were exposed to ocrelizumab postpartum via breast milk; 
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experienced no adverse events; 6 infants experienced adverse events (sleepiness 
potentially due to diphenhydramine hydrochloride exposure; excessive vomiting and 
swelling due to potential dairy allergies; conjunctivitis and otitis media, treated with 
unspecific antibiotics; life-threatening breathing disorder and mild neurodermatitis; 
pelvic inflammation and nephritis; conjunctivitis) and 19 infants had no reported 
adverse event information.  B-cell levels available for 5 infants were in line within 
reported age-specific reference ranges. 
Supporting Evidence from Other Anti-CD20 Therapies 
In a study in 9 women with MS treated with rituximab (another anti-CD20 mAb), the 
median average rituximab concentration in mature breastmilk was low, at 0.063 μg/mL 
(range 0.0460.097) in the 4 patients with serial breastmilk collection; with an estimated 
median absolute infant dose of 0.0094 mg/kg/d and a relative infant dose (RID) of 0.08% 
(range 0.06%0.10%).  Rituximab was virtually undetectable in milk by 90 days 
post-infusion (Krysko et al. 2019).  In another study in 23 patients from the German 
Multiple Sclerosis and Pregnancy Registry who received the mAbs natalizumab (n  17), 
rituximab (n  3), ocrelizumab (n  2) or rituximab  ocrelizumab (n  1) during lactation, no 
negative impact on infant health and development attributable to drug exposure through 
breastmilk was seen after a median follow-up of 1 year.  The concentration of 
natalizumab was low in breastmilk and in the serum of infants, and B-cell levels were 
normal in breastfed infants whose mothers received the anti-CD20 mAb rituximab; 
Ciplea et al. 2020). 
Uncertainties and Need for Additional Evidence 
Data on ocrelizumab kinetics in human milk and on the effects of ocrelizumab on 
breastfed infants are sparse and, as stated, no clinical studies have been performed 
evaluating the benefit-risk of ocrelizumab during breastfeeding.  Given that IgG-based 
mAbs have large molecular sizes and limited transport mechanisms, the expected 
transfer into breastmilk is low (Hurley and Theil 2011).  Additionally, most Igs have low 
oral bioavailability, which further reduces the likelihood of absorption by breastfeeding 
infants (Jasion et al. 2015).  However, it has been shown that in women with MS minimal 
transfer of other anti-CD20 mAbs (rituximab) into breastmilk occurs, while the effects on 
the immune system and developmental milestones of potentially exposed infants remain 
unknown. 
Given the unmet need for women with MS who may wish to breastfeed but are at high 
risk of postpartum relapses, and given the available evidence of minimal transfer of 
rituximab into breastmilk, a dedicated prospective interventional study to specifically 
evaluate the transfer of ocrelizumab into breastmilk and the corresponding 
pharmacodynamic effects in infants is therefore required, and justified.  This study 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 
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics of ocrelizumab in the breastmilk of 
lactating women with CIS or MS (in line with the locally approved indications) treated 
with ocrelizumab, by assessing the concentration of ocrelizumab in mature breastmilk, 
as well as the corresponding exposure and pharmacodynamic effects (blood 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 
Co-Primary Outcome Measure 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum present with B-cell 
depletion  
 
Proportion of infants with B-cell 
levels (CD19 cells, absolute counts in blood) 
below the LLN, measured at Day 30 after the 
mother’s first ocrelizumab postpartum infusion 
 
To evaluate the exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated ADID, calculated as the ocrelizumab 
average milk concentration over 60 days 
post-ocrelizumab infusion 1 multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
Secondary Outcome Measures 
 
To evaluate B-cell levels in 
infants of lactating women with 
CIS or MS receiving 
ocrelizumab postpartum 
 
B-cell levels (CD19  cells, absolute counts and 
percentage of lymphocytes) measured at 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 
 
To evaluate transfer of 
ocrelizumab into breastmilk of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
AUC of ocrelizumab in mature breastmilk (i.e., 
milk produced after Day 14 postpartum) over 
60 days after the first postpartum ocrelizumab 
infusion using the following time points: 
– 
If receiving 1  600 mg: before infusion and 
at 24 hours (Day 1), Day 7, Day 30 and 
Day 60 post-infusion 
– 
If receiving 2  300 mg: before infusion 1 and 
at 24 hours (Day 1), Day 7, Day 14, Day 15 
(24 hours after infusion 2), Day 21, Day 30, 
and Day 60 post-infusion 1 
 
Average and peak ocrelizumab milk 
concentration as well as time to reach peak milk 
concentration, measured over 60 days after the 
mother’s first postpartum ocrelizumab infusion 
ADID   average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire, 
version 3; AUC  area under the milk concentration-time curve; CIS  clinically isolated 
syndrome; EDSS  Expanded Disability Status Scale; HBV   hepatitis B virus; 
Hib  Hemophilus influenzae type b; LLN  lower limit of normal; LMP  last menstrual 
period; MDID  maximum oral daily infant dosage; MMR   measles, mumps, and rubella 
MS  multiple sclerosis; PCV-13  13-pneumococcal conjugate vaccine; RID   relative infant 
dose; WHO  World Health Organization. 


 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Objectives 
Corresponding Endpoints 
Secondary Outcome Measures (cont.) 
 
To evaluate the relative and 
maximum exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated MDID calculated as the peak 
ocrelizumab milk concentration multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
measured over 60 days after the mother’s first 
postpartum ocrelizumab infusion 
 
Average RID over 60 days, calculated as the 
ADID (mg/kg/day) divided by the maternal 
dosage (mg/kg/day) multiplied by 100 
Note:  Other pharmacokinetic and exposure 
parameters may be calculated as appropriate, 
based on the data obtained. 
 
To evaluate whether there is 
transfer of ocrelizumab from the 
mother to the infant via 
breastmilk  
 
Serum concentration of ocrelizumab in the 
infant measured at Day 30 after the mother’s 
first ocrelizumab postpartum infusion 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 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 MMR, diphtheria, tetanus, 
pertussis, Hib, HBV, and PCV-13 
 
Proportion of infants with positive humoral 
response (seroprotective titers; as defined for 
the individual vaccine) to vaccines  
Safety Objectives 
 
To evaluate the safety of 
ocrelizumab in lactating women 
with CIS or MS receiving 
ocrelizumab postpartum and in 
their respective infants 
 
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 
ADID   average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire, 
version 3; AUC  area under the milk concentration-time curve; CIS  clinically isolated 
syndrome; EDSS  Expanded Disability Status Scale; HBV   hepatitis B virus; 
Hib  Hemophilus influenzae type b; LLN  lower limit of normal; LMP  last menstrual 
period; MDID  maximum oral daily infant dosage; MMR   measles, mumps, and rubella 
MS  multiple sclerosis; PCV-13  13-pneumococcal conjugate vaccine; RID   relative infant 
dose; WHO  World Health Organization. 


 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Objectives 
Corresponding Endpoints 
Exploratory Objectives 
 
To evaluate infant’s growth 
velocity and developmental 
milestones in the first year of life 
 
Assessment of growth velocity based on age-
adjusted length, weight, head circumference, 
using monthly 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 measure disease activity in 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Number of MS relapses during the postpartum 
period (clinical relapses) 
 
Mean change in the EDSS score from last 
pre-baseline measurement (up to 1 year before 
LMP) to baseline 
 
To evaluate the evolution of 
B-cell levels over the first year 
of life in infants of lactating 
women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Trajectory (absolute and percentage changes) 
of B-cells (CD19  cells) in the infant from 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 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 
ADID  average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire, version 3; 
AUC  area under the milk concentration-time curve; CIS  clinically isolated syndrome; 
EDSS  Expanded Disability Status Scale; HBV  hepatitis B virus; Hib  Hemophilus influenzae 
type b; LLN  lower limit of normal; LMP  last menstrual period; MDID  maximum oral daily 
infant dosage; MMR  measles, mumps, and rubella MS  multiple sclerosis; 
PCV-13  13-pneumococcal conjugate vaccine; RID    relative infant dose; WHO  World 
Health Organization. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a prospective, multicenter, open-label study in lactating women with CIS or MS 
(in line with the locally approved indications) who decided together with their treating 
physician to continue on, or start treatment with, OCREVUS (ocrelizumab) postpartum 
despite ocrelizumab currently not being recommended during lactation. 
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 
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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 at least 10 women with CIS or MS who are breastfeeding or 
planning to breastfeed.  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 period 
 
Treatment and sampling period 
 
Vaccination period 
 
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 
 
ASQ-3    Ages and Stages Questionnaire, version 3; LMP  last menstrual period; MMR  measles, mumps, and rubella; OCR  ocrelizumab. 
Study description:  In this prospective, multicenter, open-label study, lactating women with CIS or MS (in line with the locally approved 
indications) who decided together with their treating physician to continue on, or start treatment with, commercial ocrelizumab postpartum will 
enter a screening period, which may be started during the third trimester of pregnancy and continue until 24 weeks postpartum.  Women who 
have delivered a healthy term infant and made a decision to breastfeed their infant will be enrolled if they and their infants fulfil the respective 
eligibility criteria.  Women resuming treatment with ocrelizumab postpartum will be included only if the last exposure to ocrelizumab occurred more 
than 3 months before the LMP (i.e., women without potential fetal exposure).  In the 60-day ( 2 days) treatment and sampling period, women 
will receive the ocrelizumab dose regimen as per the locally-approved label, at any point between Week 2 and Week 24 postpartum.  The first 
dose of ocrelizumab may be administered as two 300 mg infusions separated by 14 days (for those initiating ocrelizumab) or as a single 600 mg 
infusion (for those resuming ocrelizumab).  For women where a decision not to administer a second 300 mg infusion is taken after enrolment, 
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at their neurologist’s site as part of their standard of care treatment.  Laboratory and clinical assessments will be performed at the designated 
visits. 
Women will collect their breastmilk samples over several time points up to 60 ( 2) days after the first postpartum ocrelizumab infusion, reserving 
5 mL at each sampling point for analysis of ocrelizumab concentrations.  Infant blood samples will be collected at Day 30 ( 2 days) after the first 
postpartum ocrelizumab infusion (regardless of whether women receive a 600 mg or a 2  300 mg dose).  Infant blood samples may be collected 
at home by a visiting nurse, if not collected at the clinical site during a study visit.  In the vaccination period, infants will continue to 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 for example, the pediatrician as part of routine postnatal care, may also be used).  
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, to evaluate whether infants are able to mount humoral immune 
responses to clinically relevant vaccines, and for measurement of B-cell levels.  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 mother 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 using the lactational amenorrhea method as contraception will also be asked whether the three necessary criteria outlined in 
Section 4.1.1 to ensure adequate protection from an unplanned pregnancy are applied.  No telephone contact is needed in weeks where the 
woman is performing on-site visits.  Women who decide to discontinue the study (this includes discontinuation of either the mother or the infant) 
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 Period 
After providing written informed consent, women will enter a screening period for 
eligibility assessments.  Considering that decisions on initiating or resuming treatment 
with a DMT in the postpartum period are usually taken before or during pregnancy, 
screening may be conducted at any time from the third trimester until 24 weeks 
postpartum.  Final inclusion will only take place for women who have delivered a healthy 
term infant and have made a decision to breastfeed their infant despite ongoing 
ocrelizumab.  General health and medical history of the infant will be reviewed for 
eligibility. 
Women resuming treatment with ocrelizumab postpartum will be included only if the last 
exposure to ocrelizumab occurred more than 3 months before the last menstrual period 
(LMP), i.e., if they have no potential fetal exposure; to exclude any interference between 
fetal exposure and exposure via lactation. 
3.1.3 
Treatment and Sampling Period 
Women fulfilling the inclusion/exclusion criteria will receive the ocrelizumab dose 
regimen as per the locally approved label.  The first dose of ocrelizumab may be 
administered at any point between Week 2 and Week 24 postpartum, as an initial split 
dose of two 300 mg infusions (in 250 mL 0.9% sodium chloride) separated by 14 days or 
as a single 600 mg infusion (in 500 mL 0.9% sodium chloride), according to the local 
prescribing information.  For women where a decision not to administer a second 
300 mg infusion is taken after enrolment, continuation in the study will be allowed.  
Dosing and treatment duration are at the discretion of the physicians, in accordance 
with local clinical practice and local labeling (U.S. Prescribing Information [USPI]; 
Summary of Product Characteristics [SmPC]).  If women did not experience a serious 
infusion-related reaction (IRR) with any previous ocrelizumab infusion, a shorter (2-hour) 
infusion can be administered for subsequent 600 mg doses (SmPC, USP).  Women 
referred by healthcare professionals (HCPs) to participate in the trial may receive 
ocrelizumab treatment at their neurologist’s site as part of their standard of care 
treatment. 
Maternal breastmilk samples will be collected over several time points up to 
60 ( 2) days after the first postpartum ocrelizumab infusion at approximately the same 
time of day, although flexibility is allowed on collection timings to accommodate the 
mother and infant feeding schedule.  The only exception is the first (Day 1) post-infusion 
breastmilk sample, and in women who received a 2  300 mg dose, the second (Day 15) 
post-infusion breastmilk sample, which should be collected 24 hours after the midpoint of 
the infusion.  On days of collection, milk should be expressed from both breasts until 
completely emptied using an electric breast pump.  The milk from each breast is then 
mixed and a sample (volume  5 mL) is removed for analysis.  The infant can be 
bottle-fed the remaining expressed milk.  If the infant is not usually fed using a bottle, 
milk may be expressed from one breast only.  If the mother presents with unilateral 


 
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mastitis, milk should only be expressed from the unaffected breast, until the infection 
resolves.  If mastitis presents bilaterally (rare), breastmilk collection should be stopped 
until the infection resolves. 
The infant blood sample will be collected at Day 30 ( 2 days) of lactation after the first 
ocrelizumab infusion administered postpartum, i.e., regardless of whether women 
receive a 600 mg or a 2  300 mg dose.  The corresponding breastmilk sample should 
be collected on the same day as the infant blood sample.  Blood samples may be 
collected at home by a visiting nurse, or at the hospital as part of study visits 
(see Appendix 1, Schedule of Assessments). 
Note: If the infant’s B-cell levels are found to be below lower limit of normal (LLN), 
analyses of B-, T-, and natural killer (NK) cells will be repeated every 4 weeks until 
B-cell levels are found to be above the age-adequate LLN as per Appendix 7 (in 
consultation with the Sponsor).  The first repeat analysis will also include a complete 
blood count (CBC) and immunoglobulin levels.  
A structured telephone interview will be conducted by site personnel every 2 weeks in 
the treatment and sampling period, for a general review and to identify and collect 
information on any changes in the woman’s and infant’s health status (including the 
occurrence of MS relapses in the mother 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 using the 
lactational amenorrhea method as contraception will also be asked whether the three 
necessary criteria outlined in Section 4.1.1 to ensure adequate protection from an 
unplanned pregnancy are applied.  No telephone contact is needed in weeks where the 
woman is performing on-site visits. 
3.1.4 
Vaccination Period 
After the 60-day ( 2 days) treatment and sampling period, infants will continue to be 
followed-up for growth (age-adjusted length, weight, 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) questionnaires 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. 
Infant laboratory assessments will be performed 1 month ( 30 days) after the first or 
second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13 of age 
( 30 days), if MMR vaccine is not planned to be administered, to evaluate whether 
infants are able to mount humoral immune responses to clinically relevant vaccines, as 
well as to measure their B-cell levels.  In case the mother decides to switch to another 


 
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DMT or to stop DMT after the 60-day treatment and sampling period, the infant blood 
sample will still be collected. 
A structured telephone interview will be conducted by site personnel postpartum every 
3 months in the vaccination period (in-between ocrelizumab infusions) for a general 
review, and to identify and collect information on any changes in the woman’s and 
infant’s health status (including the occurrence of MS relapses in the mother 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 using the lactational amenorrhea method as contraception will also be 
asked whether the three necessary criteria outlined in Section 4.1.1 to ensure adequate 
protection from an unplanned pregnancy are applied.  No telephone contact is needed 
in weeks where the woman is performing on-site visits. 
3.1.5 
Discontinuation 
Women who decide to discontinue the study (this includes discontinuation of either the 
mother or the infant; this does not apply to treatment discontinuation as described in 
Section 3.1.4) will be invited to attend an early study discontinuation visit (which may be 
conducted remotely, i.e., virtually or by telephone) as soon as possible.  Depending on 
the timing of discontinuation, the following is recommended: 
 
Discontinuation before the infant blood draw at 30 ( 2) days post-infusion 1:   
– 
Collection of infant outcomes in the first year of life as per standard 
pharmacovigilance procedures 
– 
If the mother remains on treatment with ocrelizumab and decides to stop 
participating at 30 ( 2) days after the first postpartum ocrelizumab infusion, 
attempts to collect the infant sample at 30 ( 2) days should be made before 
discontinuation  
– 
If the mother switches to another DMT, the infant sample at 30 ( 2) days 
should not be collected. 
 
Discontinuation after the infant blood draw at 30 ( 2) days post-infusion 1: 
Collection of infant outcomes in the first year of life as per standard 
pharmacovigilance procedures. 
 
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 vaccine is not planned to be administered) for the 
last infant.  The primary analysis will be conducted at the end of the Treatment and 
Sampling Period (Day 60 [ 2 days]). 
The total length of the study, from screening of the first woman to the end of the study, is 
expected to be approximately 3 years.  This includes an enrolment period of 
approximately 21 months and a woman’s participation period of 16 months. 


 
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3.3 
RATIONALE FOR STUDY DESIGN 
This is a prospective, multicenter, open-label study evaluating the transfer of 
ocrelizumab into breastmilk of lactating women with CIS or MS treated with ocrelizumab 
postpartum.  Ocrelizumab targets B-cells, and a rapid depletion of CD19  B-cells in 
blood is the expected pharmacologic effect of ocrelizumab treatment (and hence, is a 
biomarker for pharmacodynamic effect).  This depletion occurs briefly even at low doses 
such as 2  10 mg (FDA 2017).  Therefore, CD19  B-cell levels will be measured as a 
co-primary endpoint (specifically, the proportion of infants with B-cells below the LLN at 
Day 30 [ 2 days] post-infusion). 
To evaluate the amount of drug that may be transferred from mother to infant through 
breastmilk, the co-primary endpoint is the average (oral) daily infant dosage (ADID), 
which expresses the average amount of ocrelizumab in breastmilk (and available to the 
infant) as an infant dose, over the observed period of 60 days ( 2 days) post-infusion.  
The excretion in breastmilk is expected to be highest during the first 60 days after the 
ocrelizumab infusion, declining thereafter over the 6-monthly dosing interval.  Breastmilk 
samples will be collected before the infusion, and at days 1, 7, 30 ( 2) and 60 ( 2) (with 
additional timepoints for mothers who are receiving a split dose, i.e., 2  300 mg), to 
cover two average half-lives of ocrelizumab in serum (26 days [USPI]) and the expected 
time window of greatest breastmilk transfer for anti-CD20 monoclonal antibodies 
(Krysko et al. 2019).  Samples will be taken only after the development of mature milk 
(i.e., milk produced after Day 14 postpartum) to avoid the collection of colostrum, which 
may contain a high concentration of antibody because of a more porous mammary 
epithelium (FDA 2019).  In addition, mothers will be instructed to completely empty both 
breasts with an electric pump, and mix milk from both breasts before removing the 
amount required for the sample.  If the infant is not usually fed using a bottle, milk may 
be expressed from one breast only.  This will reduce variability across the study, as for 
example foremilk and hindmilk (milk expressed at the start and end of feeding, 
respectively) have different compositions, which can influence the amount of drug 
available in the sample (Hebert 2016).  To account for differences in exclusive 
breastfeeding versus supplementation with formula, a feeding schedule diary completed 
by the women will record the number of breastmilk feeds and/or feed with formula milk 
(supplementation) on the day of the sample collection and the previous and following 
day, as recommended by the FDA (Food and Drug Administration; FDA 2019).  For 
mothers presenting with mastitis during the sampling period, sample collections from the 
infected breast(s) will be interrupted, given that clinical and subclinical mastitis are 
associated with increased milk concentrations of serum-derived immune factors such as 
IgG (Filteau 2003). 
To further understand the extent of ocrelizumab transfer through breastmilk and the 
exposure in infants, secondary endpoints will include the area under the milk 
concentration-time curve (AUC) of ocrelizumab in breastmilk over 60 days 
post-ocrelizumab infusion, average concentration, peak concentration, time to peak 


 
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concentration and the maximum (oral) daily infant dosage (MDID), as recommended by 
the FDA (FDA 2019).  To evaluate potential adverse impact on the infants, infant health 
and development outcomes will be assessed using growth charts according to the WHO 
Child Growth Standards (WHO 2022) 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). 
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 of lactating women 
with CIS or MS receiving ocrelizumab postpartum can mount a protective immune 
response to clinically relevant vaccines. 
As exploratory endpoints, disease activity will be measured in the mothers using 
standard assessments such as Expanded Disability Status Scale (EDSS) and number of 
MS relapses.  These endpoints are commonly used in MS clinical trials to assess 
treatment efficacy and disease progression. 
As recommended (FDA 2019), this study is designed to minimize burden on the mother 
and disruption to the infant’s feeding schedule.  For example, at sample collection time 
(when the infant would be fed the remainder of the collected milk through a bottle), 
mothers may instead collect the sample from only one breast if the infant is not normally 
fed using a bottle.  Further, the infant blood sample on Day 30 ( 2 days) post-infusion 
and at 1 month ( 30 days) after the first or second dose of MMR vaccine/Month 13 of 
age ( 30 days) may be collected at home by a visiting nurse, or at the hospital as part of 
study visits. 
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 labeling 
(USPI; SmPC).  As per the dosing regimen approved in the labeling, 600 mg 
ocrelizumab is to be given as IV infusion every 6 months.  The first dose is given as two 
300 mg IV infusions two weeks apart; and subsequent doses are given as single 600 mg 
IV infusions.  For women where a decision not to administer a second 300 mg infusion is 
taken after enrolment, continuation in the study will be allowed.  If women did not 
experience a serious IRR with any previous ocrelizumab infusion, a shorter (2-hour) 
infusion can be administered for subsequent 600 mg doses (Ocrelizumab SmPC, 
Ocrelizumab USPI). 


 
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3.3.2 
Rationale for Subject Population 
As the aim of this study is to evaluate breastmilk transfer of ocrelizumab and the 
corresponding pharmacodynamic effects in the infant, it will be conducted in women with 
CIS or MS (in line with the locally approved indications) aged 1840 years who have 
planned to start or resume ocrelizumab after delivery, while breastfeeding for a minimum 
of 60 days.  
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 1 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 (Simister 2003; Palmeira et al. 2012), it is 
assumed that a potential fetal exposure is unlikely in women whose last ocrelizumab 
infusion was earlier than 3 months before LMP.  Women who were exposed to 
ocrelizumab within 3 months of their LMP, or during pregnancy, will therefore be 
excluded to eliminate cases of potential fetal exposure to ocrelizumab that could 
confound the results of B-cell levels in the infant or the presence of ocrelizumab in 
breastmilk.   
Women who have given birth to more than one baby (i.e., have had non-singleton births) 
are excluded, because such mothers might find it difficult to comply with study 
requirements, and might find it more difficult to reserve the amount of breastmilk needed 
for the sample.  Therefore, their infants might receive a different amount of breastmilk, 
potentially confounding the B-cell level results. 
Infants who are  24 weeks of age at the mother’s first postpartum dose of ocrelizumab 
will be excluded.  Although the WHO recommends exclusive breastfeeding up to 
6 months with continued breastfeeding along with appropriate complementary foods up 
to 2 years of age or older (WHO 2020a), these recommendations are not followed in 
most countries.  Recent findings from the National Immunization Survey 20182019 in 
the United States show that the percentage of infants who are breastfed decreases from 
58.3% at 6 months to 35.3% at 1 year (Centers for Disease Control and Prevention 
2020a).  The maximum maternal age is set at 40 years, as mothers in late childbearing 
age of  35 years (in particular primiparous mothers) have been shown to have the 
greatest risk of non-initiation of exclusive breastfeeding both at discharge and at 1 month 
postpartum, even though they had the antenatal intention to exclusively breastfeed 
(Kitano et al. 2016). 
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.  
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), and all antiviral drug labels do not recommend 
breastfeeding when taking the drugs. 


 
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In addition, infants with any abnormality that may interfere with breastfeeding or milk 
absorption, such as cleft palate and/or lip, congenital diaphragmatic hernia and 
esophageal atresia are excluded, given that the co-primary aim of this study is to 
evaluate the corresponding pharmacodynamic effects of potential ocrelizumab exposure 
through breastmilk.  Infants who have had at least one documented brief resolved 
unexplained event (BRUE), are also excluded, because these potentially life-threatening 
events have an unknown impact on infant physiology and development, and may 
confound the interpretation of infant’s growth velocity and development milestones in the 
first year.  The term BRUE is defined by the American Academy of Pediatrics as an 
event occurring in an infant younger than 1 year when the observer reports a sudden, 
brief, and now resolved episode of  1 of the following:  (1) cyanosis or pallor; (2) absent, 
decreased, or irregular breathing; (3) marked change in tone (hyper- or hypotonia); and 
(4) altered level of responsiveness (Tieder et al. 2016). 
4. 
MATERIALS AND METHODS 
4.1 
STUDY PARTICIPANTS 
This study will enroll at least 10 women with CIS or MS (in line with the locally approved 
indications) who are breastfeeding or planning to breastfeed. 
4.1.1 
Inclusion Criteria 
The following criteria must be met for study entry: 
 
An Informed Consent Form (ICF) for participation of the maternal subject and her 
infant (for collection of blood, infant demographic 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 
 
Woman is able and willing to comply with the study protocol, according to the 
judgment of the investigator, in particular: 
– 
Woman is willing to breastfeed (either exclusively, or with formula 
supplementation) for at least 60 days after the first postpartum ocrelizumab 
infusion (this decision is to be taken prior to and independent from study 
participation) 
– 
Woman is willing to provide breastmilk samples before and after their first and, 
if applicable, second postpartum ocrelizumab infusion 
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. 
 
Woman is between 18 and 40 years of age at screening 
 
Woman has a diagnosis of MS or CIS (in line with the locally approved indications) 


 
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 
Woman has delivered a healthy term singleton infant ( 37 weeks gestation) 
 
Infant is between 224 weeks of age at the time of the mother’s first postpartum 
dose of ocrelizumab 
 
For women who received commercial ocrelizumab (OCREVUS) before enrolment: 
documentation that last exposure ocrelizumab occurred more than 3 months before 
the LMP (i.e., excluded a potential fetal exposure) and was given at the approved 
dose of 2  300 mg or 1  600 mg 
 
Woman agrees to use acceptable contraceptive methods or alternative methods 
during the study as described below and, if applicable, upon study treatment 
discontinuation, as defined by the local prescribing information (see Section 4.6.1). 
– 
The following contraceptive methods are considered acceptable (failure rate 
 1% [Clinical Trial Facilitation Group (CTFG)]):  progestogen-only oral hormonal 
contraception, where inhibition of ovulation is not the primary mode of action; 
male or female condom with or without spermicide; cap, diaphragm, or sponge 
with spermicide; combination of male condom with cap, diaphragm, or sponge 
with spermicide (double-barrier method). 
Birth control methods that are highly effective (i.e., failure rate  1% [CTFG]) may 
also be used but are not required, and include:  oral, intravaginal or transdermal 
combined hormonal contraception associated with inhibition of ovulation [unless not 
recommended or contraindicated during breastfeeding, see Table A2-1]; oral, 
injectable or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation; intrauterine device; intrauterine hormone-releasing system; 
bilateral tubal occlusion; vasectomized partner; sexual abstinence. 
Note:  lactational amenorrhea method can be used to ensure adequate protection 
from an unplanned pregnancy, and the following three criteria must be met:  
1) amenorrhea; 2) fully or nearly fully breastfeeding (no interval of  46 hours 
between breastfeeds); and 3)  6 months postpartum.  If any of the three listed 
criteria change at any stage during the study, an alternative or additional method of 
acceptable contraception is required.  During the structured telephone interview, 
occurring every 2 weeks during the treatment and sampling period and every 
3 months during the vaccination period, women will also be asked whether the three 
criteria are applied. 
 
4.1.2 
Exclusion Criteria 
Mothers or infants who meet any of the following criteria will be excluded from study 
entry: 
Exclusions related to the mother 
 
Hypersensitivity to ocrelizumab or to any of its excipients 
 
Woman received last dose of ocrelizumab  3 months before the LMP or during 
pregnancy (i.e., there was a potential fetal exposure to ocrelizumab) 


 
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 
Active infections (note: the woman may be included once the infection is treated and 
is resolved; women with bilateral mastitis infection should not have samples 
collected until the infection is completely resolved) 
 
Prior or current history of primary or secondary immunodeficiency, or woman in an 
otherwise severely immunocompromised state.  Woman may be re-screened and 
included if condition resolves 
 
Woman 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 high risk of 
breast malignancies undergoing prophylactic treatment with drugs such as 
tamoxifen are excluded 
 
Woman has history of breast implants, breast augmentation, breast reduction 
surgery or mastectomy 
 
Woman has prior or current history of chronic alcohol abuse or drug abuse 
 
Woman has any medical, obstetrical or psychiatric condition that, in the opinion of 
the investigator, would compromise the woman's ability to participate in this study 
 
Treatment with a DMT for CIS or MS during pregnancy and/or first weeks 
postpartum, with the exception of formulations of interferon-beta, glatiramer acetate 
or pulsed corticosteroids 
 
Drugs known to transfer to the breastmilk and with established or potential 
deleterious effects for the infant, including but not limited to aspirin (risk of Reye’s 
syndrome), tetracyclines or fluoroquinolones.  A more detailed, though not 
comprehensive, list can be found in Appendix 2 
 
Treatment with any investigational agent within 6 months or five half-lives of the 
investigational drug (whichever is longer) prior to the LMP, unless the investigational 
agent is ocrelizumab administered  3 months prior to the LMP in the context of a 
study or registry sponsored by Roche 
 
Exclusions related to the infant 
 
Infant is  24 weeks of age at the time of the mother’s first postpartum dose of 
ocrelizumab 
 
Infant has any abnormality that may interfere with breastfeeding or milk absorption, 
including but not limited to cleft palate and/or lip, congenital diaphragmatic hernia 
and esophageal atresia 
 
Infant has an active infection.  Infant may be included once the infection resolves 
 
Infant has any other medical condition or abnormality that, in the opinion of the 
investigator, could compromise the infant’s ability to participate in this study, 
including interference with the interpretation of study results 
 
Infant has at least one documented BRUE, as defined by the 2016 Guidelines of the 
American Academy of Pediatrics 
 


 
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Exclusions Related to Laboratory Findings 
 
Mother with any abnormal screening laboratory value that is clinically relevant 
should 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. 
 
Mother 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 hepatitis B virus (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. 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.  No randomization, treatment assignment or blinding is 
planned. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS 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 the United States] and SmPC [for the 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 labeling (USPI; SmPC).  No measures of treatment 
compliance are planned. 
4.3.2.1 
Study Treatment 
As per the labeling, 600 mg ocrelizumab is to be given as IV infusion every 6 months.  
The first dose of ocrelizumab may be administered at any point between Week 2 and 
Week 24 postpartum as two 300-mg IV infusions two weeks apart (in 250 mL 0.9% 
sodium chloride) or as a single 600-mg IV infusion (in 500 mL 0.9% sodium chloride); 
and subsequent doses given according to the local prescribing information.  For women 
where a decision not to administer a second 300 mg infusion is taken after enrolment, 
continuation in the study will be allowed.  If women did not experience a serious IRR with 
any previous ocrelizumab infusion, a shorter (2-hour) infusion can be administered for 


 
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subsequent 600 mg doses (SmPC, USPI).  Women referred by HCPs to participate in 
the trial may receive ocrelizumab treatment at their neurologist’s site as part of their 
standard of care treatment. 
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 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 woman participating in the study, in addition to the study 
treatment.  All such medications taken within 6 weeks prior to the baseline visit and 
throughout the study should be reported to the investigator and recorded on the 
Concomitant Medications electronic case report form (eCRF). 
4.4.1 
Prohibited Therapy 
Drugs known to transfer to the breastmilk and with established or potential deleterious 
effects for the infant, including but not limited to aspirin (risk of Reye’s syndrome), 
tetracyclines or fluoroquinolones are not permitted.  A more detailed, though not 
comprehensive, list can be found in Appendix 2. 
No formal drug-drug interaction studies have been conducted with ocrelizumab, as no 
drug-drug interactions are expected via the cytochromes P450, other metabolizing 
enzymes or transporters. 
Ocrelizumab is a monotherapy and has not been studied in combination with other 
DMTs.  As with other immunomodulatory therapies, exercise caution when initiating 
ocrelizumab after an immunosuppressive therapy, and when initiating another therapy 
after ocrelizumab, taking into consideration the potential for overlapping 
pharmacodynamic effects. 
Immunosuppressants, lymphocyte-depleting agents, or lymphocyte-trafficking blockers 
should NOT be administered while the woman is B-cell depleted. 
More information is available in Section 4.1.2 and the ocrelizumab labeling (USPI; 
SmPC). 
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 or infant. 


 
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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 their infants 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 enrolment.  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, and Disease 
Characteristics 
Women’s demographics (age, self-reported ethnicity, and level of education) and 
relevant medical history, including clinically significant diseases, surgeries/procedures, 
vaccination history, 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 the baseline visit will be recorded.  Clinically significant 
diseases and/or surgeries and concomitant medication should also be recorded 
throughout the study if available. 
Obstetric history: 
 
History of previous pregnancies 
 
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 
the LMP 
 
History of previous DMTs (prior to and during pregnancy): number of DMTs ever 
used, last DMT before ocrelizumab 
 
Treatment history with ocrelizumab (to be collected only in women who received 
commercial ocrelizumab prior to enrolment): Documentation of start of ocrelizumab 
therapy and date and dose of last ocrelizumab infusion prior to enrolment. 
 
4.5.2.2 
Physical Examinations and Related Assessments 
A complete physical examination in participating women should include an evaluation of 
head, eye, ear, nose, and throat, cardiovascular, dermatological, musculoskeletal, 
respiratory, and gastrointestinal systems, as well as vital signs (see following section).  


 
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To reduce the burden of visits on the mothers, results from physical examinations done 
as part of routine care at the woman’s HCP (obstetrician/gynecologist, pediatrician 
and/or neurologist of referred woman) 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.  Height will be recorded at 
screening only. 
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). 
See Appendix 1 (Schedule of Assessments) for the timing of 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 these measurements are performed as per clinical 
practice and are available, any abnormalities should be recorded on the General Medical 
History and Baseline Conditions eCRF.  At subsequent visits, new or worsened clinically 
significant abnormalities should be recorded on the Adverse Event section of the eCRF 
(as presented in Section 5.1.2). 
4.5.2.4 
Neurological Examinations 
A neurological examination will be performed at baseline, early study discontinuation as 
well as at unscheduled visits if applicable, to distinguish relapse in MS from another 
neurological (non-MS) disorder.  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 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 (with all available information) with immediate notification of the Medical Monitor.  
Refer to Appendix 3 for guidance for diagnosis of PML. 


 
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4.5.2.5 
Assessment of Relapses 
Potential relapses should be recorded throughout the treatment period.  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 hours, with or 
without recovery, and in the absence of fever or infection (Thompson et al. 2018).  
MS relapses should not be reported as an adverse event, unless they are serious. 
It is recommended that women with new neurological symptoms suggestive of a relapse 
have an EDSS/Functional Systems Score (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 
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 paragraphs.  For sampling procedures, storage 
conditions, and shipment instructions, see the laboratory manual.  For more details, refer 
to Schedule of Assessments (see Appendix 1). 
 
Hematology (hemoglobin, hematocrit, quantitative platelet count, red blood cell 
[RBC] count, white blood cell [WBC] absolute or/and differential count [neutrophils, 
eosinophils, lymphocytes, monocytes, basophils]). 
 
Serum chemistry (potassium, sodium, chloride, random glucose, AST, ALT, 
gamma-glutamyl transpeptidase [GGT], total bilirubin and creatinine). 
 
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. 


 
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 
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. 
 
Serum Ig concentration:  Quantitative measurement for IgG, IgM and IgA levels. 
 
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+). 
 
Ocrelizumab concentration in breastmilk:  Breastmilk samples throughout the 
study will be collected for determination of ocrelizumab concentration.  Women 
should record the volume of pumped breastmilk and indicate date and time for 
collection as well as whether breastmilk was pumped from one or both breasts.  
At each sampling point, 5 mL of breastmilk should be saved (as directed by the site 
staff) to send to the central laboratory.  The 24-hour (Day 1, as well as Day 15 for 
women who received the 2  300 mg regimen) post-infusion samples are collected 
based on the midpoint of infusion.  For example, if the infusion began at 8 a.m. and 
ended at 10 a.m., the 24-hour sample collection would occur at 9 a.m. on the day 
before and after the infusion.  For details, refer to Schedule of Assessments (see 
Appendix 1). 
 
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, CD38bright  
 Plasmablasts or plasma cells:  CD45+, CD19+, CD27+, CD38 bright 
  
4.5.3 
Infant’s Assessments 
4.5.3.1 
Medical History, Biometrics and Concomitant Medications 
 
General health and medical history 
 
Gestational age at birth 
 
Congenital malformations 
 
Mode of delivery (vaginal delivery, instrumental delivery, scheduled or urgent 
cesarean section)  
 
Appearance, Pulse, Grimace, Activity, and Respiration score (1 min, 5 min, 10 min) 
 
Infant vital biometrics (head circumference, weight, length) at birth 


 
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 
Previous and concomitant medication given to the infant should be recorded at 
screening and throughout the study.  For administered vaccinations, refer to 
Section 4.5.3.2. 
Note:  these standard-of-care data may be collected by the investigator as reported by 
the mother and/or via direct contact with the pediatrician. 
 
4.5.3.2 
Physical Examinations and Related Assessments 
 
Body weight (measured at every visit where a blood sample will be taken, i.e., at 
Day 30 [ 2 days] post-infusion 1, and 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).  Infant weight will be collected by a mobile nurse 
during home visits or by qualified site staff if the visit occurs at the site. 
 
Feeding schedule diary (during the treatment and sampling period):  Women should 
record the number of breastmilk feeds and/or feed with formula milk 
(supplementation) on the day of the sample collection and the previous and 
following day, i.e., day of collection  1 day.  The mother’s record of the feeding 
schedule diary will be collected by study personnel at the site or by a mobile nurse 
during visits to the mother. 
 
Feeding status (during the vaccination period): Women 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, at Months 2, 4, 6, 9, and 12, as applicable and depending 
on the infant’s age at enrolment.  The mother’s record of feeding status will be 
collected by study personnel at the site or by a mobile nurse during visits to the 
mother. 
 
ASQ-3 at Months 2, 4, 6, 9, and 12, as applicable and depending on the infant’s age 
at enrolment. 
 
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) at Months 2, 4, 6, 9, and 12, as applicable 
and depending on the infant’s age at enrolment. 
 
Documentation of vaccinations: 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 30 days after the first postpartum ocrelizumab infusion 
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 Month 
13/1 month after first or second MMR dose, and may include diphtheria, tetanus, 
and pertussis, Hemophilus influenzae type b (Hib), 13-pneumococcal conjugate 
vaccine (PCV-13), HBV and MMR.  Documentation of vaccinations will be collected 
by the investigator via interview and documentation provided by the mother 
(e.g., vaccine card) or via direct contact with the pediatrician. 


 
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See Appendix 1 (Schedule of Assessments) for the timing of assessments and 
Appendix 6 for the time windows for infant growth velocity and child developmental 
milestone assessments. 
4.5.3.3 
Laboratory, Biomarker, and Other Biological Samples 
Routine laboratory assessments (performed in the central laboratory) are listed in the 
following sections.  For sampling procedures, storage conditions, and shipment 
instructions, see the laboratory manual.  For more details, refer to Schedule of 
Assessments (see Appendix 1). 
Day 30 ( 2 days) post-infusion 1 
 
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 in serum 
 
Note:  If the infant’s B-cell levels are found to be below LLN at any visit, analyses of B-, 
T-, and NK cells will be repeated every 4 weeks until B-cell levels are found to be above 
the age-adequate LLN as per Appendix 7 (in consultation with the Sponsor).  The first 
repeat analysis will also include CBC and immunoglobulin levels. 
Infant samples will be collected by venipuncture at one timepoint.  As per the 
recommendations 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. 
Table 3 
Prioritization Order for Infant Blood Sample Assessments at 
Day 30 (2 days) Post-Infusion 1 
Order of Priority 
Assessment 
1 
Any necessary 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 The same sample will be used to measure B-cell counts (CD19  ), T-cell counts (CD3 , 
CD4 , 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 


 
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Month 13 of chronological age ( 30 days) if MMR is not planned to be 
administered 
 
Mean titers (IgG) of antibody immune response(s) to common childhood 
vaccinations with full or partial doses given prior to 1 year will be measured (which 
include responses to MMR, diphtheria, tetanus, pertussis, Hib, HBV, and PCV-13).  
Titers will be measured at 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. 
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. 
a) Lymphocyte subtypes:  A blood sample will be collected to measure B-cell 
counts (CD19 ); the same sample will be used to measure T-cell counts 
(CD3 , CD4 , CD8  ), and NK cell counts (CD16+CD56+). 
 
Note:  If the infant’s B-cell levels are found to be below LLN at any visit, analyses of B-, 
T-, and NK cells will be repeated every 4 weeks until B-cell levels are found to be above 
the age-adequate LLN as per Appendix 7 (in consultation with the Sponsor).  The first 
repeat analysis will also include a CBC and immunoglobulin levels. 
Infant samples will be collected by venipuncture at one timepoint.  As per the 
recommendations 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. 
Table 4 
Prioritization Order for Infant Blood Sample Assessments 
1 Month ( 30 days) After the First/Second Dose of MMR Vaccine 
or at Month 13 of Age ( 30 Days) if MMR Vaccine Is Not Planned 
to Be Administered 
Order of Priority 
Assessment 
1 
Any necessary safety laboratory samples (scheduled or unscheduled and 
performed at the discretion of the investigator) 
2 
Mean titers (IgG) of antibody immune response(s) to vaccinations a 
3 
Lymphocyte subtypes blood sample b 
Ab    antibody; IgG  immunoglobulin G; MMR   measles, mumps, rubella; NK  natural 
killer; PCV  13-valent pneumococcal conjugate vaccine. 
a The following antibody titers will be measured:  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 The same sample will be used to measure B-cell counts (CD19  ), T-cell counts (CD3 , 
CD4 , CD8  ), and NK cell counts (CD16+CD56+). 
 


 
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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 (with the 
exception of an accidental pregnancy, as described below).  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. 
In case a woman enrolled in the study becomes accidentally pregnant again during 
breastfeeding, she will remain on study and discontinue treatment with commercial 
ocrelizumab until the pregnancy completion.  She and her infant should continue with all 
study assessments (including breastmilk sample collection).  The investigator should 
complete the Global Clinical Trial Pregnancy Form and submit to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator will submit to the Sponsor a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. 
4.6.2 
Discontinuation from the Study 
Women and their 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; this does not apply to treatment 
discontinuation as described in Section 3.1.4) will be invited to attend an early study 
discontinuation visit as soon as possible (further details in Section 3.1.5). 
Reasons for women’s discontinuation from the study may include, but are not limited to, 
the following: 
 
Woman’s withdrawal of consent 
 
Study termination or site closure 
 
AE 
 
Loss to follow-up 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the woman’s or infant’s safety 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 the woman’s discontinuation from 
the study.  The primary reason for discontinuation from the study should be 


 
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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. 
● 
Enrolment 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) 
 
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 
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5.1.1.1 
Adverse Events 
According to the ICH, an adverse event is any untoward medical occurrence in a subject 
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 
 
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) 
 
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 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). 


 
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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. 
 
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. 
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. 


 
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5.1.2 
Methods and Timing for Capturing and Assessing 
Safety Parameters 
The investigator is accountable for ensuring that all adverse events collected as per 
protocol (see Section 5.1.1.1 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 
The 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 
occurring in a pregnant woman pre- and post- study period should be reported to the 
marketing authorization holder (MAH), as a follow-up spontaneous pregnancy report to 
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 instruction regarding: 
 
IRRs 
 
Diagnosis versus signs and symptoms 
 
Adverse events occurring secondary to other adverse events 
 
Persistent or recurrent AEs 
 
Abnormal laboratory values 
 
Abnormal vital sign values 
 
Abnormal liver function tests 
 
Deaths 


 
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– 
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 Investigator to Sponsor 
5.1.3.1 
Immediate Reporting Requirements from Investigator 
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 
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: 
 
SAEs 
 
Non-serious adverse events of special interest 
 
Pregnancy occurred during breastfeeding (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 


 
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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 Institutional Review Board (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, 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. 
5.1.3.4 
If Electronic Data Capture 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 
woman enrolled in the study becomes accidentally pregnant again during breastfeeding, 
she will remain on study and discontinue treatment with commercial ocrelizumab until 
pregnancy completion.  She and her infant should continue with all study assessments 
(including breastmilk sample collection).  The investigator should complete the Global 
Clinical Trial Pregnancy Form and submit it to the Sponsor or its designee immediately 


 
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(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Pregnancy should not be recorded on the Adverse Event eCRF.  
The investigator 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 
breastfeeding (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 
The study enrolls postpartum women breastfeeding their infants following the first 
postpartum ocrelizumab dose.  In case a woman enrolled in the study becomes 
accidentally pregnant again during breastfeeding, she will remain on study and 
discontinue treatment with commercial ocrelizumab until pregnancy completion.  She 
and her infant should continue with all study assessments (including breastmilk sample 
collection). 
In case of a spontaneous abortion in an accidental pregnancy during breastfeeding, the 
spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), 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). 
If a therapeutic or elective abortion was performed in an accidental pregnancy during 
breastfeeding because of an underlying maternal or embryofetal toxicity, the toxicity 
should be classified as an serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.1.3.1).  A therapeutic or elective abortion performed for reasons 
other than an underlying maternal or embryofetal toxicity is not considered an AE. 
All abortions that occur in an accidental pregnancy during breastfeeding should be 
reported as pregnancy outcomes on the paper Clinical Trial Pregnancy Reporting Form. 
Congenital Anomalies/Birth Defects 
The study enrolls women postpartum who delivered a healthy term infant and who plan 
to breastfeed their infants following the first postpartum ocrelizumab dose.  In case a 
woman enrolled in the study becomes accidentally pregnant again during breastfeeding, 
she will remain on study and discontinue treatment with commercial ocrelizumab until 
pregnancy completion.  She and her infant should continue with all study assessments 
(including breastmilk sample collection). 
Any congenital anomaly/birth defect in a child born to a woman who became accidentally 
pregnant during breastfeeding and was exposed to the medicinal product should be 


 
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classified as an 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 (see also Section 5.1.3.5) 
 
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) 


 
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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 (e.g., SmPC for the EU). 
 
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. 
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 conducted after the last breastmilk sample collection at the 
end of the 60-day treatment and sampling period.  Full analysis, including analysis of the 
vaccination response in infants, 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 


 
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study database, and may include further exploratory analyses not explicitly described in 
this section. 
6.1 
ANALYSIS POPULATIONS 
Full Analysis Set 
The full analysis set (FAS) population of women will include all women who meet the 
eligibility criteria and receive any postpartum dose of ocrelizumab. 
The FAS population of infants will include all the infants of the FAS population of women. 
Safety Population 
The safety population will be the same as the FAS.  The safety population of infants will 
include all infants of women in the FAS population. 
6.2 
DETERMINATION OF SAMPLE SIZE 
There is no formal sample size calculation, as no confirmatory hypothesis testing is 
planned.  The primary analysis will be descriptive.  The study will include at least 
10 women with CIS or MS (in line with the locally approved indications) who are 
breastfeeding or planning to breastfeed.   
With 10 infants, a precision (width of the two-sided 95% CI) of 0.443 is expected if one 
event is observed (defined as B-cells below the LLN) and a precision of 0.531 if two 
events are observed in the study.  If no event is observed during the study, there is a 
95% confidence that the event rate is below 0.31. 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
Enrolment, screening failures, ocrelizumab administration, and discontinuations from 
the study will be summarized using descriptive statistics (frequency tables for 
categorical endpoints and mean, median, range, SD, and 25th75th quartiles for the 
continuous endpoints).  Subject disposition will be tabulated, with treatment 
discontinuations summarized by reason for discontinuation.  Major protocol violations, 
including violations of inclusion/exclusion criteria, will also be summarized.  Women and 
infants enrolled but excluded from the FAS will be listed. 
6.4 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
For women, demographics (age and self-reported race), medical history, and 
neurological examination will be summarized.  The following will also be summarized: 
MS disease history (duration since first MS symptoms, duration of MS since diagnosis, 
relapses in the past year), and other important variables. 
Characteristics of infants at birth will also be summarized (gender, weight, gestational 
age at birth and other endpoints collected).  Values at the mother’s first ocrelizumab 


 
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infusion visit (which may take place any time between Week 2 and Week 24 
postpartum) will be considered as baseline. 
6.5 
PRIMARY ANALYSES 
6.5.1 
Primary Endpoint 
The primary analysis will be conducted on the FAS (defined earlier).  The analysis will 
be performed after the last breastmilk sample collection at the end of the 60-day 
treatment and sampling period. 
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 estimated 
ADID will be analyzed using descriptive statistics.  Mean, corresponding 95% CI, SD, 
and other statistics will be presented. 
The estimand of the proportion of infants with B-cell levels below the LLN is defined as 
below: 
 
Population: all infants of women in the FAS population who have B-cell levels 
measured at Day 30 after the mother’s first ocrelizumab postpartum infusion. 
 
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 will be handled as follows: 
– 
Incomplete dosing, including delayed second (300 mg) ocrelizumab infusion:  
all the B-cell data will be included in the analysis. 
– 
Infant did not receive any breastmilk before B-cell measurement during the 
entire 30-day period after the mother’s first ocrelizumab postpartum infusion:  
B-cell data will be excluded from the analysis. 
– 
Mother used other DMT during breastfeeding before B-cell measurement on 
Day 30 post-ocrelizumab infusion 1:  B-cell data will be excluded from the 
analysis. 
– 
Mother used other medication before B-cell measurement on Day 30 
post-ocrelizumab infusion 1 that is not allowed by protocol during breastfeeding:  
B-cell data will be excluded from the analysis. 
– 
Infant’s blood sample collected before assessment window (i.e., before Day 28):  
Data will be excluded from the analysis. 
– 
Infant’s blood sample collected beyond the assessment window:  B-cell data 
might be included or excluded depending on the cause of the delay (rules will 
be specified in the SAP) and schedule of delayed visit. 
– 
Infant's blood sample collected while infant has an illness:  B-cell data will be 
excluded on a case-by-case basis if there is a strong biological rationale that the 
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 
Population-level summary:  The proportion of infants with B-cell levels below LLN 
will be reported with the two-sided 95% CI; 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. 
 
The estimand of the ADID in breastmilk is defined as below: 
 
Population:  all women in the FAS population who provide any breastmilk samples 
(primary analysis set of mother) 
 
Variable:  ADID 
 
Intercurrent events will be handled as follows: 
– 
Incomplete dosing, including delayed second (300 mg) ocrelizumab infusion: all 
the ADID data will be collected and included in the analysis.  No adjustments 
based on actual dose will be made. 
– 
Mother used other DMT during breastfeeding:  ADID data will be included. 
– 
Mother used other medication not allowed by protocol during breastfeeding:  
ADID data will be included in the analysis. 
– 
Mother has mastitis infection during the sample collection period: ADID data will 
be included from milk samples obtained from the non-infected breast (in case of 
bilateral mastitis, breastmilk sampling will be interrupted until the infection 
resolves). 
 
Population-level summary:  The summary statistics together with 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 milk samples with all supporting information are collected. 
 
More details about missing data handling, as well as sensitivity analyses based on 
alternative imputation approaches, will be specified in the SAP. 
6.5.2 
Secondary Endpoints 
The ocrelizumab concentration in mature breastmilk at each time point, MDID, RID, 
and AUC will be summarized descriptively.  Continuous variables at each month 
(e.g., length and weight of infants), as well change from baseline (if applicable) will be 
analyzed primarily using descriptive statistics. 
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 for the overall 
population.  For PCV-13, positive humoral responses (as defined by antibody 
concentrations  0.35 g/mL) will be described for all pneumococcal vaccine serotypes 
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Continuous variables at each visit, as well change from baseline (if applicable) will be 
analyzed primarily using descriptive statistics.  Mean, corresponding 95% CIs, SD, and 
other statistics will be presented. 
6.5.3 
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. 
6.6 
SAFETY ANALYSES 
6.6.1 
Analyses of Exposure, Adverse Event, Laboratory, and Vital 
Signs Data 
The safety outcome measures 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. 
All safety analyses will be conducted on data collected from the first postpartum 
ocrelizumab infusion until the end of the study.  The safety analysis will be performed on 
the safety populations of women and infants separately.  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 events, 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. 
Concomitant medications recorded during the study will be summarized using frequency 
tables. 
6.7 
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. 


 
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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, 
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. 


 
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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. 
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. 


 
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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 United States or under a U.S. Investigational New Drug (IND) 
Application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the 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 patient the objectives, 
methods, and potential risks associated with each optional procedure.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
for any reason.  A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures.  Patients who decline to participate will 
not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before 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 patient shall document the informed consent process and that written 
informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 


 
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If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the 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. 
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 


 
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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 Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective 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.  
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 healthcare professionals 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 access, 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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10. 
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east London. Mult SclerJ 2017;23:3642 
Council on Children with Disabilities; Section on Developmental Behavioral Pediatrics; 
Bright Futures Steering Committee; Medical Home Initiatives for Children with 
Special Needs Project Advisory Committee. Identifying infants and young children 
with developmental disorders in the medical home: an algorithm for developmental 
surveillance and screening. Pediatrics 2006;118:40520. doi: 10.1542/peds.2006-
1231. Erratum in: Pediatrics 2006;118:18089. 
American College of Obstetricians and Gynecologists (ACOG). Committee Opinion No. 
644: The Apgar Score. Obstet Gynecol 2015;126:e5255. doi: 
10.1097/AOG.0000000000001108. 
Anderson DW, Ellenberg JH, Leventhal CM, et al. Revised estimate of the prevalence of 
multiple sclerosis in the United States. Ann Neurol 1992;31:3336. 
Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in 
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Appendix 1:  Schedule of Assessments: Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
84/Protocol MN42989, Version 4 (United States) 
APGAR  appearance, pulse, grimace, activity, and respiration; ASQ-3  Ages and Stages Questionnaire, version 3; BRUE  brief resolved 
unexplained event; 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; HCPs  Healthcare professionals; Hib  Hemophilus influenzae type b; ICF  Informed 
Consent Form; IRR    infusion-related reaction; 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; SmPC    Summary of Product Characteristics; 
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 telephone interview will not be conducted in a week where there will be an on-site visit). 
a Visits 2a, 3a and 4a are only applicable for women who will be 
receiving the first ocrelizumab dose as two 300 mg infusions. 
b The length of the screening period is variable and depends on 
local timings for performing some of the eligibility assessments.  It 
is possible that visit 1 (screening) is completed in one day or over 
several days/weeks.  Screening may be started during the third 
trimester of pregnancy and continue until 24 weeks postpartum. 
c Samples 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 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. 
d The following diagnoses are accepted:  MS or CIS (in line with the 
locally approved indications). 
e 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. 
f 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 
baseline visit.  Demographic data will include age, self-reported 
race/ethnicity, and level of education.  Clinically significant 
diseases and/or surgeries and concomitant medication should also 
be recorded throughout the study.  Information on vaccinations 
administered to the mother during the study will be collected under 
concomitant medications. 
g Documentation of start of ocrelizumab (OCREVUS) therapy and 
date and dose of last ocrelizumab infusion prior to enrolment.  
Ocrelizumab-related information to be collected only in women 
who received commercial ocrelizumab prior to enrolment. 


Appendix 1:  Schedule of Assessments: Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
85/Protocol MN42989, Version 4 (United States) 
h A complete physical examination should be performed at the 
screening and baseline visits and at all visits during the treatment 
period (results from examinations done as part of routine care at 
subject’s HCPs [obstetrician/gynecologist, pediatrician, neurologist 
of referred subjects] 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. 
i Neurological examinations will be used to distinguish relapse in 
MS from another neurological (non-MS) disorder.  Potential 
relapses should be recorded throughout the treatment period.  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. 
j Women should record the volume of pumped breastmilk and 
indicate date and time for collection as well as whether breastmilk 
was pumped from one or both breasts.  For sampling on Day 0 
(baseline), the sample should be taken before the infusion. For 
24 hours post-infusion (Day 1 and Day 15), samples are collected 
based on the midpoint of infusion.  For example, if the infusion 
began at 8 am and ended at 10 a.m., the 24-hour sample 
collection would occur at 9 a.m. on the day after the infusion.  With 
the exception of the 24-hour (Day 1; and [for women who received 
a 2  300 mg dose] Day 15) post-infusion breastmilk collection time 
points, flexibility is allowed on collection timing to accommodate 
the mother and the infant feeding schedule.  If the mother presents 
with unilateral mastitis, milk should only be expressed from the 
unaffected breast, until the infection resolves.  If mastitis presents 
bilaterally (rare), breastmilk collection should be stopped until the 
infection resolves. 
k Hematology will include hemoglobin, hematocrit, RBCs, 
WBC absolute or/and differential count (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils), and quantitative platelet 
count.  Chemistry will include potassium, sodium, chloride, random 
glucose, AST, ALT, GGT, creatinine, total bilirubin.  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. 
l 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. 
m Blood samples will be collected to measure B-cell counts 
(CD19   and B-cell subsets [Table 2]),T-cell counts (CD3 , CD4 , 
and CD8  ), and NK cell counts (CD16+CD56+). 
n 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 
86/Protocol MN42989, Version 4 (United States) 
o In line with the dose regimen in the local label, the first dose of 
ocrelizumab may be administered as an initial split dose of two 
300 mg infusions (in 250 mL 0.9% sodium chloride) separated by 
14 days, or as a single 600 mg infusion (in 500 mL 0.9% sodium 
chloride), at any point between Week 2 and 24 postpartum.  
For women where a decision not to administer a second 300 mg 
infusion is taken after enrolment, continuation in the study will be 
allowed.  Dosing and treatment duration are at the discretion of 
the physicians, in accordance with local clinical practice and 
local labeling (USPI; SmPC).  If women did not experience a 
serious IRR with any previous ocrelizumab infusion, a shorter 
(2-hour) infusion can be administered for subsequent 600 mg 
doses.  Women referred by HCPs to participate in the trial may 
receive ocrelizumab treatment at their neurologist’s site as part of 
their standard of care treatment. 
p General health and medical history for infants includes screening 
for the following (infants should be excluded from the study if any 
are present): age  24 weeks of age at the time of the mother’s first 
postpartum dose of ocrelizumab; any abnormality that may 
interfere with breastfeeding or milk absorption, including but not 
limited to cleft palate and/or lip, congenital diaphragmatic hernia 
and esophageal atresia; an active infection (the infant may be 
included once the infection resolves); at least one documented 
BRUE, as defined by the 2016 Guidelines of the American 
Academy of Pediatrics. 
q These will include: mode of delivery (vaginal delivery, instrumental 
delivery, scheduled or urgent cesarean section); APGAR score 
(1 min, 5 min, 10 min); gestational age at birth; infant’s 
measurements (weight, length, head circumference); and 
congenital malformations. 
r During the treatment and sampling period, women should record 
the number of breastmilk feeds and/or feeds with formula milk 
(supplementation) on the day of the sample collection and the 
previous and following day, i.e., day of collection  1 day.  During 
the vaccination period, women 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, at Months 2, 4, 6, 
9, and 12, as applicable and depending on the infant’s age at 
enrolment. 
s 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 as 
applicable and depending on the infant’s age at enrolment (see 
Appendix 6 for details of time windows of infant growth velocity 
and child developmental milestone assessments). 
t Growth charts (according to the WHO Child Growth Standards; 
WHO 2022) will be used, as well as absolute values; other 
standard measurements recorded by e.g., the pediatrician as part 
of routine post-natal care may also be used).  Infant growth will be 
captured at Months 2, 4, 6, 9, and 12 (see Appendix 6 for details of 
time windows of infant growth velocity and child developmental 
milestone assessments). 
u Including documentation of past or current medications as well as 
clinically significant pediatric disease/abnormality.  Changes to 
concomitant medication given to the infant should be recorded 
throughout the study. 
v 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 13/1 month after first or second MMR dose. 


Appendix 1:  Schedule of Assessments: Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
87/Protocol MN42989, Version 4 (United States) 
w  Infant sampling at Day 30 ( 2 days) post-infusion 1 and at 
1 month ( 30 days) after first or second dose of MMR, or 
Month 13 of age in case MMR vaccine is not planned to be 
administered ( 30 days) may be conducted via in-home nurse 
visits or at the hospital as part of study visits.  CD19  B-cell level 
at Day 30 ( 2 days) post-infusion 1 represents the co-primary 
endpoint measurement. 
x 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 sample at Day 30 ( 2 days) post-
infusion 1, (1) safety laboratory samples [scheduled or 
unscheduled and performed at the discretion of the investigator] 
(2) lymphocyte subtypes sample for B-cell counts (CD19 ) and 
T-cell counts (CD3 , CD4 , and CD8  ), and NK cell counts 
(CD16+CD56+). (3) serum ocrelizumab concentration; for the 
Month 13 of age/1 month after first/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 ) and T-cell counts (CD3 , CD4 , 
and CD8  ), and NK cell counts (CD16+CD56+). 
y If the infant’s B-cell levels are found to be below LLN, analyses of 
B-, T-, and NK cells will be repeated every 4 weeks until B-cell 
levels are found to be above the age-adequate LLN as per 
Appendix 7  (in consultation with the Sponsor).  The first repeat 
analysis will also include a complete blood count and 
immunoglobulin levels. 
z For 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, all efforts will be made to collect 
samples.  However, if they cannot be collected, it will not be 
considered a protocol deviation. 
aa Serum anti-vaccine antibody (IgG) titers will be measured to 
vaccines administered as per local practice over the first year of 
life (which include MMR, diphtheria, tetanus, pertussis, Hib, HBV 
and PCV-13); 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. 
bb A structured telephone interview will be conducted by site 
personnel postpartum every 2 weeks during the treatment and 
sampling period and every 3 months during the vaccination period 
(in-between ocrelizumab infusions) for a general review, and to 
identify and collect information on any changes in the woman’s 
and infant’s health status (including the occurrence of MS relapses 
in the mother 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 using the lactational amenorrhea 
method as contraception will also be asked whether the three 
necessary criteria outlined in Section 4.1.1 to ensure adequate 
protection from an unplanned pregnancy are applied.  No 
telephone contact is needed in weeks where the woman is 
performing on-site visits. 


Appendix 1:  Schedule of Assessments: Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
88/Protocol MN42989, Version 4 (United States) 
cc Adverse events in both mother and infant will be reported 
throughout the study as per standard pharmacovigilance 
procedures.  Adverse events will also be captured at screening for 
women who received ocrelizumab before pregnancy. 
dd Documentation of premedication is not required. 
 
 
 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
89/Protocol MN42989, Version 4 (United States) 
Appendix 2  
Compatibility of Common Medications with Breastfeeding 
The following information is compiled from guidance provided by the New Zealand 
Medicines and Medical Devices Safety Authority (Medsafe), available at 
https://www.medsafe.govt.nz/profs/puarticles/June2015/June2015Lactation.htm and 
https://www.medsafe.govt.nz/profs/puarticles/lactation.htm. 
An up-to-date database of medicine levels in breastmilk and infant blood and possible 
adverse reactions in the nursing infant is available at LactMed 
(https://www.ncbi.nlm.nih.gov/books/NBK501922/).  The WHO has also produced a 
classification guide for medicines use in breastfeeding based on the WHO list of 
essential drugs (www.who.int/maternal_child_adolescent/documents/55732/en/). 
Medicines with inherent toxicity or those with high infant exposure and therefore 
potential for significant toxicity are contraindicated during breastfeeding, and include: 
 
Cytotoxic agents 
 
Immunosuppressive agents 
 
Amiodarone 
 
Lithium 
 
Ergotamine 
 
Gold salts 
 
Isotretinoin 
 
Radiopharmaceutical administration also requires temporary cessation of breastfeeding. 
There are a range of health issues that affect women who are breastfeeding.  These 
most commonly include infection, depressive disorders, pain, contraception, low milk 
supply and atopic conditions.  Table A2-1 provides information on the compatibility of 
medicines used in the treatment of these conditions with breastfeeding. 
 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
90/Protocol MN42989, Version 4 (United States) 
Table A2-1 Compatibility of Commonly Used Medicines with Breastfeeding 
Condition 
Treatment 
Breastfeeding Recommendation 
Additional Information 
Infection 
Antibiotics 
β-lactams 
(e.g., amoxicillin) 
Compatible 
Gastrointestinal flora changes possible; monitor infant for 
diarrhea, vomiting, thrush 
Macrolides 
(e.g., erythromycin) 
Compatible 
Single dose of azithromycin considered safe 
Cephalosporins 
(e.g., cephalexin) 
Compatible 
May also affect infant gut flora (third generation more 
likely) 
Fluoroquinolones 
(e.g., ciprofloxacin) 
Avoid if possible 
Potential risk of arthropathies 
Trimethoprim 
Compatible 
 
Nitrofurantoin 
Compatible 
Avoid nitrofurantoin if infant less than 1 month old or 
premature 
Metronidazole 
Avoid if possible 
If single 2 g metronidazole dose given, discontinue 
breastfeeding for 12 hours 
Antifungals 
Azoles 
(e.g., fluconazole) 
Compatible 
If applying miconazole oral gel to nipples, apply after 
breastfeeding 
Nystatin 
Compatible 
 
Antivirals 
Acyclovir 
Compatible 
 
Depressive 
disorders 
Antidepressants 
SSRIs 
(e.g., paroxetine) 
Compatible 
Paroxetine and sertraline preferred due to shorter half-
lives 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
91/Protocol MN42989, Version 4 (United States) 
Condition 
Treatment 
Breastfeeding Recommendation 
Additional Information 
TCAs 
(e.g., amitriptyline) 
Less preferred due to potential 
toxicity 
Amitriptyline compatible in doses up to 150 mg/day 
Anxiolytics 
Benzodiazepines 
(e.g., temazepam) 
Compatible in a single dose; avoid 
repeated doses 
Short-acting benzodiazepines preferred as accumulation 
may occur 
Monitor infant for drowsiness 
Pain 
Analgesics 
Paracetamol 
Compatible 
Paracetamol analgesic of choice 
NSAIDs 
(e.g., ibuprofen) 
Compatible 
Avoid breastfeeding with long-term acetylsalicylic acid 
treatment 
Opiates 
(e.g., codeine) 
Compatible in occasional doses 
Monitor infant for drowsiness, apnea, bradycardia and 
cyanosis 
Use codeine with caution in rapid metabolizers 
Tramadol 
Compatible 
 
Contraception 
Hormonal methods 
Progesterone 
Compatible 
See data sheet 
Estrogen 
Avoid if possible 
May inhibit lactation 
Allergies and hay 
fever 
Antihistamines 
Sedating 
(e.g., promethazine) 
Probably compatible 
Occasional use probably safe 
Monitor for sedation in mother and infant 
Non-sedating 
(e.g., loratadine) 
Compatible 
 
Topical 
Corticosteroids 
(e.g., hydrocortisone) 
Compatible 
If applying to breasts apply after feeding 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
92/Protocol MN42989, Version 4 (United States) 
Condition 
Treatment 
Breastfeeding Recommendation 
Additional Information 
Asthma 
β2- adrenergic 
(e.g., salbutamol) 
Compatible 
 
Corticosteroids 
(e.g., budesonide) 
Compatible 
 
Other 
Warfarin 
Compatible 
 
Metformin 
Compatible 
 
NSAIDs  non-steroidal anti-inflammatory drugs; SSRIs  Selective serotonin reuptake inhibitors; TCAs  Tricyclic antidepressants. 
Source:  Medsafe. URL: https://www.medsafe.govt.nz/profs/puarticles/June2015/June2015Lactation.htm. (Accessed 17 December 2020). 
 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
93/Protocol MN42989, Version 4 (United States) 
TABULATED SUMMARY OF DRUG DISTRIBUTION INTO BREASTMILK 
Table A2-2 shows published milk/plasma (M/P) ratios from the literature and provides an 
estimate of the weight-adjusted infant dose.  Interpretation of these requires an 
understanding of the limitations associated with published data, such as the availability 
of only single pairs of plasma and milk concentrations.  Infant clearance (related to 
post-conceptual age) should always be considered. 
 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
94/Protocol MN42989, Version 4 (United States) 
Table A2-2 Summary of Distribution of Drugs into Breastmilk 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Acid-suppressants: 
Cimetidine 
1.7-5.8 
5.46.7 
Avoid in favor of safer alternatives with lower potential for side effects.  May accumulate in 
milk due to active transport. 
Famotidine 
1.5 
1.6 
Probably safe. 
Ranitidine 
2.8 
5.07.8 
Probably safe when restricted to sporadic doses or a single dose at night-time.  May 
accumulate in milk due to active transport. 
Analgesics: 
Aspirin 
0.06 
3.2 
Avoid due to possible association with Reye’s syndrome. 
Codeine 
2.16 
6.8 
Considered safe. 
Ibuprofen 
0 
 0.6 
Considered safe.  Not detected in milk. 
Indomethacin 
0.37 
 1.0 
Considered safe.  One case of seizures (causality questionable). 
Mefenamic acid 
ID 
0.3 
Probably safe. 
Methadone 
0.47 
2.2 
Considered safe in methadone maintenance as 60% of infants born to mothers in 
maintenance programs develop symptoms of withdrawal. 
Morphine 
2.46 
0.4 
Considered safe. 
Naproxen 
ID 
1.1 
Probably safe. 
Nefopam 
ID 
0.4 
Probably safe. 
Piroxicam 
ID 
510 
Use a NSAID with a shorter half-life where possible. 
Paracetamol 
0.8 
2.97.9 
Considered safe. 
Sumatriptan 
4.15.7 
0.36.7 
Exposure limited by low oral availability in term infants.  Expressing for 8 hours post-dose 
will almost completely avoid exposure. 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
95/Protocol MN42989, Version 4 (United States) 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Antibiotics: 
Aminoglycosides 
Gentamicin 
0.17 
2.2 
Considered compatible with breastfeeding due to low transfer and low oral availability. 
Cephalosporins 
Cefaclor 
ID 
0.7 
Considered safe.  Low transfer into milk.  Third generation cephalosporins have greater 
potential to alter bowel flora. 
Cefalexin 
0.09 
0.51.2 
Cefotaxime 
ID 
0.3 
Ceftriaxone 
0.04 
0.74.7 
Fluoroquinolones 
Ciprofloxacin 
2.17 
4.8 
Avoid fluoroquinolones due to theoretical risk of arthropathies. 
Macrolides 
Clarithromycin 
0.25 
1.8 
Considered safe.  May alter bowel flora. 
Erythromycin 
0.41 
2.1 
Penicillins 
Amoxicillin 
ID 
0.7 
Considered safe.  Note: although amoxicillin/clavulanic acid combination is used extensively 
in lactation, there are no published data on the safety of clavulanic acid. 
Benzylpenicillin 
0.37 
0.8 
Phenoxymethyl-
penicillin 
ID 
0.25 
Tetracyclines 
Minocycline 
ID 
3.6 
Avoid tetracyclines where feasible due to the possible risks of dental staining and adverse 
effects on bone development. 
Tetracycline 
0.58 
4.8 
Others 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
96/Protocol MN42989, Version 4 (United States) 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Acyclovir 
ID 
1.11.2 
Considered safe.  No adverse effects noted in breastfed infants. 
Fluconazole 
0.75 
11 
Potential for accumulation particularly in premature infants. 
Metronidazole 
0.91.1 
0.136.0 
Controversial as exposure may be high.  With high doses consider expressing and 
discarding milk. 
Nitrofurantoin 
ID 
0.66.0 
Avoid in G6PD-deficient infants (due to the risk of hemolysis). 
Sulphamethoxazole 
and Trimethoprim 
(i.e., co-trimoxazole) 
0.1 
1.26 
22.5 
3.85.5 
Avoid suphaemethoxazole in infants with hyperbilirubinemia and G6PD deficiency. 
Anticoagulants 
Warfarin 
0 
 4.4 
Probably safe.  No changes in prothrombin times detected in breastfeeding infants.  Monitor 
prothrombin time. 
Anticonvulsants: 
Carbamazepine 
0.360.39 
2.87.3 
Considered safe.  Monitor for sedation, poor suckling. 
Lamotrigine 
ID 
1022 
Concentrations in breastfed infants have been consistent with those expected to produce 
clinical effect.  Best to avoid. 
Phenobarbitone 
ID 
23156 
Avoid due to high infant exposure. 
Phenytoin 
0.130.18 
3.07.2 
Considered safe.  Observe for sedation, poor suckling.  One report of methemoglobinemia, 
poor suckling and sedation. 
Sodium valproate 
0.05 
1.8 
Considered safe at low doses.  High doses may increase the risk of hepatitis. 
Vigabatrin 
ID 
 1% 
Avoid until further data are available. 
Antidepressants: 
Tricyclics: 
Amitriptyline 
0.83 
0.60.9 
Probably safe.  Negligible or no concentrations detected in breastfed infants. 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
97/Protocol MN42989, Version 4 (United States) 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Desipramine 
ID 
0.51.0 
Dothiepin 
0.81.6 
0.2-1.5 
Doxepin 
ID 
0.01 
Imipramine 
ID 
0.13 
Nortriptyline 
ID 
0.53 
Others 
Moclobemide 
0.72 
1.6 
Probably safe. 
Antiemetics: 
Domperidone 
ID 
0.05 
Probably safe.  May increase milk secretion. 
Metoclopramide 
ID 
4.711.3 
Low dose or sporadic use probably safe.  May increase milk secretion. 
Antihistamines: 
Loratadine 
1.2 
0.7 
Probably safe.  No adverse effects reported in infants. 
Triprolidine 
0.53 
0.9 
Considered safe. 
Antipsychotics: 
Chlorpromazine 
ID 
0.2 
Probably safe.  May increase milk secretion.  Monitor infant for sedation, irritability etc. 
Flupenthixol 
ID 
0.50.8 
Haloperidol 
ID 
0.152.0 
Cardiovascular: 
Amiodarone 
ID 
37 
Avoid in breastfeeding. 
Atenolol 
2.34.5 
5.719.2 
Avoid in favor of antihypertensives with lower infant exposure. 
Captopril 
0.03 
0.014 
Considered safe. 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
98/Protocol MN42989, Version 4 (United States) 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Digoxin 
0.60.9 
2.35.6 
Considered safe. 
Diltiazem 
0.98 
0.9 
Unlikely to be problematical in breastfeeding. 
Enalapril 
0.02 
 0.1 
Considered safe. 
Metoprolol 
2.8-3.6 
1.73.3 
Probably safe. 
Nadolol 
4.6 
5.1 
Consider choosing a beta-blocker with a lower infant dose, if feasible. 
Propranolol 
0.320.76 
0.20.9 
Probably safe. 
Quinapril 
0.12 
1.6 
Considered safe. 
Verapamil 
0.6 
0.140.84 
Considered safe. 
Sedatives/hypnotics: 
Clonazepam 
ID 
1.53.0 
Short-term use of low doses is probably safe. 
Diazepam 
0.16 
2.02.3 
Reasonable to breastfeed after a low single dose but potential for accumulation with 
prolonged use.  Sedation has been reported in breastfed infants. 
Lorazepam 
ID 
2.2 
Short-term use of low doses is probably safe. 
Midazolam 
0.16 
0.7 
Short-term use of low doses is probably safe. 
Nitrazepam 
ID 
ID 
Short-term use of low doses is probably safe.  Potential for accumulation with prolonged 
administration. 
Zopiclone 
0.5 
4.1 
Short-term use of low doses is probably safe. 
Social Drugs: 
Cannabis (THC) 
ID 
ID 
Avoid as long-term effects are unknown. 
Caffeine 
0.50.8 
0.621.0 
Low intake probably safe.  Restlessness and irritability documented.  Prolonged half-life 
(80100 hours) in neonates. 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
99/Protocol MN42989, Version 4 (United States) 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Ethanol 
0.9 
3-4 
Occasional low usage probably safe.  Chronic intake may be associated with impairment of 
psychomotor development.  Consider withholding breastfeeding for 12 hours per standard 
drink. 
Nicotine 
2.92 
ID 
Cigarette smoking should be avoided due to health hazards associated with smoking.  
Use of nicotine patches may be considered compatible with breastfeeding and is favored 
over smoking. 
Miscellaneous: 
Ethinyloestradiol 
ID 
0.3 
May suppress lactation. 
Levonorgestrel 
ID 
1.1 
Considered safe. 
Medroxyprogesterone 
ID0.72 
3.45.0 
Considered safe. 
Norethisterone 
ID0.26 
0.02-1.9 
Considered safe. 
Prednisone 
ID 
0.26 
Short courses of low doses ( 20 mg daily) are probably safe.  Note: there are insufficient 
data on other systemic corticosteroids (e.g., betamethasone, dexamethasone). 
Pseudoephedrine 
2.5 
4.0 
Low doses or sporadic use probably safe. 
Sulphasalazine 
ID 
1.27.0 
Avoid in infants with hyperbilirubinemia or G6PD deficiency. 
AUC  area under the concentration-time curves; G6PD  glucose-6-phosphate dehydrogenase; ID  insufficient data; M/PAUC  AUC of the drug 
in maternal milk and plasma; NSAID  nonsteroidal anti-inflammatory drug; THC  Tetrahydrocannabinol. 
Source:  Medsafe. URL: https://www.medsafe.govt.nz/profs/puarticles/lactation.htm. 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
100/Protocol MN42989, Version 4 (United States) 
Appendix 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 John Cunningham 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 
 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
101/Protocol MN42989, Version 4 (United States) 
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 
(see 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 from Wattjes 2018.8 
 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
102/Protocol MN42989, Version 4 (United States) 
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 
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 
 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
103/Protocol MN42989, Version 4 (United States) 
Table A3-2 Imaging characteristics of MS and PML1,6,7 (cont.) 
Parameters 
MS 
PML 
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; 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 
imaging, either because the JCV-induced disease progresses or because the 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
104/Protocol MN42989, Version 4 (United States) 
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 
A3–3.1 
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; NTZ  natalizumab; ND  not done or equivocal result; 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 
 
A3–3.2 
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). 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
105/Protocol MN42989, Version 4 (United States) 
 
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. 
 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
106/Protocol MN42989, Version 4 (United States) 
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 
107/Protocol MN42989, Version 4 (United States) 
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 wash-out 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 
108/Protocol MN42989, Version 4 (United States) 
 
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 
109/Protocol MN42989, Version 4 (United States) 
Appendix 4  
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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 
110/Protocol MN42989, Version 4 (United States) 
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. 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 
 
3. PYRAMIDAL FSS 
0 
normal 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
111/Protocol MN42989, Version 4 (United States) 
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 
112/Protocol MN42989, Version 4 (United States) 
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 
113/Protocol MN42989, Version 4 (United States) 
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. 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 
114/Protocol MN42989, Version 4 (United States) 
A4–2 
EDSS BY TELEPHONE 
 
 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
115/Protocol MN42989, Version 4 (United States) 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
116/Protocol MN42989, Version 4 (United States) 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
117/Protocol MN42989, Version 4 (United States) 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
118/Protocol MN42989, Version 4 (United States) 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
119/Protocol MN42989, Version 4 (United States) 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
120/Protocol MN42989, Version 4 (United States) 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
121/Protocol MN42989, Version 4 (United States) 
Appendix 5  
Methods for Assessing and Recording Adverse Events 
A5–1 
Assessment of Severity of Adverse Events............................... 122 
A5–2 
Assessment of Causality of Adverse Events ............................. 122 
A5–3 
Procedures for recording Adverse Events................................. 123 
A5–3.1 
Infusion-Related Reactions ....................................................... 123 
A5–3.2 
Diagnosis versus Signs and Symptoms .................................... 123 
A5–3.3 
Adverse Events Occurring Secondary to Other Events ............ 123 
A5–3.4 
Persistent or Recurrent Adverse Events ................................... 124 
A5–3.5 
Abnormal Laboratory Values..................................................... 124 
A5–3.6 
Abnormal Vital Sign Values....................................................... 125 
A5–3.7 
Abnormal Liver Function Tests ................................................. 126 
A5–3.8 
Deaths ...................................................................................... 126 
A5–3.9 
Pre-existing Medical Conditions ................................................ 127 
A5–3.10 
Lack of Therapeutic Efficacy ..................................................... 127 
A5–3.11 
Hospitalisation or Prolonged Hospitalisation ............................. 127 
A5–3.12 
Overdoses, Misuses, Abuses, Off-Label Use, Occupational 
Exposure, or Medication Error .................................................. 128 
A5–3.13 
Quality Defects, Falsified Products and Product Complaints .... 128 
A5–3.14 
Drug Interactions ....................................................................... 128 
 


Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
122/Protocol MN42989, Version 4 (United States) 
A5–1 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The adverse event severity grading scale for the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE; version 5.0) 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 (version 5.0), 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 
123/Protocol MN42989, Version 4 (United States) 
 
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 
124/Protocol MN42989, Version 4 (United States) 
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 
125/Protocol MN42989, Version 4 (United States) 
 
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 "hyperkalemia." 
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 AEs). 
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 
126/Protocol MN42989, Version 4 (United States) 
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 AEs). 
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 


Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
127/Protocol MN42989, Version 4 (United States) 
the 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 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 
128/Protocol MN42989, Version 4 (United States) 
 
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 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). 
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). 


 
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Appendix 6  
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 2 
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 
 
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, the Ages and Stages Questionnaire, version 3 (ASQ-3) age 
calculator2 can be used:  https://agesandstages.com/free-resources/asq-calculator/. 
Assessment of growth velocity at Months 2, 4, 6, 9, and 12 (as applicable and 
depending on the infant’s age at enrolment) 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 
post-natal care visits performed by e.g., the pediatrician. 
 
 
 


 
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Appendix 7  
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 - MN42989 - OCREVUS - v4 - United States - Published
System identifier: RIM-CLIN-512701
Approval Task
Deputy EU QPPV
19-Dec-2023 08:04:45 GMT+0000
Approval Task
Company Signatory
20-Dec-2023 17:12:29 GMT+0000


 
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 MN42989, Version 3 
PROTOCOL 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL 
STUDY EVALUATING B-CELL LEVELS IN 
INFANTS OF LACTATING WOMEN WITH CIS OR 
MS RECEIVING OCRELIZUMAB – THE 
SOPRANINO STUDY 
PROTOCOL NUMBER: 
MN42989 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2021-000063-79 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998851 
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 MN42989, Version 3 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
3 
See electronic date 
stamp on the final 
page of this document. 
2 
1 April 2022 
1 
15 March 2021 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
3/Protocol MN42989, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol MN42989 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 infant postpartum exposure to ocrelizumab via breastmilk 
has been updated to present data from an analysis performed with a cut-off date of 
31 March 2022, replacing data from an analysis performed up to 31 March 2021 
(Section 1.3). 
 
The secondary objectives have been amended to include the evaluation of the 
relative exposure to ocrelizumab in infants of lactating women with clinically isolated 
syndrome (CIS) or multiple sclerosis (MS) receiving ocrelizumab postpartum.  The 
average relative infant dose will be assessed over 60 days, calculated as the 
average oral daily infant dosage (mg/kg/day) divided by the maternal dosage 
(mg/kg/day), multiplied by 100 (Sections 2 [Table 1] and 6.5.2). 
 
In the endpoint for the exploratory objective “to evaluate the evolution of B-cell 
levels over the first year of life in infants of lactating women with CIS or MS 
receiving ocrelizumab postpartum”, language has been clarified that trajectory 
(absolute and percentage changes) of B-cells (CD19  cell) in the infant will be 
measured from Day 30 after the mother’s first ocrelizumab postpartum infusion to 
1 month after the first or second dose of 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 sample size has been reduced from at least 20 to at least 10 women with CIS 
or MS.  Given that women with CIS or MS are not routinely treated with ocrelizumab 
during breastfeeding 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 6.2). 
 
It has been clarified throughout the protocol that dosing and treatment duration are 
at the discretion of the physicians, in accordance with local clinical practice and local 
labeling (U.S. Prescribing Information and the Summary of Product Characteristics) 
(Section 3.1.3; Appendix 1). 
 
The total length of the study has been increased from approximately 2 years to 
approximately 3 years, due to the extension of the enrolment period from 
approximately 8 months to approximately 21 months (Section 3.2). 
 
Language has been added to clarify that, based on the ocrelizumab average 
terminal half-life of 26 days, it is assumed that a potential fetal exposure is unlikely 
in women whose last ocrelizumab infusion was earlier than 3 months before last 
menstrual period (Section 3.3.2). 
 
To reduce the burden of visits on the mothers, it has been detailed that results from 
neurological examinations, done as part of routine care, may be used.  For women 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
4/Protocol MN42989, Version 3 
referred to the investigator, results from routine visits at the woman’s neurologist 
may be used (Section 4.5.2.4; Appendix 1 [footnote “i"]). 
 
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 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 
4.5.2.7 and 4.5.3.3 [Tables 3 and 4]; Appendix 1). 
 
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 4.5.3.3). 
 
The list of antibody (Ab) titers of responses to vaccines administered as per local 
practice, has been updated to detail that the following will be included:  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, Hemophilus influenza B IgG (Section 4.5.3.3 [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). 
 
The full analysis set (FAS) population of infants has been amended to remove the 
requirement to only include infants of the FAS population of women whose B-cell 
level data at Day 30 post-infusion 1 are available; the FAS population of infants will 
include all the infants of the FAS population of women (Section 6.1). 
 
Due to a reduction in sample size, the precision (width of the two-sided 95% CIs) for 
event rates (an event is defined as B-cells below the lower limit of normal [LLN]) 
have been amended (Section 6.2). 
 
A reference to Appendix 7 (B-cell reference ranges by week of life [absolute and 
percentage counts]) has been added (Section 6.5.1). 
 
The handling of intercurrent events of the estimand of the proportion of infants with 
B-cell levels below the LLN (Section 6.5.1) have been amended to include the 
following: 
– 
If an infant does not receive any breastmilk before B-cell measurement during 
the entire 30-day period after the mother’s first ocrelizumab postpartum 
infusion, B-cell data will be excluded from the analysis. 
– 
If an infant’s blood sample is collected before the assessment window 
(i.e., before Day 28), the data will be excluded from the analysis. 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
5/Protocol MN42989, Version 3 
– 
If an infant’s blood sample is collected while the infant has an illness, the B-cell 
data will be excluded on a case-by-case basis if the illness is likely to confound 
the B-cell data. 
 
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). 
 
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 following changes have been made to the Schedule of Assessments 
(Appendix 1): 
– 
The requirement to measure breastmilk ocrelizumab concentration at screening 
has been removed. 
– 
The requirement to collect documentation of collection of second postpartum 
ocrelizumab administration at Visit 7 has been included, with a corresponding 
footnote (footnote “ee”) detailing that documentation of premedication is not 
required. 
– 
The corresponding footnote to the assessment “Whole blood sample for 
lymphocyte subtype sample” in infant laboratory assessments has been 
corrected to footnote “y”. 
– 
It has been clarified that breastmilk samples that are to be collected on Day 0 
(baseline) should be taken before the infusion (footnote “j”). 
 
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. 
 


 
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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 ........................................................................... 28 
3.1 
Description of the Study ........................................................... 28 
3.1.1 
Overview of Study Design........................................................ 29 
3.1.2 
Screening Period ..................................................................... 32 
3.1.3 
Treatment and Sampling Period .............................................. 32 
3.1.4 
Vaccination Period ................................................................... 33 
3.1.5 
Discontinuation ........................................................................ 34 
3.2 
End of Study and Length of Study ........................................... 34 
3.3 
Rationale for Study Design ...................................................... 34 
3.3.1 
Rationale for Ocrelizumab Dose and Schedule ....................... 36 
3.3.2 
Rationale for Subject Population .............................................. 36 
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 and Other Treatments 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 ...................................................................... 41 
4.3.2.2 
Premedication .......................................................................... 41 
4.4 
Concomitant Therapy .............................................................. 41 
4.4.1 
Prohibited Therapy .................................................................. 42 


 
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4.5 
Study Assessments ................................................................. 42 
4.5.1 
Informed Consent Forms and Screening Log .......................... 42 
4.5.2 
Mother’s Assessments ............................................................. 43 
4.5.2.1 
Demographics, Medical and MS History, and Disease 
Characteristics ......................................................................... 43 
4.5.2.2 
Physical Examinations and Related Assessments .................. 43 
4.5.2.3 
Vital Signs ................................................................................ 44 
4.5.2.4 
Neurological Examinations ...................................................... 44 
4.5.2.5 
Assessment of Relapses ......................................................... 44 
4.5.2.6 
Assessment of Disability .......................................................... 45 
4.5.2.7 
Laboratory, Biomarker, and Other Biological Samples ............ 45 
4.5.3 
Infant’s Assessments ............................................................... 46 
4.5.3.1 
Medical History, Biometrics and Concomitant Medications ..... 46 
4.5.3.2 
Physical Examinations and Related Assessments .................. 46 
4.5.3.3 
Laboratory, Biomarker, and Other Biological Samples ............ 47 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 49 
4.6.1 
Study Treatment Discontinuation ............................................. 49 
4.6.2 
Discontinuation from the Study ................................................ 50 
4.6.3 
Study Discontinuation .............................................................. 50 
4.6.4 
Site Discontinuation ................................................................. 50 
5. 
ASSESSMENT OF SAFETY ......................................................... 51 
5.1 
Safety Reporting Requirements for Studied Medicinal 
Products .................................................................................. 51 
5.1.1 
Safety Parameters and Definitions .......................................... 51 
5.1.1.1 
Adverse Events ........................................................................ 51 
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 ........................................................................ 52 
5.1.2 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 53 
5.1.2.1 
Adverse Event Reporting Period .............................................. 53 
5.1.2.2 
Procedures for Recording Adverse Events .............................. 54 
5.1.3 
Reporting Requirements from Investigator to Sponsor ............ 55 


 
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5.1.3.1 
Immediate Reporting Requirements from Investigator 
to Sponsor ............................................................................... 55 
5.1.3.2 
Medical Monitors and Emergency Medical Contacts .............. 55 
5.1.3.3 
Reporting Requirements for Non-Serious Adverse Events ...... 56 
5.1.3.4 
If Electronic Data Capture System Is Temporarily 
Unavailable .............................................................................. 56 
5.1.3.5 
Reporting Requirements for Pregnancies, 
Abortions/Congenital Anomalies/Birth Defects ........................ 56 
5.1.4 
Follow-Up of Patients after Adverse Events............................. 57 
5.1.4.1 
Investigator Follow-Up ............................................................. 57 
5.1.4.2 
Sponsor Follow-Up .................................................................. 58 
5.2 
Safety Reporting Requirements for Non-Studied Medicinal 
Products .................................................................................. 58 
5.3 
Reporting of Product Complaints without Adverse Events ....... 58 
5.4 
Expedited Reporting to Health Authorities, Physicians, 
Institutional Review Boards, and Ethics Committees ............... 59 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 59 
6.1 
Analysis Populations ................................................................ 59 
6.2 
Determination of Sample Size ................................................. 60 
6.3 
Summaries of Conduct of Study .............................................. 60 
6.4 
Summaries of Demographic and Baseline Characteristics ...... 60 
6.5 
Primary Analyses ..................................................................... 60 
6.5.1 
Primary Endpoint ..................................................................... 60 
6.5.2 
Secondary Endpoints ............................................................... 62 
6.5.3 
Exploratory Endpoints .............................................................. 62 
6.6 
Safety Analyses ....................................................................... 63 
6.6.1 
Analyses of Exposure, Adverse Event, Laboratory, and 
Vital Signs Data ....................................................................... 63 
6.7 
Interim analysis ........................................................................ 63 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 63 
7.1 
Data Quality Assurance ........................................................... 63 
7.2 
Electronic Case Report Forms ................................................. 64 
7.3 
Source Data Documentation .................................................... 64 
7.4 
Use of Computerized Systems ................................................ 65 


 
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7.5 
Retention of Records ............................................................... 65 
8. 
ETHICAL CONSIDERATIONS ...................................................... 65 
8.1 
Compliance with Laws and Regulations .................................. 65 
8.2 
Informed Consent .................................................................... 65 
8.3 
Institutional Review Board or Ethics Committee ...................... 67 
8.4 
Confidentiality .......................................................................... 67 
8.5 
Financial Disclosure ................................................................. 68 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 68 
9.1 
Study Documentation .............................................................. 68 
9.2 
Protocol Deviations .................................................................. 68 
9.3 
Management of Study Quality .................................................. 69 
9.4 
Site Inspections ....................................................................... 69 
9.5 
Administrative Structure ........................................................... 69 
9.6 
Dissemination of Data and Protection of Trade Secrets .......... 69 
9.7 
Protocol Amendments ............................................................. 70 
10. 
REFERENCES.............................................................................. 71 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 26 
Table 2 
B-Cell Subsets ............................................................................. 46 
Table 3 
Prioritization Order for Infant Blood Sample Assessments at 
Day 30 (2 days) Post-Infusion 1 ................................................ 48 
Table 4 
Prioritization Order for Infant Blood Sample Assessments 
1 Month ( 30 days) After the First/Second Dose of MMR 
Vaccine or at Month 13 of Age ( 30 Days) if MMR Vaccine 
Is Not Planned to Be Administered ............................................. 49 
 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design ........................................................... 30 
 


 
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LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments: Screening through the End of 
Treatment Period ........................................................................ 77 
Appendix 2 
Compatibility of Common Medications with Breastfeeding ......... 87 
Appendix 3 
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy ................................................................. 98 
Appendix 4 
Expanded Disability Status Scale (EDSS) ................................ 107 
Appendix 5 
Methods for Assessing and Recording Adverse Events ........... 119 
Appendix 6 
Time Windows for Infant Growth Velocity and Child 
Developmental Milestone Assessments ................................... 127 
Appendix 7 
B-Cell Reference Ranges by Week of Life:  Absolute and 
Percentage Counts .................................................................... 128 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
11/Protocol MN42989, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY 
EVALUATING B-CELL LEVELS IN INFANTS OF 
LACTATING WOMEN WITH CIS OR MS RECEIVING 
OCRELIZUMAB – THE SOPRANINO STUDY 
PROTOCOL NUMBER: 
MN42989 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2021-000063-79 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998851 
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 MN42989, Version 3 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY EVALUATING 
B-CELL LEVELS IN INFANTS OF LACTATING WOMEN WITH CIS 
OR MS RECEIVING OCRELIZUMAB – THE SOPRANINO STUDY 
PROTOCOL NUMBER: 
MN42989 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2021-000063-79 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998851 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
Phase IV 
INDICATION: 
Multiple Sclerosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics of ocrelizumab in the breastmilk of lactating 
women with clinically isolated syndrome (CIS) or multiple sclerosis (MS) [in line with the locally 
approved indications] treated with ocrelizumab, by assessing the concentration of ocrelizumab 
in mature breastmilk, as well as the corresponding exposure and pharmacodynamic effects 
(blood B-cell levels) in the infants.  Specific objectives and corresponding endpoints for the 
study are outlined below. 
Objectives 
Corresponding Endpoints 
Co-Primary Outcome Measure 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum present with B-cell 
depletion 
 
Proportion of infants with B-cell levels 
(CD19  cells, absolute counts in blood) below 
the LLN, measured at Day 30 after the mother’s 
first ocrelizumab postpartum infusion 
 
To evaluate the exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated ADID, calculated as the ocrelizumab 
average milk concentration over 60 days 
post-ocrelizumab infusion 1 multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
Secondary Outcome Measures 
 
To evaluate B-cell levels in 
infants of lactating women with 
CIS or MS receiving 
ocrelizumab postpartum 
 
B-cell levels (CD19  cells, absolute counts and 
percentage of lymphocytes) measured at 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 


 
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Objectives 
Corresponding Endpoints 
Objectives 
Corresponding Endpoints 
Secondary Outcome Measures (cont.) 
 
To evaluate transfer of 
ocrelizumab into breastmilk of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
AUC of ocrelizumab in mature breastmilk 
(i.e., milk produced after Day 14 postpartum) 
over 60 days after the first postpartum 
ocrelizumab infusion using the following time 
points: 
– 
If receiving 1  600 mg: before infusion and 
at 24 hours (Day 1), Day 7, Day 30 and Day 
60 post-infusion 
– 
If receiving 2  300 mg: before infusion 1 
and at 24 hours (Day 1), Day 7, Day 14, 
Day 15 (24 hours after infusion 2), Day 21, 
Day 30, and Day 60 post-infusion 1 
 
Average and peak ocrelizumab milk 
concentration as well as time to reach peak milk 
concentration, measured over 60 days after the 
mother’s first postpartum ocrelizumab infusion 
 
To evaluate the relative and 
maximum exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated MDID calculated as the peak 
ocrelizumab milk concentration multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
measured over 60 days after the mother’s first 
postpartum ocrelizumab infusion 
 
Average RID over 60 days, calculated as the 
ADID (mg/kg/day) divided by the maternal 
dosage (mg/kg/day) multiplied by 100 
Note:  Other pharmacokinetic and exposure 
parameters may be calculated as appropriate, 
based on the data obtained 
 
To evaluate whether there is 
transfer of ocrelizumab from the 
mother to the infant via 
breastmilk  
 
Serum concentration of ocrelizumab in the 
infant measured at Day 30 after the mother’s 
first ocrelizumab postpartum infusion 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 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 MMR, diphtheria, tetanus, 
pertussis, Hib, HBV, and PCV-13 
 
Proportion of infants with positive humoral 
response (seroprotective titers; as defined for 
the individual vaccine) to vaccines 
Safety Objectives 
 
To evaluate the safety of 
ocrelizumab in lactating women 
with CIS or MS receiving 
ocrelizumab postpartum and in 
their respective infants 
 
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 
 


 
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Objectives 
Corresponding Endpoints 
Exploratory Objectives 
 
To evaluate infant’s growth 
velocity and developmental 
milestones in the first year of life 
 
Assessment of growth velocity based on 
age-adjusted length, weight, head 
circumference, using monthly 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 measure disease activity in 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Number of MS relapses during the postpartum 
period (clinical relapses) 
 
Mean change in the EDSS score from last 
pre-baseline measurement (up to 1 year before 
LMP) to baseline 
 
To evaluate the evolution of 
B-cell levels over the first year 
of life in infants of lactating 
women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Trajectory (absolute and percentage changes) 
of B-cells (CD19  cells) in the infant from 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 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 
ADID  average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire version 3; 
AUC  area under the milk concentration-time curve; CIS  clinically isolated syndrome; 
EDSS  Expanded Disability Status Scale; HBV  hepatitis B virus; Hib  Hemophilus influenzae 
type b; LLN  lower limit of normal; LMP  last menstrual period; MDID  maximum oral daily 
infant dosage; MMR  measles, mumps, and rubella MS  multiple sclerosis; PCV-
13  13-pneumococcal conjugate vaccine; RID    relative infant dose; WHO  World Health 
Organization. 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a prospective, multicenter, open-label study in lactating women with CIS or MS (in line 
with the locally approved indications) who decided together with their treating physician to 
continue on, or start treatment with, OCREVUS (ocrelizumab) postpartum despite ocrelizumab 
currently not being recommended during lactation. 
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 at least 10 women with CIS or MS who are breastfeeding or planning to 
breastfeed. 


 
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The study will consist of the following periods: 
 
Screening period:  After providing written informed consent, women will enter a screening 
period for eligibility assessments.  Considering that decisions on initiating or resuming 
treatment with a disease-modifying therapy (DMT) in the postpartum period are usually 
taken before or during pregnancy, screening may be conducted at any time from the third 
trimester until 24 weeks postpartum.  Final inclusion will only take place for women who 
have delivered a healthy term infant and have made a decision to breastfeed their infant 
despite ongoing ocrelizumab treatment.  General health and medical history of the infant 
will also be reviewed for eligibility. 
Women resuming treatment with ocrelizumab postpartum will be included only if the last 
exposure to ocrelizumab occurred more than 3 months before the last menstrual period 
(LMP) (i.e., women without potential fetal exposure) to exclude any interference between 
fetal exposure and exposure via lactation. 
 
Treatment and sampling period:  Women fulfilling the inclusion/exclusion criteria will receive 
the ocrelizumab dose regimen as per the locally approved label.  The first dose of 
ocrelizumab may be administered at any point between Week 2 and Week 24 postpartum, 
as an initial split dose of two 300 mg infusions (in 250 mL 0.9% sodium chloride) separated 
by 14 days or as a single 600 mg infusion (in 500 mL 0.9% sodium chloride) according to 
the local prescribing information.  For women where a decision not to administer a second 
300 mg infusion is taken after enrolment, continuation in the study will be allowed.  Dosing 
and treatment duration are at the discretion of the physicians, in accordance wit h local 
clinical practice and local labeling (U.S. Prescribing Information [USPI]; Summary of 
Product Characteristics [SmPC]).  If women did not experience a serious infusion-related 
reaction (IRR) with any previous ocrelizumab infusion, a shorter (2-hour) infusion can be 
administered for subsequent 600 mg doses (Summary of Product Characteristics [SmPC], 
United States Prescribing Information [USPI]).  Women referred by healthcare professionals 
(HCPs) to participate in the trial may receive ocrelizumab treatment at their neurologist’s 
site as part of their standard of care treatment. 
Maternal breastmilk samples will be collected over several time points up to 60 ( 2) days 
after the first postpartum ocrelizumab infusion at approximately the same time of day, 
although flexibility is allowed on collection timings to accommodate the mother and infant 
feeding schedule.  The only exception is the first (Day 1) post-infusion breastmilk sample 
and, in women who received a 2  300 mg dose, the second (Day 15) post-infusion 
breastmilk sample, which should be collected 24 hours after the midpoint of the infusion.  
On days of collection, milk should be expressed from both breasts until completely emptied 
using an electric breast pump.  The milk from each breast is then mixed and a sample 
(volume  5 mL) is removed for analysis.  The infant can be bottle-fed the remaining 
expressed milk.  If the infant is not usually fed using a bottle, milk may be expressed from 
one breast only.  If the mother presents with unilateral mastitis, milk should only be 
expressed from the unaffected breast, until the infection resolves.  If mastitis presents 
bilaterally (rare), breastmilk collection should be stopped until the infection resolves. 
The infant blood sample will be collected at Day 30 ( 2 days) of lactation after the first 
ocrelizumab infusion administered postpartum, i.e., regardless of whether women receive a 
600 mg or a 2  300 mg dose.  Blood samples may be collected at home by a visiting nurse, 
or at the hospital as part of study visits.  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). 
A structured telephone interview will be conducted by site personnel every 2 weeks in the 
treatment and sampling period, for a general review, and to identify and collect information 
on any changes in the woman’s and infant’s health status (including the occurrence of 
MS relapses in the mother and use of and 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. 


 
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 Vaccination period:  After the 60-day ( 2 days) treatment and sampling period, infants will 
continue to be followed-up for growth (age-adjusted length, weight, head circumference) 
and developmental milestones up to 12 months of age.  Growth charts (following the World 
Health Organization 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 post-natal care, may also be used. 
Infant laboratory assessments will be performed 1 month ( 30 days) after the first or 
second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13 of age 
( 30 days), in case MMR vaccine is not planned to be administered, to evaluate whether 
infants are able to mount humoral immune responses to clinically relevant vaccines, and for 
measurement of B-cell levels.  In case the mother decides to switch to another DMT or to 
stop DMT after the 60-day treatment and sampling period, the infant blood sample will still 
be collected. 
A structured telephone interview will be conducted by site personnel postpartum every 
3 months in the vaccination period (in-between ocrelizumab infusions) for a general review, 
and to identify and collect information on any changes in the woman’s and infant’s health 
status (including the occurrence of MS relapses in the mother and use of and 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 visit. 
 
Discontinuation:  Women who decide to discontinue the study (this includes discontinuation 
of either the mother or the infant; this does not apply to treatment discontinuation) will be 
invited to attend an early study discontinuation visit (which may be conducted remotely, 
i.e., virtually or by telephone) as soon as possible.  Depending on the timing of 
discontinuation, the following is recommended: 
Discontinuation before the infant blood draw at 30 ( 2) days post-infusion 1:  Collection 
of infant outcomes in the first year of life as per standard pharmacovigilance procedures 
– 
If the mother remains on treatment with ocrelizumab and decides to stop 
participating at 30 ( 2) days after the first postpartum ocrelizumab infusion, 
attempts to collect the infant sample at 30 ( 2) days should be made before 
discontinuation. 
– 
If the mother switches to another DMT, the infant sample at 30 ( 2) days should 
not be collected. 
Discontinuation after the infant blood draw at 30 ( 2) days post-infusion 1:  Collection 
of infant outcomes in the first year of life as per standard pharmacovigilance 
procedures. 
 
NUMBER OF WOMEN 
This study will enroll at least 10 women with CIS or MS (in line with the locally approved 
indications) who are breastfeeding or planning to breastfeed. 
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.  
The primary analysis will be conducted at the end of the Treatment and Sampling Period 
(Day 60 [ 2 days]). 
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 3 years.  This includes an enrolment period of approximately 
21 months and a woman’s participation period of 16 months. 


 
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TARGET POPULATION 
INCLUSION CRITERIA 
The following criteria must be met for study entry: 
 
An Informed Consent Form (ICF) for participation of the maternal subject and her infant 
(for collection of blood, infant demographic 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 
 
Woman is able and willing to comply with the study protocol, according to the judgment of 
the investigator, in particular: 
– 
Woman is willing to breastfeed (either exclusively, or with formula supplementation) for 
at least 60 days after the first postpartum ocrelizumab infusion (this decision is to be 
taken prior to and independent from study participation) 
– 
Woman is willing to provide breastmilk samples before and after their first and, 
if applicable, second postpartum ocrelizumab infusion 
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. 
 
Woman is between 18 and 40 years of age at screening 
 
Woman has a diagnosis of MS or CIS (in line with the locally approved indications) 
 
Woman has delivered a healthy term singleton infant ( 37 weeks gestation)  
 
Infant is between 224 weeks of age at the time of the mother’s first postpartum dose of 
ocrelizumab 
 
For women who received commercial ocrelizumab (OCREVUS) before enrolment: 
documentation that last exposure to ocrelizumab occurred more than 3 months before the 
LMP (i.e., excluded a potential fetal exposure) and was given at the approved dose of 
2  300 mg or 1  600 mg 
 
Woman agrees to use acceptable contraceptive methods or alternative methods during the 
study as described below and, if applicable, upon study treatment discontinuation, as 
defined by the local prescribing information 
– 
The following contraceptive methods are considered acceptable (failure rate  1% 
[Clinical Trial Facilitation Group (CTFG)]):  progestogen-only oral hormonal 
contraception, where inhibition of ovulation is not the primary mode of action; male or 
female condom with or without spermicide; cap, diaphragm, or sponge with spermicide; 
combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier method). 
Birth control methods that are highly effective (i.e., failure rate  1% [CTFG]) may also be 
used but are not required, and include: oral, intravaginal or transdermal combined hormonal 
contraception associated with inhibition of ovulation [unless not recommended or 
contraindicated during breastfeeding];  oral, injectable or implantable progestogen-only 
hormonal contraception associated with inhibition of ovulation; intrauterine device; 
intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; 
sexual abstinence. 
Note:  lactational amenorrhea method can be used to ensure adequate protection from an 
unplanned pregnancy, and the following three criteria must be met: 1) amenorrhea; 2) fully 
or nearly fully breastfeeding (no interval of  46 hours between breastfeeds); and 
3)  6 months postpartum.  If any of the three listed criteria change at any stage during the 
study, an alternative or additional method of acceptable contraception is required. 
 


 
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EXCLUSION CRITERIA 
Mothers/infants who meet any of the following criteria will be excluded from study entry: 
Exclusions related to the mother 
 
Hypersensitivity to ocrelizumab or to any of its excipients 
 
Woman received last dose of ocrelizumab  3 months before the LMP or during pregnancy 
(i.e., there was a potential fetal exposure to ocrelizumab) 
 
Active infections (note: the woman may be included once the infection is treated and is 
resolved; women with bilateral mastitis infection should not have samples collected until the 
infection is completely resolved) 
 
Prior or current history of primary or secondary immunodeficiency, or woman in an 
otherwise severely immunocompromised state.  Woman may be re-screened and included 
if condition resolves 
 
Woman 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 high risk of breast malignancies 
undergoing prophylactic treatment with drugs such as tamoxifen are excluded  
 
Woman has history of breast implants, breast augmentation, breast reduction surgery or 
mastectomy 
 
Woman has prior or current history of chronic alcohol abuse or drug abuse 
 
Woman has any medical, obstetrical or psychiatric condition that, in the opinion of the 
investigator, would compromise the woman's ability to participate in this study 
 
Treatment with a DMT for CIS or MS during pregnancy and/or first weeks postpartum, with 
the exception of formulations of interferon-beta, glatiramer acetate or pulsed corticosteroids 
 
Drugs known to transfer to the breastmilk and with established or potential deleterious 
effects for the infant, including but not limited to aspirin (risk of Reye’s syndrome), 
tetracyclines or fluoroquinolones 
 
Treatment with any investigational agent within 6 months or five half-lives of the 
investigational drug (whichever is longer) prior to the LMP, unless the investigational agent 
is ocrelizumab administered  3 months prior to the LMP in the context of a study or registry 
sponsored by Roche 
 
Exclusions related to the infant 
 
Infant is  24 weeks of age at the time of the mother’s first postpartum dose of ocrelizumab 
 
Infant has any abnormality that may interfere with breastfeeding or milk absorption, 
including but not limited to cleft palate and/or lip, congenital diaphragmatic hernia and 
esophageal atresia 
 
Infant has an active infection.  Infant may be included once the infection resolves 
 
Infant has any other medical condition or abnormality that, in the opinion of the investigator, 
could compromise the infant’s ability to participate in this study, including interference with 
the interpretation of study results 
 
Infant has any other medical condition or abnormality that, in the opinion of the investigator, 
could compromise the infant’s ability to participate in this study, including interference with 
the interpretation of study results 
 
Infant has at least one documented brief resolved unexplained event (BRUE), as defined by 
the 2016 Guidelines of the American Academy of Pediatrics 
 
Exclusions related to laboratory findings 
 
Mother with any abnormal screening laboratory value that is clinically relevant should 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. 


 
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 
Mother 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 (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. 
 
STUDY TREATMENT 
The study treatment is commercial ocrelizumab. 
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 IRRs.  Premedication with an antipyretic (e.g., paracetamol) may also 
be considered prior to each ocrelizumab infusion 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary analysis will be conducted on the full analysis set (all women who meet the 
eligibility criteria and received any postpartum dose of ocrelizumab) and infants of women in the 
full analysis set.  The analysis will be performed after the last breastmilk sample collection at the 
end of the 60-day treatment and sampling period. 
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 estimated average 
oral daily infant dosage will be analyzed using descriptive statistics.  Mean, corresponding 
95% CI, standard deviation, and other statistics will be presented. 
More details about missing data handling, as well as sensitivity analyses based on alternative 
imputation approaches, will be specified in the statistical analysis plan. 
DETERMINATION OF SAMPLE SIZE 
The study will include at least 10 women with CIS or MS (in line with the locally approved 
indications) who are breastfeeding or planning to breastfeed.   
With 10 infants, a precision (width of the two-sided 95% CI) of 0.443 is expected if one event is 
observed (defined as B-cells below the LLN) and a precision of 0.531 if two events are 
observed in the study.  If no event is observed during the study, there is a 95% confidence that 
the event rate is below 0.31. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
definition 
ADID 
average (oral) daily infant dosage 
AE 
adverse event 
AESI 
adverse events of special interest 
ASQ-3 
Ages And Stages Questionnaire, version 3 
AUC 
area under the milk concentration-time curve 
BRUE 
brief resolved unexplained event 
CIS 
clinically isolated syndrome 
CRO 
contract research organization 
CTFG 
clinical trial facilitation group 
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 
Food and Drug Administration 
FSS 
functional systems score 
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 
HCV 
hepatitis c virus infection 
Hib 
Hemophilus influenzae type b 
HIPAA 
health insurance portability and accountability act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
IMP 
investigational medicinal product 


 
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Abbreviation 
definition 
IND 
investigational new drug 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
LLN 
lower limit of normal 
LMP 
last menstrual period 
mAb 
monoclonal antibody 
MAH 
marketing authorization holder 
MDID 
maximum (oral) daily infant dosage 
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-pneumococcal conjugate vaccine 
PML 
progressive multifocal leukoencephalopathy 
PPMS 
primary-progressive multiple sclerosis 
QTL 
quality tolerance limit 
RID 
relative infant dose 
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 
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).  Multiple 
sclerosis 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 multiple sclerosis (RRMS), secondary 
progressive multiple sclerosis (SPMS), and primary-progressive multiple sclerosis 
(PPMS; Lublin et al. 2014).  Relapsing-remitting multiple sclerosis 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, Zhao, and 
Devonshire 2008; Weinshenker et al. 1989).  Primary-progressive multiple sclerosis 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 (for example, magnetic 
resonance imaging [MRI], lumbar puncture, evoked potentials) evidence 
(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 (mAb) 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-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).  The appropriate treatment strategy during pregnancy and after 
birth remains uncertain, since none of the many DMTs available for MS are 
recommended during pregnancy or breastfeeding (LaHue et al. 2019).  There is no 
consensus on how soon after birth may DMTs be safely resumed.  Women often have to 
choose between breastfeeding and early resumption of a disease-modifying therapy 
(DMT) postpartum.  This can have a significant impact on disease management since 
the risk of postpartum relapse is high.  About 30% of women experience a relapse in the 
first 3 months postpartum (Vukusic et al. 2004).  Such relapses may in turn worsen 
disability (Portaccio et al. 2014). 
The general benefits of breastfeeding are well established, both for mothers as well as 
for infants.  Infants who are exclusively breastfed have a lower risk of gastrointestinal as 
well as respiratory infections (Kramer and Kakuma 2012), and mothers who breastfeed 
have a reduced risk of breast, ovarian, and endometrial cancer (Ip et al. 2007; Kramer 
and Kakuma 2012; Jordan et al. 2017; Collaborative Group on Hormonal Factors in 
Breast Cancer, 2002).  In addition, there is good evidence that exclusive breastfeeding 
may reduce the risk of postpartum relapses.  A systematic literature 
review/meta-analysis of 24 studies exploring the association between breastfeeding and 
MS relapse reported a pooled adjusted hazard ratio (HR) for the association of 
breastfeeding and postpartum relapses of 0.57 (95% CI:  0.38 to 0.85; p  0.006) vs. 
non-breastfeeding (Krysko et al. 2020); and a study of a cohort of 466 pregnancies in 


 
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375 women with MS (based on electronic health records) found that exclusive 
breastfeeding reduced the risk of early postpartum relapses (adjusted HR  0.37, 
p  0.009; Langer-Gould et al. 2020).  Despite reduction in postpartum relapses with 
breastfeeding, annual relapse rates remain fairly high after birth, highlighting the need 
for additional strategies to prevent such relapses (Krysko et al. 2020).  An efficacious 
mAb therapy that could safely be resumed soon after birth would significantly reduce the 
risk of postpartum relapses (LaHue et al. 2020). 
Available Evidence 
In a pre- and post-natal development study in cynomolgus monkeys, administration of 
ocrelizumab from gestation day 20 to approximately 5 weeks postpartum was associated 
with glomerulopathy, lymphoid follicle formation in bone marrow, lymphoplasmacytic 
renal inflammation, and decreased testicular weight in offspring.  There were two cases 
of moribundity, one attributed to weakness due to premature birth accompanied by 
opportunistic infection and the other to an infective meningoencephalitis involving the 
cerebellum of the neonate from a maternal dam with an active infection (mastitis).  The 
course of both neonatal infections could have potentially been impacted by B-cell 
depletion.  Newborn offspring of maternal animals exposed to ocrelizumab were noted to 
have depleted B-cell populations during the post-natal phase.  Measurable levels of 
ocrelizumab were detected in milk (approximated 0.2% of steady state through serum 
levels) during the lactation period.  Overall, it has to be taken into account that 
ocrelizumab was administered as 15/20 and 75/100 mg/kg loading/study doses, which 
correspond to human equivalent doses of approximately 3000 mg (approximately 
5  clinical dose) and 15,000 mg (approximately 25  clinical dose), respectively.  
Maternal doses administered in this study resulted in mean maximum serum 
concentrations (Cmax) that were 4.5- and 21-fold above those anticipated in the clinical 
setting.  Moreover, preclinical studies studying ocrelizumab exposure through lactation 
only (i.e., administering ocrelizumab only postpartum) have not been conducted. 
Clinical studies of the effects on infants associated with the use of ocrelizumab during 
lactation have not been performed.  A few cases of exposure through breastmilk have 
been reported.  Reduced B-cell levels at birth were reported in an infant born to a mother 
exposed to ocrelizumab during the second trimester of pregnancy (following relapse 
activity post-alemtuzumab), who also received a single 300-mg dose postpartum.  
Two months after this dose, the infant’s B-cell levels were normal.  The authors also 
reported an infant who was exposed through breastmilk to a single 600-mg dose 
postpartum, in whom B-cell levels were normal 39 days afterwards.  Neither infant had 
hospitalizations or infections requiring antibiotic or hospitalization, during the period of 
exposure through breastfeeding (Ciplea et al. 2020). 
As of 31 March 2022, 40 cases of infant postpartum exposure to ocrelizumab via 
breastmilk have been reported in the Roche global safety database (Oreja-Guevara et 
al. 2022).  Thirty-three infants were exposed to ocrelizumab postpartum via breast milk; 
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experienced no adverse events; 6 infants experienced adverse events (sleepiness 
potentially due to diphenhydramine hydrochloride exposure; excessive vomiting and 
swelling due to potential dairy allergies; conjunctivitis and otitis media, treated with 
unspecific antibiotics; life-threatening breathing disorder and mild neurodermatitis; 
pelvic inflammation and nephritis; conjunctivitis) and 19 infants had no reported 
adverse event information.  B-cell levels available for 5 infants were in line within 
reported age-specific reference ranges. 
Supporting Evidence from Other Anti-CD20 Therapies 
In a study in 9 women with MS treated with rituximab (another anti-CD20 mAb), the 
median average rituximab concentration in mature breastmilk was low, at 0.063 μg/mL 
(range 0.0460.097) in the 4 patients with serial breastmilk collection; with an estimated 
median absolute infant dose of 0.0094 mg/kg/d and a relative infant dose (RID) of 0.08% 
(range 0.06%0.10%).  Rituximab was virtually undetectable in milk by 90 days 
post-infusion (Krysko et al. 2019).  In another study in 23 patients from the German 
Multiple Sclerosis and Pregnancy Registry who received the mAbs natalizumab (n  17), 
rituximab (n  3), ocrelizumab (n  2) or rituximab  ocrelizumab (n  1) during lactation, no 
negative impact on infant health and development attributable to drug exposure through 
breastmilk was seen after a median follow-up of 1 year.  The concentration of 
natalizumab was low in breastmilk and in the serum of infants, and B-cell levels were 
normal in breastfed infants whose mothers received the anti-CD20 mAb rituximab; 
Ciplea et al. 2020). 
Uncertainties and Need for Additional Evidence 
Data on ocrelizumab kinetics in human milk and on the effects of ocrelizumab on 
breastfed infants are sparse and, as stated, no clinical studies have been performed 
evaluating the benefit-risk of ocrelizumab during breastfeeding.  Given that IgG-based 
mAbs have large molecular sizes and limited transport mechanisms, the expected 
transfer into breastmilk is low (Hurley and Theil 2011).  Additionally, most Igs have low 
oral bioavailability, which further reduces the likelihood of absorption by breastfeeding 
infants (Jasion et al. 2015).  However, it has been shown that in women with MS minimal 
transfer of other anti-CD20 mAbs (rituximab) into breastmilk occurs, while the effects on 
the immune system and developmental milestones of potentially exposed infants remain 
unknown. 
Given the unmet need for women with MS who may wish to breastfeed but are at high 
risk of postpartum relapses, and given the available evidence of minimal transfer of 
rituximab into breastmilk, a dedicated prospective interventional study to specifically 
evaluate the transfer of ocrelizumab into breastmilk and the corresponding 
pharmacodynamic effects in infants is therefore required, and justified.  This study 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 
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics of ocrelizumab in the breastmilk of 
lactating women with CIS or MS (in line with the locally approved indications) treated 
with ocrelizumab, by assessing the concentration of ocrelizumab in mature breastmilk, 
as well as the corresponding exposure and pharmacodynamic effects (blood 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 
Co-Primary Outcome Measure 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum present with B-cell 
depletion  
 
Proportion of infants with B-cell 
levels (CD19 cells, absolute counts in blood) 
below the LLN, measured at Day 30 after the 
mother’s first ocrelizumab postpartum infusion 
 
To evaluate the exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated ADID, calculated as the ocrelizumab 
average milk concentration over 60 days 
post-ocrelizumab infusion 1 multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
Secondary Outcome Measures 
 
To evaluate B-cell levels in 
infants of lactating women with 
CIS or MS receiving 
ocrelizumab postpartum 
 
B-cell levels (CD19  cells, absolute counts and 
percentage of lymphocytes) measured at 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 
 
To evaluate transfer of 
ocrelizumab into breastmilk of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
AUC of ocrelizumab in mature breastmilk (i.e., 
milk produced after Day 14 postpartum) over 
60 days after the first postpartum ocrelizumab 
infusion using the following time points: 
– 
If receiving 1  600 mg: before infusion and 
at 24 hours (Day 1), Day 7, Day 30 and 
Day 60 post-infusion 
– 
If receiving 2  300 mg: before infusion 1 and 
at 24 hours (Day 1), Day 7, Day 14, Day 15 
(24 hours after infusion 2), Day 21, Day 30, 
and Day 60 post-infusion 1 
 
Average and peak ocrelizumab milk 
concentration as well as time to reach peak milk 
concentration, measured over 60 days after the 
mother’s first postpartum ocrelizumab infusion 
ADID   average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire, 
version 3; AUC  area under the milk concentration-time curve; CIS  clinically isolated 
syndrome; EDSS  Expanded Disability Status Scale; HBV   hepatitis B virus; 
Hib  Hemophilus influenzae type b; LLN  lower limit of normal; LMP  last menstrual 
period; MDID  maximum oral daily infant dosage; MMR   measles, mumps, and rubella 
MS  multiple sclerosis; PCV-13  13-pneumococcal conjugate vaccine; RID   relative infant 
dose; WHO  World Health Organization. 


 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Objectives 
Corresponding Endpoints 
Secondary Outcome Measures (cont.) 
 
To evaluate the relative and 
maximum exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated MDID calculated as the peak 
ocrelizumab milk concentration multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
measured over 60 days after the mother’s first 
postpartum ocrelizumab infusion 
 
Average RID over 60 days, calculated as the 
ADID (mg/kg/day) divided by the maternal 
dosage (mg/kg/day) multiplied by 100 
Note:  Other pharmacokinetic and exposure 
parameters may be calculated as appropriate, 
based on the data obtained. 
 
To evaluate whether there is 
transfer of ocrelizumab from the 
mother to the infant via 
breastmilk  
 
Serum concentration of ocrelizumab in the 
infant measured at Day 30 after the mother’s 
first ocrelizumab postpartum infusion 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 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 MMR, diphtheria, tetanus, 
pertussis, Hib, HBV, and PCV-13 
 
Proportion of infants with positive humoral 
response (seroprotective titers; as defined for 
the individual vaccine) to vaccines  
Safety Objectives 
 
To evaluate the safety of 
ocrelizumab in lactating women 
with CIS or MS receiving 
ocrelizumab postpartum and in 
their respective infants 
 
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 
ADID   average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire, 
version 3; AUC  area under the milk concentration-time curve; CIS  clinically isolated 
syndrome; EDSS  Expanded Disability Status Scale; HBV   hepatitis B virus; 
Hib  Hemophilus influenzae type b; LLN  lower limit of normal; LMP  last menstrual 
period; MDID  maximum oral daily infant dosage; MMR   measles, mumps, and rubella 
MS  multiple sclerosis; PCV-13  13-pneumococcal conjugate vaccine; RID   relative infant 
dose; WHO  World Health Organization. 


 
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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Objectives 
Corresponding Endpoints 
Exploratory Objectives 
 
To evaluate infant’s growth 
velocity and developmental 
milestones in the first year of life 
 
Assessment of growth velocity based on age-
adjusted length, weight, head circumference, 
using monthly 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 measure disease activity in 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Number of MS relapses during the postpartum 
period (clinical relapses) 
 
Mean change in the EDSS score from last 
pre-baseline measurement (up to 1 year before 
LMP) to baseline 
 
To evaluate the evolution of 
B-cell levels over the first year 
of life in infants of lactating 
women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Trajectory (absolute and percentage changes) 
of B-cells (CD19  cells) in the infant from 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 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 
ADID  average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire, version 3; 
AUC  area under the milk concentration-time curve; CIS  clinically isolated syndrome; 
EDSS  Expanded Disability Status Scale; HBV  hepatitis B virus; Hib  Hemophilus influenzae 
type b; LLN  lower limit of normal; LMP  last menstrual period; MDID  maximum oral daily 
infant dosage; MMR  measles, mumps, and rubella MS  multiple sclerosis; 
PCV-13  13-pneumococcal conjugate vaccine; RID    relative infant dose; WHO  World 
Health Organization. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a prospective, multicenter, open-label study in lactating women with CIS or MS 
(in line with the locally approved indications) who decided together with their treating 
physician to continue on, or start treatment with, OCREVUS (ocrelizumab) postpartum 
despite ocrelizumab currently not being recommended during lactation. 
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 
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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 at least 10 women with CIS or MS who are breastfeeding or 
planning to breastfeed.  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 period 
 
Treatment and sampling period 
 
Vaccination period 
 
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 
 
ASQ-3    Ages and Stages Questionnaire, version 3; LMP  last menstrual period; MMR  measles, mumps, and rubella; OCR  ocrelizumab. 
Study description:  In this prospective, multicenter, open-label study, lactating women with CIS or MS (in line with the locally approved 
indications) who decided together with their treating physician to continue on, or start treatment with, commercial ocrelizumab postpartum will 
enter a screening period, which may be started during the third trimester of pregnancy and continue until 24 weeks postpartum.  Women who 
have delivered a healthy term infant and made a decision to breastfeed their infant will be enrolled if they and their infants fulfil the respective 
eligibility criteria.  Women resuming treatment with ocrelizumab postpartum will be included only if the last exposure to ocrelizumab occurred more 
than 3 months before the LMP (i.e., women without potential fetal exposure).  In the 60-day ( 2 days) treatment and sampling period, women 
will receive the ocrelizumab dose regimen as per the locally-approved label, at any point between Week 2 and Week 24 postpartum.  The first 
dose of ocrelizumab may be administered as two 300 mg infusions separated by 14 days (for those initiating ocrelizumab) or as a single 600 mg 
infusion (for those resuming ocrelizumab).  For women where a decision not to administer a second 300 mg infusion is taken after enrolment, 
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at their neurologist’s site as part of their standard of care treatment.  Laboratory and clinical assessments will be performed at the designated 
visits. 
Women will collect their breastmilk samples over several time points up to 60 ( 2) days after the first postpartum ocrelizumab infusion, reserving 
5 mL at each sampling point for analysis of ocrelizumab concentrations.  Infant blood samples will be collected at Day 30 ( 2 days) after the first 
postpartum ocrelizumab infusion (regardless of whether women receive a 600 mg or a 2  300 mg dose).  Infant blood samples may be collected 
at home by a visiting nurse, if not collected at the clinical site during a study visit.  In the vaccination period, infants will continue to 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 for example, the pediatrician as part of routine postnatal care, may also be used).  
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, to evaluate whether infants are able to mount humoral immune 
responses to clinically relevant vaccines, and for measurement of B-cell levels.  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 mother 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.  Women who decide to discontinue the study (this 
includes discontinuation of either the mother or the infant) 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 Period 
After providing written informed consent, women will enter a screening period for 
eligibility assessments.  Considering that decisions on initiating or resuming treatment 
with a DMT in the postpartum period are usually taken before or during pregnancy, 
screening may be conducted at any time from the third trimester until 24 weeks 
postpartum.  Final inclusion will only take place for women who have delivered a healthy 
term infant and have made a decision to breastfeed their infant despite ongoing 
ocrelizumab.  General health and medical history of the infant will be reviewed for 
eligibility. 
Women resuming treatment with ocrelizumab postpartum will be included only if the last 
exposure to ocrelizumab occurred more than 3 months before the last menstrual period 
(LMP), i.e., if they have no potential fetal exposure; to exclude any interference between 
fetal exposure and exposure via lactation. 
3.1.3 
Treatment and Sampling Period 
Women fulfilling the inclusion/exclusion criteria will receive the ocrelizumab dose 
regimen as per the locally approved label.  The first dose of ocrelizumab may be 
administered at any point between Week 2 and Week 24 postpartum, as an initial split 
dose of two 300 mg infusions (in 250 mL 0.9% sodium chloride) separated by 14 days or 
as a single 600 mg infusion (in 500 mL 0.9% sodium chloride), according to the local 
prescribing information.  For women where a decision not to administer a second 
300 mg infusion is taken after enrolment, continuation in the study will be allowed.  
Dosing and treatment duration are at the discretion of the physicians, in accordance 
with local clinical practice and local labeling (U.S. Prescribing Information [USPI]; 
Summary of Product Characteristics [SmPC]).  If women did not experience a serious 
infusion-related reaction (IRR) with any previous ocrelizumab infusion, a shorter (2-hour) 
infusion can be administered for subsequent 600 mg doses (SmPC, USP).  Women 
referred by healthcare professionals (HCPs) to participate in the trial may receive 
ocrelizumab treatment at their neurologist’s site as part of their standard of care 
treatment. 
Maternal breastmilk samples will be collected over several time points up to 
60 ( 2) days after the first postpartum ocrelizumab infusion at approximately the same 
time of day, although flexibility is allowed on collection timings to accommodate the 
mother and infant feeding schedule.  The only exception is the first (Day 1) post-infusion 
breastmilk sample, and in women who received a 2  300 mg dose, the second (Day 15) 
post-infusion breastmilk sample, which should be collected 24 hours after the midpoint of 
the infusion.  On days of collection, milk should be expressed from both breasts until 
completely emptied using an electric breast pump.  The milk from each breast is then 
mixed and a sample (volume  5 mL) is removed for analysis.  The infant can be 
bottle-fed the remaining expressed milk.  If the infant is not usually fed using a bottle, 
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mastitis, milk should only be expressed from the unaffected breast, until the infection 
resolves.  If mastitis presents bilaterally (rare), breastmilk collection should be stopped 
until the infection resolves. 
The infant blood sample will be collected at Day 30 ( 2 days) of lactation after the first 
ocrelizumab infusion administered postpartum, i.e., regardless of whether women 
receive a 600 mg or a 2  300 mg dose.  The corresponding breastmilk sample should 
be collected on the same day as the infant blood sample.  Blood samples may be 
collected at home by a visiting nurse, or at the hospital as part of study visits 
(see Appendix 1, Schedule of Assessments). 
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). 
A structured telephone interview will be conducted by site personnel every 2 weeks in 
the treatment and sampling period, for a general review and to identify and collect 
information on any changes in the woman’s and infant’s health status (including the 
occurrence of MS relapses in the mother 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. 
3.1.4 
Vaccination Period 
After the 60-day ( 2 days) treatment and sampling period, infants will continue to be 
followed-up for growth (age-adjusted length, weight, 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) questionnaires 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. 
Infant laboratory assessments will be performed 1 month ( 30 days) after the first or 
second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13 of age 
( 30 days), if MMR vaccine is not planned to be administered, to evaluate whether 
infants are able to mount humoral immune responses to clinically relevant vaccines, as 
well as to measure their B-cell levels.  In case the mother decides to switch to another 
DMT or to stop DMT after the 60-day treatment and sampling period, the infant blood 
sample will still be collected. 
A structured telephone interview will be conducted by site personnel postpartum every 
3 months in the vaccination period (in-between ocrelizumab infusions) for a general 
review, and to identify and collect information on any changes in the woman’s and 


 
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infant’s health status (including the occurrence of MS relapses in the mother 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. 
3.1.5 
Discontinuation 
Women who decide to discontinue the study (this includes discontinuation of either the 
mother or the infant; this does not apply to treatment discontinuation as described in 
Section 3.1.4) will be invited to attend an early study discontinuation visit (which may be 
conducted remotely, i.e., virtually or by telephone) as soon as possible.  Depending on 
the timing of discontinuation, the following is recommended: 
 
Discontinuation before the infant blood draw at 30 ( 2) days post-infusion 1:   
– 
Collection of infant outcomes in the first year of life as per standard 
pharmacovigilance procedures 
– 
If the mother remains on treatment with ocrelizumab and decides to stop 
participating at 30 ( 2) days after the first postpartum ocrelizumab infusion, 
attempts to collect the infant sample at 30 ( 2) days should be made before 
discontinuation  
– 
If the mother switches to another DMT, the infant sample at 30 ( 2) days 
should not be collected. 
 
Discontinuation after the infant blood draw at 30 ( 2) days post-infusion 1: 
Collection of infant outcomes in the first year of life as per standard 
pharmacovigilance procedures. 
 
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 vaccine is not planned to be administered) for the 
last infant.  The primary analysis will be conducted at the end of the Treatment and 
Sampling Period (Day 60 [ 2 days]). 
The total length of the study, from screening of the first woman to the end of the study, is 
expected to be approximately 3 years.  This includes an enrolment period of 
approximately 21 months and a woman’s participation period of 16 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
This is a prospective, multicenter, open-label study evaluating the transfer of 
ocrelizumab into breastmilk of lactating women with CIS or MS treated with ocrelizumab 
postpartum.  Ocrelizumab targets B-cells, and a rapid depletion of CD19  B-cells in 
blood is the expected pharmacologic effect of ocrelizumab treatment (and hence, is a 
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such as 2  10 mg (FDA 2017).  Therefore, CD19  B-cell levels will be measured as a 
co-primary endpoint (specifically, the proportion of infants with B-cells below the LLN at 
Day 30 [ 2 days] post-infusion). 
To evaluate the amount of drug that may be transferred from mother to infant through 
breastmilk, the co-primary endpoint is the average (oral) daily infant dosage (ADID), 
which expresses the average amount of ocrelizumab in breastmilk (and available to the 
infant) as an infant dose, over the observed period of 60 days ( 2 days) post-infusion.  
The excretion in breastmilk is expected to be highest during the first 60 days after the 
ocrelizumab infusion, declining thereafter over the 6-monthly dosing interval.  Breastmilk 
samples will be collected before the infusion, and at days 1, 7, 30 ( 2) and 60 ( 2) (with 
additional timepoints for mothers who are receiving a split dose, i.e., 2  300 mg), to 
cover two average half-lives of ocrelizumab in serum (26 days [USPI]) and the expected 
time window of greatest breastmilk transfer for anti-CD20 monoclonal antibodies 
(Krysko et al. 2019).  Samples will be taken only after the development of mature milk 
(i.e., milk produced after Day 14 postpartum) to avoid the collection of colostrum, which 
may contain a high concentration of antibody because of a more porous mammary 
epithelium (FDA 2019).  In addition, mothers will be instructed to completely empty both 
breasts with an electric pump, and mix milk from both breasts before removing the 
amount required for the sample.  If the infant is not usually fed using a bottle, milk may 
be expressed from one breast only.  This will reduce variability across the study, as for 
example foremilk and hindmilk (milk expressed at the start and end of feeding, 
respectively) have different compositions, which can influence the amount of drug 
available in the sample (Hebert 2016).  To account for differences in exclusive 
breastfeeding versus supplementation with formula, a feeding schedule diary completed 
by the women will record the number of breastmilk feeds and/or feed with formula milk 
(supplementation) on the day of the sample collection and the previous and following 
day, as recommended by the FDA (Food and Drug Administration; FDA 2019).  For 
mothers presenting with mastitis during the sampling period, sample collections from the 
infected breast(s) will be interrupted, given that clinical and subclinical mastitis are 
associated with increased milk concentrations of serum-derived immune factors such as 
IgG (Filteau 2003). 
To further understand the extent of ocrelizumab transfer through breastmilk and the 
exposure in infants, secondary endpoints will include the area under the milk 
concentration-time curve (AUC) of ocrelizumab in breastmilk over 60 days 
post-ocrelizumab infusion, average concentration, peak concentration, time to peak 
concentration and the maximum (oral) daily infant dosage (MDID), as recommended by 
the FDA (FDA 2019).  To evaluate potential adverse impact on the infants, infant health 
and development outcomes will be assessed using growth charts according to the WHO 
Child Growth Standards (WHO 2022) and the ASQ-3, a widely accepted tool for 
measuring development in young children (Lipkin et al. 2020; American Association of 
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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 of lactating women 
with CIS or MS receiving ocrelizumab postpartum can mount a protective immune 
response to clinically relevant vaccines. 
As exploratory endpoints, disease activity will be measured in the mothers using 
standard assessments such as Expanded Disability Status Scale (EDSS) and number of 
MS relapses.  These endpoints are commonly used in MS clinical trials to assess 
treatment efficacy and disease progression. 
As recommended (FDA 2019), this study is designed to minimize burden on the mother 
and disruption to the infant’s feeding schedule.  For example, at sample collection time 
(when the infant would be fed the remainder of the collected milk through a bottle), 
mothers may instead collect the sample from only one breast if the infant is not normally 
fed using a bottle.  Further, the infant blood sample on Day 30 ( 2 days) post-infusion 
and at 1 month ( 30 days) after the first or second dose of MMR vaccine/Month 13 of 
age ( 30 days) may be collected at home by a visiting nurse, or at the hospital as part of 
study visits. 
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 labeling 
(USPI; SmPC).  As per the dosing regimen approved in the labeling, 600 mg 
ocrelizumab is to be given as IV infusion every 6 months.  The first dose is given as two 
300 mg IV infusions two weeks apart; and subsequent doses are given as single 600 mg 
IV infusions.  For women where a decision not to administer a second 300 mg infusion is 
taken after enrolment, continuation in the study will be allowed.  If women did not 
experience a serious IRR with any previous ocrelizumab infusion, a shorter (2-hour) 
infusion can be administered for subsequent 600 mg doses (Ocrelizumab SmPC, 
Ocrelizumab USPI). 
3.3.2 
Rationale for Subject Population 
As the aim of this study is to evaluate breastmilk transfer of ocrelizumab and the 
corresponding pharmacodynamic effects in the infant, it will be conducted in women with 
CIS or MS (in line with the locally approved indications) aged 1840 years who have 
planned to start or resume ocrelizumab after delivery, while breastfeeding for a minimum 
of 60 days.  
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 


 
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terminal half-life recorded as 53 days in 1 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 (Simister 2003; Palmeira et al. 2012), it is 
assumed that a potential fetal exposure is unlikely in women whose last ocrelizumab 
infusion was earlier than 3 months before LMP.  Women who were exposed to 
ocrelizumab within 3 months of their LMP, or during pregnancy, will therefore be 
excluded to eliminate cases of potential fetal exposure to ocrelizumab that could 
confound the results of B-cell levels in the infant or the presence of ocrelizumab in 
breastmilk.   
Women who have given birth to more than one baby (i.e., have had non-singleton births) 
are excluded, because such mothers might find it difficult to comply with study 
requirements, and might find it more difficult to reserve the amount of breastmilk needed 
for the sample.  Therefore, their infants might receive a different amount of breastmilk, 
potentially confounding the B-cell level results. 
Infants who are  24 weeks of age at the mother’s first postpartum dose of ocrelizumab 
will be excluded.  Although the WHO recommends exclusive breastfeeding up to 
6 months with continued breastfeeding along with appropriate complementary foods up 
to 2 years of age or older (WHO 2020a), these recommendations are not followed in 
most countries.  Recent findings from the National Immunization Survey 20182019 in 
the United States show that the percentage of infants who are breastfed decreases from 
58.3% at 6 months to 35.3% at 1 year (Centers for Disease Control and Prevention 
2020a).  The maximum maternal age is set at 40 years, as mothers in late childbearing 
age of  35 years (in particular primiparous mothers) have been shown to have the 
greatest risk of non-initiation of exclusive breastfeeding both at discharge and at 1 month 
postpartum, even though they had the antenatal intention to exclusively breastfeed 
(Kitano et al. 2016). 
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.  
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), and all antiviral drug labels do not recommend 
breastfeeding when taking the drugs. 
In addition, infants with any abnormality that may interfere with breastfeeding or milk 
absorption, such as cleft palate and/or lip, congenital diaphragmatic hernia and 
esophageal atresia are excluded, given that the co-primary aim of this study is to 
evaluate the corresponding pharmacodynamic effects of potential ocrelizumab exposure 
through breastmilk.  Infants who have had at least one documented brief resolved 
unexplained event (BRUE), are also excluded, because these potentially life-threatening 
events have an unknown impact on infant physiology and development, and may 
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first year.  The term BRUE is defined by the American Academy of Pediatrics as an 
event occurring in an infant younger than 1 year when the observer reports a sudden, 
brief, and now resolved episode of  1 of the following:  (1) cyanosis or pallor; (2) absent, 
decreased, or irregular breathing; (3) marked change in tone (hyper- or hypotonia); and 
(4) altered level of responsiveness (Tieder et al. 2016). 
4. 
MATERIALS AND METHODS 
4.1 
STUDY PARTICIPANTS 
This study will enroll at least 10 women with CIS or MS (in line with the locally approved 
indications) who are breastfeeding or planning to breastfeed. 
4.1.1 
Inclusion Criteria 
The following criteria must be met for study entry: 
 
An Informed Consent Form (ICF) for participation of the maternal subject and her 
infant (for collection of blood, infant demographic 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 
 
Woman is able and willing to comply with the study protocol, according to the 
judgment of the investigator, in particular: 
– 
Woman is willing to breastfeed (either exclusively, or with formula 
supplementation) for at least 60 days after the first postpartum ocrelizumab 
infusion (this decision is to be taken prior to and independent from study 
participation) 
– 
Woman is willing to provide breastmilk samples before and after their first and, 
if applicable, second postpartum ocrelizumab infusion 
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. 
 
Woman is between 18 and 40 years of age at screening 
 
Woman has a diagnosis of MS or CIS (in line with the locally approved indications) 
 
Woman has delivered a healthy term singleton infant ( 37 weeks gestation) 
 
Infant is between 224 weeks of age at the time of the mother’s first postpartum 
dose of ocrelizumab 
 
For women who received commercial ocrelizumab (OCREVUS) before enrolment: 
documentation that last exposure ocrelizumab occurred more than 3 months before 
the LMP (i.e., excluded a potential fetal exposure) and was given at the approved 
dose of 2  300 mg or 1  600 mg 


 
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 
Woman agrees to use acceptable contraceptive methods or alternative methods 
during the study as described below and, if applicable, upon study treatment 
discontinuation, as defined by the local prescribing information (see Section 4.6.1). 
– 
The following contraceptive methods are considered acceptable (failure rate 
 1% [Clinical Trial Facilitation Group (CTFG)]):  progestogen-only oral hormonal 
contraception, where inhibition of ovulation is not the primary mode of action; 
male or female condom with or without spermicide; cap, diaphragm, or sponge 
with spermicide; combination of male condom with cap, diaphragm, or sponge 
with spermicide (double-barrier method). 
Birth control methods that are highly effective (i.e., failure rate  1% [CTFG]) may 
also be used but are not required, and include:  oral, intravaginal or transdermal 
combined hormonal contraception associated with inhibition of ovulation [unless not 
recommended or contraindicated during breastfeeding, see Table A2-1]; oral, 
injectable or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation; intrauterine device; intrauterine hormone-releasing system; 
bilateral tubal occlusion; vasectomized partner; sexual abstinence. 
Note:  lactational amenorrhea method can be used to ensure adequate protection 
from an unplanned pregnancy, and the following three criteria must be met:  
1) amenorrhea; 2) fully or nearly fully breastfeeding (no interval of  46 hours 
between breastfeeds); and 3)  6 months postpartum.  If any of the three listed 
criteria change at any stage during the study, an alternative or additional method of 
acceptable contraception is required. 
 
4.1.2 
Exclusion Criteria 
Mothers or infants who meet any of the following criteria will be excluded from study 
entry: 
Exclusions related to the mother 
 
Hypersensitivity to ocrelizumab or to any of its excipients 
 
Woman received last dose of ocrelizumab  3 months before the LMP or during 
pregnancy (i.e., there was a potential fetal exposure to ocrelizumab) 
 
Active infections (note: the woman may be included once the infection is treated and 
is resolved; women with bilateral mastitis infection should not have samples 
collected until the infection is completely resolved) 
 
Prior or current history of primary or secondary immunodeficiency, or woman in an 
otherwise severely immunocompromised state.  Woman may be re-screened and 
included if condition resolves 
 
Woman 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 high risk of 
breast malignancies undergoing prophylactic treatment with drugs such as 
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 
Woman has history of breast implants, breast augmentation, breast reduction 
surgery or mastectomy 
 
Woman has prior or current history of chronic alcohol abuse or drug abuse 
 
Woman has any medical, obstetrical or psychiatric condition that, in the opinion of 
the investigator, would compromise the woman's ability to participate in this study 
 
Treatment with a DMT for CIS or MS during pregnancy and/or first weeks 
postpartum, with the exception of formulations of interferon-beta, glatiramer acetate 
or pulsed corticosteroids 
 
Drugs known to transfer to the breastmilk and with established or potential 
deleterious effects for the infant, including but not limited to aspirin (risk of Reye’s 
syndrome), tetracyclines or fluoroquinolones.  A more detailed, though not 
comprehensive, list can be found in Appendix 2 
 
Treatment with any investigational agent within 6 months or five half-lives of the 
investigational drug (whichever is longer) prior to the LMP, unless the investigational 
agent is ocrelizumab administered  3 months prior to the LMP in the context of a 
study or registry sponsored by Roche 
 
Exclusions related to the infant 
 
Infant is  24 weeks of age at the time of the mother’s first postpartum dose of 
ocrelizumab 
 
Infant has any abnormality that may interfere with breastfeeding or milk absorption, 
including but not limited to cleft palate and/or lip, congenital diaphragmatic hernia 
and esophageal atresia 
 
Infant has an active infection.  Infant may be included once the infection resolves 
 
Infant has any other medical condition or abnormality that, in the opinion of the 
investigator, could compromise the infant’s ability to participate in this study, 
including interference with the interpretation of study results 
 
Infant has at least one documented BRUE, as defined by the 2016 Guidelines of the 
American Academy of Pediatrics 
 
Exclusions Related to Laboratory Findings 
 
Mother with any abnormal screening laboratory value that is clinically relevant 
should 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. 
 
Mother 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 hepatitis B virus (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 
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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. 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.  No randomization, treatment assignment or blinding is 
planned. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS 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 the United States] and SmPC [for the 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 labeling (USPI; SmPC).  No measures of treatment 
compliance are planned. 
4.3.2.1 
Study Treatment 
As per the labeling, 600 mg ocrelizumab is to be given as IV infusion every 6 months.  
The first dose of ocrelizumab may be administered at any point between Week 2 and 
Week 24 postpartum as two 300-mg IV infusions two weeks apart (in 250 mL 0.9% 
sodium chloride) or as a single 600-mg IV infusion (in 500 mL 0.9% sodium chloride); 
and subsequent doses given according to the local prescribing information.  For women 
where a decision not to administer a second 300 mg infusion is taken after enrolment, 
continuation in the study will be allowed.  If women did not experience a serious IRR with 
any previous ocrelizumab infusion, a shorter (2-hour) infusion can be administered for 
subsequent 600 mg doses (SmPC, USPI).  Women referred by HCPs to participate in 
the trial may receive ocrelizumab treatment at their neurologist’s site as part of their 
standard of care treatment. 
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 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, 
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supplements) used by a woman participating in the study, in addition to the study 
treatment.  All such medications taken within 6 weeks prior to the baseline visit and 
throughout the study should be reported to the investigator and recorded on the 
Concomitant Medications electronic case report form (eCRF). 
4.4.1 
Prohibited Therapy 
Drugs known to transfer to the breastmilk and with established or potential deleterious 
effects for the infant, including but not limited to aspirin (risk of Reye’s syndrome), 
tetracyclines or fluoroquinolones are not permitted.  A more detailed, though not 
comprehensive, list can be found in Appendix 2. 
No formal drug-drug interaction studies have been conducted with ocrelizumab, as no 
drug-drug interactions are expected via the cytochromes P450, other metabolizing 
enzymes or transporters. 
Ocrelizumab is a monotherapy and has not been studied in combination with other 
DMTs.  As with other immunomodulatory therapies, exercise caution when initiating 
ocrelizumab after an immunosuppressive therapy, and when initiating another therapy 
after ocrelizumab, taking into consideration the potential for overlapping 
pharmacodynamic effects. 
Immunosuppressants, lymphocyte-depleting agents, or lymphocyte-trafficking blockers 
should NOT be administered while the woman is B-cell depleted. 
More information is available in Section 4.1.2 and the ocrelizumab labeling (USPI; 
SmPC). 
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 or 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 their infants 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 enrolment.  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 
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4.5.2 
Mother’s Assessments 
4.5.2.1 
Demographics, Medical and MS History, and Disease 
Characteristics 
Women’s demographics (age, self-reported ethnicity, and level of education) and 
relevant medical history, including clinically significant diseases, surgeries/procedures, 
vaccination history, 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 the baseline visit will be recorded.  Clinically significant 
diseases and/or surgeries and concomitant medication should also be recorded 
throughout the study if available. 
Obstetric history: 
 
History of previous pregnancies 
 
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 
the LMP 
 
History of previous DMTs (prior to and during pregnancy): number of DMTs ever 
used, last DMT before ocrelizumab 
 
Treatment history with ocrelizumab (to be collected only in women who received 
commercial ocrelizumab prior to enrolment): Documentation of start of ocrelizumab 
therapy and date and dose of last ocrelizumab infusion prior to enrolment. 
 
4.5.2.2 
Physical Examinations and Related Assessments 
A complete physical examination in participating women should include 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 at the woman’s HCP (obstetrician/gynecologist, pediatrician 
and/or neurologist of referred woman) 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.  Height will be recorded at 
screening only. 
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). 
See Appendix 1 (Schedule of Assessments) for the timing of assessments. 


 
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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 these measurements are performed as per clinical 
practice and are available, any abnormalities should be recorded on the General Medical 
History and Baseline Conditions eCRF.  At subsequent visits, new or worsened clinically 
significant abnormalities should be recorded on the Adverse Event section of the eCRF 
(as presented in Section 5.1.2). 
4.5.2.4 
Neurological Examinations 
A neurological examination will be performed at baseline, early study discontinuation as 
well as at unscheduled visits if applicable, to distinguish relapse in MS from another 
neurological (non-MS) disorder.  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 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 (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 treatment period.  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 hours, with or 
without recovery, and in the absence of fever or infection (Thompson et al. 2018).  
MS relapses should not be reported as an adverse event, unless they are serious. 
It is recommended that women with new neurological symptoms suggestive of a relapse 
have an EDSS/Functional Systems Score (FSS) assessment performed as soon as 


 
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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 
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 paragraphs.  For sampling procedures, storage 
conditions, and shipment instructions, see the laboratory manual.  For more details, refer 
to Schedule of Assessments (see Appendix 1). 
 
Hematology (hemoglobin, hematocrit, quantitative platelet count, red blood cell 
[RBC] count, white blood cell [WBC] absolute or/and differential count [neutrophils, 
eosinophils, lymphocytes, monocytes, basophils]). 
 
Serum chemistry (potassium, sodium, chloride, random glucose, AST, ALT, 
gamma-glutamyl transpeptidase [GGT], total bilirubin and creatinine). 
 
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. 
 
Serum Ig concentration:  Quantitative measurement for IgG, IgM and IgA levels. 
 
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+). 
 
Ocrelizumab concentration in breastmilk:  Breastmilk samples throughout the 
study will be collected for determination of ocrelizumab concentration.  Women 


 
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should record the volume of pumped breastmilk and indicate date and time for 
collection as well as whether breastmilk was pumped from one or both breasts.  
At each sampling point, 5 mL of breastmilk should be saved (as directed by the site 
staff) to send to the central laboratory.  The 24-hour (Day 1, as well as Day 15 for 
women who received the 2  300 mg regimen) post-infusion samples are collected 
based on the midpoint of infusion.  For example, if the infusion began at 8 a.m. and 
ended at 10 a.m., the 24-hour sample collection would occur at 9 a.m. on the day 
before and after the infusion.  For details, refer to Schedule of Assessments (see 
Appendix 1). 
 
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, CD38bright  
 Plasmablasts or plasma cells:  CD45+, CD19+, CD27+, CD38 bright 
  
4.5.3 
Infant’s Assessments 
4.5.3.1 
Medical History, Biometrics and Concomitant Medications 
 
General health and medical history 
 
Gestational age at birth 
 
Congenital malformations 
 
Mode of delivery (vaginal delivery, instrumental delivery, scheduled or urgent 
cesarean section)  
 
Appearance, Pulse, Grimace, Activity, and Respiration score (1 min, 5 min, 10 min) 
 
Infant vital biometrics (head circumference, weight, length) at birth 
 
Previous and concomitant medication given to the infant should be recorded at 
screening and throughout the study.  For administered vaccinations, refer to 
Section 4.5.3.2. 
 
4.5.3.2 
Physical Examinations and Related Assessments 
 
Body weight (measured at every visit where a blood sample will be taken, i.e., at 
Day 30 [ 2 days] post-infusion 1, and 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). 
 
Feeding schedule diary (during the treatment and sampling period):  Women should 
record the number of breastmilk feeds and/or feed with formula milk 
(supplementation) on the day of the sample collection and the previous and 
following day, i.e., day of collection  1 day. 


 
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 
Feeding status (during the vaccination period): Women 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, at Months 2, 4, 6, 9, and 12, as applicable and depending 
on the infant’s age at enrolment. 
 
ASQ-3 at Months 2, 4, 6, 9, and 12, as applicable and depending on the infant’s age 
at enrolment. 
 
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) at Months 2, 4, 6, 9, and 12, as applicable 
and depending on the infant’s age at enrolment. 
 
Documentation of vaccinations: 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 30 days after the first postpartum ocrelizumab infusion 
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 Month 
13/1 month after first or second MMR dose, and may include diphtheria, tetanus, 
and pertussis, Hemophilus influenzae type b (Hib), 13-pneumococcal conjugate 
vaccine (PCV-13), HBV and MMR. 
 
See Appendix 1 (Schedule of Assessments) for the timing of assessments and 
Appendix 6 for the time windows for infant growth velocity and child developmental 
milestone assessments. 
4.5.3.3 
Laboratory, Biomarker, and Other Biological Samples 
Routine laboratory assessments (performed in the central laboratory) are listed in the 
following sections.  For sampling procedures, storage conditions, and shipment 
instructions, see the laboratory manual.  For more details, refer to Schedule of 
Assessments (see Appendix 1). 
Day 30 ( 2 days) post-infusion 1 
 
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 in serum 
 
Note:  If the infant’s B-cell levels are found to be below LLN at any visit, repeat analyses 
may be done at unscheduled visits at the discretion of the investigator (in consultation 
with the Sponsor). 


 
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Infant samples will be collected by venipuncture.  As per the recommendations 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. 
Table 3 
Prioritization Order for Infant Blood Sample Assessments at 
Day 30 (2 days) Post-Infusion 1 
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 The same sample will be used to measure B-cell counts (CD19  ), T-cell counts (CD3 , 
CD4 , 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 is not planned to be 
administered 
 
Mean titers (IgG) of antibody immune response(s) to common childhood 
vaccinations with full or partial doses given prior to 1 year will be measured (which 
include responses to MMR, diphtheria, tetanus, pertussis, Hib, HBV, and PCV-13).  
Titers will be measured at 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. 
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. 
a) Lymphocyte subtypes:  A blood sample will be collected to measure B-cell 
counts (CD19 ); the same sample will be used to measure T-cell counts 
(CD3 , CD4 , CD8  ), and NK cell counts (CD16+CD56+). 
 
Note:  If the infant’s B-cell levels are found to be below LLN at any visit, 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 recommendations 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 


 
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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. 
Table 4 
Prioritization Order for Infant Blood Sample Assessments 
1 Month ( 30 days) After the First/Second Dose of MMR Vaccine 
or at Month 13 of Age ( 30 Days) if MMR Vaccine Is Not Planned 
to Be Administered 
Order of Priority 
Assessment 
1 
Any safety laboratory samples (scheduled or unscheduled and 
performed at the discretion of the investigator) 
2 
Mean titers (IgG) of antibody immune response(s) to vaccinations a 
3 
Lymphocyte subtypes blood sample b 
Ab    antibody; IgG  immunoglobulin G; MMR   measles, mumps, rubella; NK  natural 
killer; PCV  13-valent pneumococcal conjugate vaccine. 
a The following antibody titers will be measured:  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 The same sample will be used to measure B-cell counts (CD19  ), T-cell counts (CD3 , 
CD4 , CD8  ), and NK cell counts (CD16+CD56+). 
 
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 (with the 
exception of an accidental pregnancy, as described below).  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. 
In case a woman enrolled in the study becomes accidentally pregnant again during 
breastfeeding, she will remain on study and discontinue treatment with commercial 
ocrelizumab until the pregnancy completion.  She and her infant should continue with all 
study assessments (including breastmilk sample collection).  The investigator should 
complete the Global Clinical Trial Pregnancy Form and submit to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator will submit to the Sponsor a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. 


 
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4.6.2 
Discontinuation from the Study 
Women and their 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; this does not apply to treatment 
discontinuation as described in Section 3.1.4) will be invited to attend an early study 
discontinuation visit as soon as possible (further details in Section 3.1.5). 
Reasons for women’s discontinuation from the study may include, but are not limited to, 
the following: 
 
Woman’s withdrawal of consent 
 
Study termination or site closure 
 
AE 
 
Loss to follow-up 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the woman’s or infant’s safety 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 the woman’s 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. 
● 
Enrolment 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 


 
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 
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) 
 
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 subject 
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 
 


 
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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) 
 
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 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. 
 


 
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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. 
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 and Assessing 
Safety Parameters 
The investigator is accountable for ensuring that all adverse events collected as per 
protocol (see Section 5.1.1.1 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 
The investigator will seek information on adverse events at each patient contact.  All 
adverse events subject to the collecting and reporting requirements outlined in this 


 
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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 
occurring in a pregnant woman pre- and post- study period should be reported to the 
marketing authorization holder (MAH), as a follow-up spontaneous pregnancy report to 
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 instruction regarding: 
 
IRRs 
 
Diagnosis versus signs and symptoms 
 
Adverse events occurring secondary to other adverse events 
 
Persistent or recurrent AEs 
 
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 


 
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 
Drug interactions 
 
5.1.3 
Reporting Requirements from Investigator to Sponsor 
5.1.3.1 
Immediate Reporting Requirements from Investigator 
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 
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: 
 
SAEs 
 
Non-serious adverse events of special interest 
 
Pregnancy occurred during breastfeeding (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 Institutional Review Board (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 


 
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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, 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. 
5.1.3.4 
If Electronic Data Capture 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 
woman enrolled in the study becomes accidentally pregnant again during breastfeeding, 
she will remain on study and discontinue treatment with commercial ocrelizumab until 
pregnancy completion.  She and her infant should continue with all study assessments 
(including breastmilk sample collection).  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 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 
breastfeeding (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 
The study enrolls postpartum women breastfeeding their infants following the first 
postpartum ocrelizumab dose.  In case a woman enrolled in the study becomes 


 
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accidentally pregnant again during breastfeeding, she will remain on study and 
discontinue treatment with commercial ocrelizumab until pregnancy completion.  She 
and her infant should continue with all study assessments (including breastmilk sample 
collection). 
In case of a spontaneous abortion in an accidental pregnancy during breastfeeding, the 
spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), 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). 
If a therapeutic or elective abortion was performed in an accidental pregnancy during 
breastfeeding because of an underlying maternal or embryofetal toxicity, the toxicity 
should be classified as an serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.1.3.1).  A therapeutic or elective abortion performed for reasons 
other than an underlying maternal or embryofetal toxicity is not considered an AE. 
All abortions that occur in an accidental pregnancy during breastfeeding should be 
reported as pregnancy outcomes on the paper Clinical Trial Pregnancy Reporting Form. 
Congenital Anomalies/Birth Defects 
The study enrolls women postpartum who delivered a healthy term infant and who plan 
to breastfeed their infants following the first postpartum ocrelizumab dose.  In case a 
woman enrolled in the study becomes accidentally pregnant again during breastfeeding, 
she will remain on study and discontinue treatment with commercial ocrelizumab until 
pregnancy completion.  She and her infant should continue with all study assessments 
(including breastmilk sample collection). 
Any congenital anomaly/birth defect in a child born to a woman who became accidentally 
pregnant during breastfeeding and was exposed to the medicinal product should be 
classified as an 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. 


 
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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 (see also Section 5.1.3.5) 
 
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 


 
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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 (e.g., SmPC for the EU). 
 
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. 
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 conducted after the last breastmilk sample collection at the 
end of the 60-day treatment and sampling period.  Full analysis, including analysis of the 
vaccination response in infants, 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. 
6.1 
ANALYSIS POPULATIONS 
Full Analysis Set 
The full analysis set (FAS) population of women will include all women who meet the 
eligibility criteria and receive any postpartum dose of ocrelizumab. 
The FAS population of infants will include all the infants of the FAS population of women. 


 
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Safety Population 
The safety population will be the same as the FAS.  The safety population of infants will 
include all infants of women in the FAS population. 
6.2 
DETERMINATION OF SAMPLE SIZE 
There is no formal sample size calculation, as no confirmatory hypothesis testing is 
planned.  The primary analysis will be descriptive.  The study will include at least 
10 women with CIS or MS (in line with the locally approved indications) who are 
breastfeeding or planning to breastfeed.   
With 10 infants, a precision (width of the two-sided 95% CI) of 0.443 is expected if one 
event is observed (defined as B-cells below the LLN) and a precision of 0.531 if two 
events are observed in the study.  If no event is observed during the study, there is a 
95% confidence that the event rate is below 0.31. 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
Enrolment, screening failures, ocrelizumab administration, and discontinuations from 
the study will be summarized using descriptive statistics (frequency tables for 
categorical endpoints and mean, median, range, SD, and 25th75th quartiles for the 
continuous endpoints).  Subject disposition will be tabulated, with treatment 
discontinuations summarized by reason for discontinuation.  Major protocol violations, 
including violations of inclusion/exclusion criteria, will also be summarized.  Women and 
infants enrolled but excluded from the FAS will be listed. 
6.4 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
For women, demographics (age and self-reported race), medical history, and 
neurological examination will be summarized.  The following will also be summarized: 
MS disease history (duration since first MS symptoms, duration of MS since diagnosis, 
relapses in the past year), and other important variables. 
Characteristics of infants at birth will also be summarized (gender, weight, gestational 
age at birth and other endpoints collected).  Values at the mother’s first ocrelizumab 
infusion visit (which may take place any time between Week 2 and Week 24 
postpartum) will be considered as baseline. 
6.5 
PRIMARY ANALYSES 
6.5.1 
Primary Endpoint 
The primary analysis will be conducted on the FAS (defined earlier).  The analysis will 
be performed after the last breastmilk sample collection at the end of the 60-day 
treatment and sampling period. 


 
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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 estimated 
ADID will be analyzed using descriptive statistics.  Mean, corresponding 95% CI, SD, 
and other statistics will be presented. 
The estimand of the proportion of infants with B-cell levels below the LLN is defined as 
below: 
 
Population: all infants of women in the FAS population who have B-cell levels 
measured at Day 30 after the mother’s first ocrelizumab postpartum infusion. 
 
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 will be handled as follows: 
– 
Incomplete dosing, including delayed second (300 mg) ocrelizumab infusion:  
all the B-cell data will be included in the analysis. 
– 
Infant did not receive any breastmilk before B-cell measurement during the 
entire 30-day period after the mother’s first ocrelizumab postpartum infusion:  
B-cell data will be excluded from the analysis. 
– 
Mother used other DMT during breastfeeding before B-cell measurement on 
Day 30 post-ocrelizumab infusion 1:  B-cell data will be excluded from the 
analysis. 
– 
Mother used other medication before B-cell measurement on Day 30 
post-ocrelizumab infusion 1 that is not allowed by protocol during breastfeeding:  
B-cell data will be excluded from the analysis. 
– 
Infant’s blood sample collected before assessment window (i.e., before Day 28):  
Data will be excluded from the analysis. 
– 
Infant’s blood sample collected beyond the assessment window:  B-cell data 
might be included or excluded depending on the cause of the delay (rules will 
be specified in the SAP) and schedule of delayed visit. 
– 
Infant's blood sample collected while infant has an illness:  B-cell data will be 
excluded on a case-by-case basis if there is a strong biological rationale that the 
illness may confound the B-cell data. 
 
Population-level summary:  The proportion of infants with B-cell levels below LLN 
will be reported with the two-sided 95% CI; 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. 
 
The estimand of the ADID in breastmilk is defined as below: 
 
Population:  all women in the FAS population who provide any breastmilk samples 
(primary analysis set of mother) 


 
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 
Variable:  ADID 
 
Intercurrent events will be handled as follows: 
– 
Incomplete dosing, including delayed second (300 mg) ocrelizumab infusion: all 
the ADID data will be collected and included in the analysis.  No adjustments 
based on actual dose will be made. 
– 
Mother used other DMT during breastfeeding:  ADID data will be included. 
– 
Mother used other medication not allowed by protocol during breastfeeding:  
ADID data will be included in the analysis. 
– 
Mother has mastitis infection during the sample collection period: ADID data will 
be included from milk samples obtained from the non-infected breast (in case of 
bilateral mastitis, breastmilk sampling will be interrupted until the infection 
resolves). 
 
Population-level summary:  The summary statistics together with 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 milk samples with all supporting information are collected. 
 
More details about missing data handling, as well as sensitivity analyses based on 
alternative imputation approaches, will be specified in the SAP. 
6.5.2 
Secondary Endpoints 
The ocrelizumab concentration in mature breastmilk at each time point, MDID, RID, 
and AUC will be summarized descriptively.  Continuous variables at each month 
(e.g., length and weight of infants), as well change from baseline (if applicable) will be 
analyzed primarily using descriptive statistics. 
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 for the overall 
population. 
Continuous variables at each visit, as well change from baseline (if applicable) will be 
analyzed primarily using descriptive statistics.  Mean, corresponding 95% CIs, SD, and 
other statistics will be presented. 
6.5.3 
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. 


 
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6.6 
SAFETY ANALYSES 
6.6.1 
Analyses of Exposure, Adverse Event, Laboratory, and Vital 
Signs Data 
The safety outcome measures 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. 
All safety analyses will be conducted on data collected from the first postpartum 
ocrelizumab infusion until the end of the study.  The safety analysis will be performed on 
the safety populations of women and infants separately.  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 events, 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. 
Concomitant medications recorded during the study will be summarized using frequency 
tables. 
6.7 
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. 


 
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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, 
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. 


 
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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. 
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 United States or under a U.S. Investigational New Drug (IND) 
Application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the 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 


 
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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 patient the objectives, 
methods, and potential risks associated with each optional procedure.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
for any reason.  A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures.  Patients who decline to participate will 
not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before 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 patient shall document the informed consent process and that written 
informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 


 
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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. 
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 Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 


 
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patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, 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 
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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.  
CROs will provide clinical operations management, data management and biostatistics. 
Patient data will be recorded via an EDC system using eCRFs. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, 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 access, 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 


 
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country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Appendix 1:  Schedule of Assessments: Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
82/Protocol MN42989, Version 3 
APGAR  appearance, pulse, grimace, activity, and respiration; ASQ-3  Ages and Stages Questionnaire, version 3; BRUE  brief resolved 
unexplained event; 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; HCPs  Healthcare professionals; Hib  Hemophilus influenzae type b; ICF  Informed 
Consent Form; IRR    infusion-related reaction; 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; SmPC    Summary of Product Characteristics; 
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 telephone interview will not be conducted in a week where there will be an on-site visit). 
a Visits 2a, 3a and 4a are only applicable for women who will be 
receiving the first ocrelizumab dose as two 300 mg infusions. 
b The length of the screening period is variable and depends on 
local timings for performing some of the eligibility assessments.  It 
is possible that visit 1 (screening) is completed in one day or over 
several days/weeks.  Screening may be started during the third 
trimester of pregnancy and continue until 24 weeks postpartum. 
c Samples 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 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. 
d The following diagnoses are accepted:  MS or CIS (in line with the 
locally approved indications). 
e 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. 
f 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 
baseline visit.  Demographic data will include age, self-reported 
race/ethnicity, and level of education.  Clinically significant 
diseases and/or surgeries and concomitant medication should also 
be recorded throughout the study.  Information on vaccinations 
administered to the mother during the study will be collected under 
concomitant medications. 
g Documentation of start of ocrelizumab (OCREVUS) therapy and 
date and dose of last ocrelizumab infusion prior to enrolment.  
Ocrelizumab-related information to be collected only in women 
who received commercial ocrelizumab prior to enrolment. 


Appendix 1:  Schedule of Assessments: Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
83/Protocol MN42989, Version 3 
h A complete physical examination should be performed at the 
screening and baseline visits and at all visits during the treatment 
period (results from examinations done as part of routine care at 
subject’s HCPs [obstetrician/gynecologist, pediatrician, neurologist 
of referred subjects] 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. 
i Neurological examinations will be used to distinguish relapse in 
MS from another neurological (non-MS) disorder.  Potential 
relapses should be recorded throughout the treatment period.  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. 
j Women should record the volume of pumped breastmilk and 
indicate date and time for collection as well as whether breastmilk 
was pumped from one or both breasts.  For sampling on Day 0 
(baseline), the sample should be taken before the infusion. For 
24 hours post-infusion (Day 1 and Day 15), samples are collected 
based on the midpoint of infusion.  For example, if the infusion 
began at 8 am and ended at 10 a.m., the 24-hour sample 
collection would occur at 9 a.m. on the day after the infusion.  With 
the exception of the 24-hour (Day 1; and [for women who received 
a 2  300 mg dose] Day 15) post-infusion breastmilk collection time 
points, flexibility is allowed on collection timing to accommodate 
the mother and the infant feeding schedule.  If the mother presents 
with unilateral mastitis, milk should only be expressed from the 
unaffected breast, until the infection resolves.  If mastitis presents 
bilaterally (rare), breastmilk collection should be stopped until the 
infection resolves. 
k Hematology will include hemoglobin, hematocrit, RBCs, 
WBC absolute or/and differential count (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils), and quantitative platelet 
count.  Chemistry will include potassium, sodium, chloride, random 
glucose, AST, ALT, GGT, creatinine, total bilirubin.  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. 
l 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. 
m Blood samples will be collected to measure B-cell counts 
(CD19   and B-cell subsets [Table 2]),T-cell counts (CD3 , CD4 , 
and CD8  ), and NK cell counts (CD16+CD56+). 
n 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 
84/Protocol MN42989, Version 3 
o In line with the dose regimen in the local label, the first dose of 
ocrelizumab may be administered as an initial split dose of two 
300 mg infusions (in 250 mL 0.9% sodium chloride) separated by 
14 days, or as a single 600 mg infusion (in 500 mL 0.9% sodium 
chloride), at any point between Week 2 and 24 postpartum.  
For women where a decision not to administer a second 300 mg 
infusion is taken after enrolment, continuation in the study will be 
allowed.  Dosing and treatment duration are at the discretion of 
the physicians, in accordance with local clinical practice and 
local labeling (USPI; SmPC).  If women did not experience a 
serious IRR with any previous ocrelizumab infusion, a shorter 
(2-hour) infusion can be administered for subsequent 600 mg 
doses.  Women referred by HCPs to participate in the trial may 
receive ocrelizumab treatment at their neurologist’s site as part of 
their standard of care treatment. 
p General health and medical history for infants includes screening 
for the following (infants should be excluded from the study if any 
are present): age  24 weeks of age at the time of the mother’s first 
postpartum dose of ocrelizumab; any abnormality that may 
interfere with breastfeeding or milk absorption, including but not 
limited to cleft palate and/or lip, congenital diaphragmatic hernia 
and esophageal atresia; an active infection (the infant may be 
included once the infection resolves); at least one documented 
BRUE, as defined by the 2016 Guidelines of the American 
Academy of Pediatrics. 
q These will include: mode of delivery (vaginal delivery, instrumental 
delivery, scheduled or urgent cesarean section); APGAR score 
(1 min, 5 min, 10 min); gestational age at birth; infant’s 
measurements (weight, length, head circumference); and 
congenital malformations. 
r During the treatment and sampling period, women should record 
the number of breastmilk feeds and/or feeds with formula milk 
(supplementation) on the day of the sample collection and the 
previous and following day, i.e., day of collection  1 day.  During 
the vaccination period, women 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, at Months 2, 4, 6, 
9, and 12, as applicable and depending on the infant’s age at 
enrolment. 
s 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 as 
applicable and depending on the infant’s age at enrolment (see 
Appendix 6 for details of time windows of infant growth velocity 
and child developmental milestone assessments). 
t Growth charts (according to the WHO Child Growth Standards; 
WHO 2022) will be used, as well as absolute values; other 
standard measurements recorded by e.g., the pediatrician as part 
of routine post-natal care may also be used).  Infant growth will be 
captured at Months 2, 4, 6, 9, and 12 (see Appendix 6 for details of 
time windows of infant growth velocity and child developmental 
milestone assessments). 
u Including documentation of past or current medications as well as 
clinically significant pediatric disease/abnormality.  Changes to 
concomitant medication given to the infant should be recorded 
throughout the study. 
v Documentation of vaccinations administered to the infant will be 
collected throughout the study. 


Appendix 1:  Schedule of Assessments: Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
85/Protocol MN42989, Version 3 
w  Infant sampling at Day 30 ( 2 days) post-infusion 1 and at 
1 month ( 30 days) after first or second dose of MMR, or 
Month 13 of age in case MMR vaccine is not planned to be 
administered ( 30 days) may be conducted via in-home nurse 
visits or at the hospital as part of study visits.  CD19  B-cell level 
at Day 30 ( 2 days) post-infusion 1 represents the co-primary 
endpoint measurement. 
x If the infant’s B-cell levels are found to be below LLN, repeat 
analyses may be done at unscheduled visits at the discretion of 
the investigator (in consultation with the Sponsor). 
y 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 sample at Day 30 ( 2 days) post-
infusion 1, (1) safety laboratory samples [scheduled or 
unscheduled and performed at the discretion of the investigator] 
(2) lymphocyte subtypes sample for B-cell counts (CD19 ) and 
T-cell counts (CD3 , CD4 , and CD8  ), and NK cell counts 
(CD16+CD56+). (3) serum ocrelizumab concentration; for the 
Month 13 of age/1 month after first/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 ) and T-cell counts (CD3 , CD4 , 
and CD8  ), and NK cell counts (CD16+CD56+). 
z For 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, all efforts will be made to collect 
samples.  However, if they cannot be collected, it will not be 
considered a protocol deviation. 
aa Serum anti-vaccine antibody (IgG) titers will be measured to 
vaccines administered as per local practice over the first year of 
life (which include MMR, diphtheria, tetanus, pertussis, Hib, HBV 
and PCV-13); 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. 
bb 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 13/1 month after first or second MMR dose. 
cc A structured telephone interview will be conducted by site 
personnel postpartum every 2 weeks during the treatment and 
sampling period and every 3 months during the vaccination period 
(in-between ocrelizumab infusions) for a general review, and to 
identify and collect information on any changes in the woman’s 
and infant’s health status (including the occurrence of MS relapses 
in the mother 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. 
dd Adverse events in both mother and infant will be reported 
throughout the study as per standard pharmacovigilance 
procedures.  Adverse events will also be captured at screening for 
women who received ocrelizumab before pregnancy. 


Appendix 1:  Schedule of Assessments: Screening Through the End of Treatment Period 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
86/Protocol MN42989, Version 3 
ee Documentation of premedication is not required. 
 
 
 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
87/Protocol MN42989, Version 3 
Appendix 2  
Compatibility of Common Medications with Breastfeeding 
The following information is compiled from guidance provided by the New Zealand 
Medicines and Medical Devices Safety Authority (Medsafe), available at 
https://www.medsafe.govt.nz/profs/puarticles/June2015/June2015Lactation.htm and 
https://www.medsafe.govt.nz/profs/puarticles/lactation.htm. 
An up-to-date database of medicine levels in breastmilk and infant blood and possible 
adverse reactions in the nursing infant is available at LactMed 
(https://www.ncbi.nlm.nih.gov/books/NBK501922/).  The WHO has also produced a 
classification guide for medicines use in breastfeeding based on the WHO list of 
essential drugs (www.who.int/maternal_child_adolescent/documents/55732/en/). 
Medicines with inherent toxicity or those with high infant exposure and therefore 
potential for significant toxicity are contraindicated during breastfeeding, and include: 
 
Cytotoxic agents 
 
Immunosuppressive agents 
 
Amiodarone 
 
Lithium 
 
Ergotamine 
 
Gold salts 
 
Isotretinoin 
 
Radiopharmaceutical administration also requires temporary cessation of breastfeeding. 
There are a range of health issues that affect women who are breastfeeding.  These 
most commonly include infection, depressive disorders, pain, contraception, low milk 
supply and atopic conditions.  Table A2-1 provides information on the compatibility of 
medicines used in the treatment of these conditions with breastfeeding. 
 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
88/Protocol MN42989, Version 3 
Table A2-1 Compatibility of Commonly Used Medicines with Breastfeeding 
Condition 
Treatment 
Breastfeeding Recommendation 
Additional Information 
Infection 
Antibiotics 
β-lactams 
(e.g., amoxicillin) 
Compatible 
Gastrointestinal flora changes possible; monitor infant for 
diarrhea, vomiting, thrush 
Macrolides 
(e.g., erythromycin) 
Compatible 
Single dose of azithromycin considered safe 
Cephalosporins 
(e.g., cephalexin) 
Compatible 
May also affect infant gut flora (third generation more 
likely) 
Fluoroquinolones 
(e.g., ciprofloxacin) 
Avoid if possible 
Potential risk of arthropathies 
Trimethoprim 
Compatible 
 
Nitrofurantoin 
Compatible 
Avoid nitrofurantoin if infant less than 1 month old or 
premature 
Metronidazole 
Avoid if possible 
If single 2 g metronidazole dose given, discontinue 
breastfeeding for 12 hours 
Antifungals 
Azoles 
(e.g., fluconazole) 
Compatible 
If applying miconazole oral gel to nipples, apply after 
breastfeeding 
Nystatin 
Compatible 
 
Antivirals 
Acyclovir 
Compatible 
 
Depressive 
disorders 
Antidepressants 
SSRIs 
(e.g., paroxetine) 
Compatible 
Paroxetine and sertraline preferred due to shorter half-
lives 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
89/Protocol MN42989, Version 3 
Condition 
Treatment 
Breastfeeding Recommendation 
Additional Information 
TCAs 
(e.g., amitriptyline) 
Less preferred due to potential 
toxicity 
Amitriptyline compatible in doses up to 150 mg/day 
Anxiolytics 
Benzodiazepines 
(e.g., temazepam) 
Compatible in a single dose; avoid 
repeated doses 
Short-acting benzodiazepines preferred as accumulation 
may occur 
Monitor infant for drowsiness 
Pain 
Analgesics 
Paracetamol 
Compatible 
Paracetamol analgesic of choice 
NSAIDs 
(e.g., ibuprofen) 
Compatible 
Avoid breastfeeding with long-term acetylsalicylic acid 
treatment 
Opiates 
(e.g., codeine) 
Compatible in occasional doses 
Monitor infant for drowsiness, apnea, bradycardia and 
cyanosis 
Use codeine with caution in rapid metabolizers 
Tramadol 
Compatible 
 
Contraception 
Hormonal methods 
Progesterone 
Compatible 
See data sheet 
Estrogen 
Avoid if possible 
May inhibit lactation 
Allergies and hay 
fever 
Antihistamines 
Sedating 
(e.g., promethazine) 
Probably compatible 
Occasional use probably safe 
Monitor for sedation in mother and infant 
Non-sedating 
(e.g., loratadine) 
Compatible 
 
Topical 
Corticosteroids 
(e.g., hydrocortisone) 
Compatible 
If applying to breasts apply after feeding 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
90/Protocol MN42989, Version 3 
Condition 
Treatment 
Breastfeeding Recommendation 
Additional Information 
Asthma 
β2- adrenergic 
(e.g., salbutamol) 
Compatible 
 
Corticosteroids 
(e.g., budesonide) 
Compatible 
 
Other 
Warfarin 
Compatible 
 
Metformin 
Compatible 
 
NSAIDs  non-steroidal anti-inflammatory drugs; SSRIs  Selective serotonin reuptake inhibitors; TCAs  Tricyclic antidepressants. 
Source:  Medsafe. URL: https://www.medsafe.govt.nz/profs/puarticles/June2015/June2015Lactation.htm. (Accessed 17 December 2020). 
 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
91/Protocol MN42989, Version 3 
TABULATED SUMMARY OF DRUG DISTRIBUTION INTO BREASTMILK 
Table A2-2 shows published milk/plasma (M/P) ratios from the literature and provides an 
estimate of the weight-adjusted infant dose.  Interpretation of these requires an 
understanding of the limitations associated with published data, such as the availability 
of only single pairs of plasma and milk concentrations.  Infant clearance (related to 
post-conceptual age) should always be considered. 
 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
92/Protocol MN42989, Version 3 
Table A2-2 Summary of Distribution of Drugs into Breastmilk 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Acid-suppressants: 
Cimetidine 
1.7-5.8 
5.46.7 
Avoid in favor of safer alternatives with lower potential for side effects.  May accumulate in 
milk due to active transport. 
Famotidine 
1.5 
1.6 
Probably safe. 
Ranitidine 
2.8 
5.07.8 
Probably safe when restricted to sporadic doses or a single dose at night-time.  May 
accumulate in milk due to active transport. 
Analgesics: 
Aspirin 
0.06 
3.2 
Avoid due to possible association with Reye’s syndrome. 
Codeine 
2.16 
6.8 
Considered safe. 
Ibuprofen 
0 
 0.6 
Considered safe.  Not detected in milk. 
Indomethacin 
0.37 
 1.0 
Considered safe.  One case of seizures (causality questionable). 
Mefenamic acid 
ID 
0.3 
Probably safe. 
Methadone 
0.47 
2.2 
Considered safe in methadone maintenance as 60% of infants born to mothers in 
maintenance programs develop symptoms of withdrawal. 
Morphine 
2.46 
0.4 
Considered safe. 
Naproxen 
ID 
1.1 
Probably safe. 
Nefopam 
ID 
0.4 
Probably safe. 
Piroxicam 
ID 
510 
Use a NSAID with a shorter half-life where possible. 
Paracetamol 
0.8 
2.97.9 
Considered safe. 
Sumatriptan 
4.15.7 
0.36.7 
Exposure limited by low oral availability in term infants.  Expressing for 8 hours post-dose 
will almost completely avoid exposure. 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
93/Protocol MN42989, Version 3 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Antibiotics: 
Aminoglycosides 
Gentamicin 
0.17 
2.2 
Considered compatible with breastfeeding due to low transfer and low oral availability. 
Cephalosporins 
Cefaclor 
ID 
0.7 
Considered safe.  Low transfer into milk.  Third generation cephalosporins have greater 
potential to alter bowel flora. 
Cefalexin 
0.09 
0.51.2 
Cefotaxime 
ID 
0.3 
Ceftriaxone 
0.04 
0.74.7 
Fluoroquinolones 
Ciprofloxacin 
2.17 
4.8 
Avoid fluoroquinolones due to theoretical risk of arthropathies. 
Macrolides 
Clarithromycin 
0.25 
1.8 
Considered safe.  May alter bowel flora. 
Erythromycin 
0.41 
2.1 
Penicillins 
Amoxicillin 
ID 
0.7 
Considered safe.  Note: although amoxicillin/clavulanic acid combination is used extensively 
in lactation, there are no published data on the safety of clavulanic acid. 
Benzylpenicillin 
0.37 
0.8 
Phenoxymethyl-
penicillin 
ID 
0.25 
Tetracyclines 
Minocycline 
ID 
3.6 
Avoid tetracyclines where feasible due to the possible risks of dental staining and adverse 
effects on bone development. 
Tetracycline 
0.58 
4.8 
Others 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
94/Protocol MN42989, Version 3 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Acyclovir 
ID 
1.11.2 
Considered safe.  No adverse effects noted in breastfed infants. 
Fluconazole 
0.75 
11 
Potential for accumulation particularly in premature infants. 
Metronidazole 
0.91.1 
0.136.0 
Controversial as exposure may be high.  With high doses consider expressing and 
discarding milk. 
Nitrofurantoin 
ID 
0.66.0 
Avoid in G6PD-deficient infants (due to the risk of hemolysis). 
Sulphamethoxazole 
and Trimethoprim 
(i.e., co-trimoxazole) 
0.1 
1.26 
22.5 
3.85.5 
Avoid suphaemethoxazole in infants with hyperbilirubinemia and G6PD deficiency. 
Anticoagulants 
Warfarin 
0 
 4.4 
Probably safe.  No changes in prothrombin times detected in breastfeeding infants.  Monitor 
prothrombin time. 
Anticonvulsants: 
Carbamazepine 
0.360.39 
2.87.3 
Considered safe.  Monitor for sedation, poor suckling. 
Lamotrigine 
ID 
1022 
Concentrations in breastfed infants have been consistent with those expected to produce 
clinical effect.  Best to avoid. 
Phenobarbitone 
ID 
23156 
Avoid due to high infant exposure. 
Phenytoin 
0.130.18 
3.07.2 
Considered safe.  Observe for sedation, poor suckling.  One report of methemoglobinemia, 
poor suckling and sedation. 
Sodium valproate 
0.05 
1.8 
Considered safe at low doses.  High doses may increase the risk of hepatitis. 
Vigabatrin 
ID 
 1% 
Avoid until further data are available. 
Antidepressants: 
Tricyclics: 
Amitriptyline 
0.83 
0.60.9 
Probably safe.  Negligible or no concentrations detected in breastfed infants. 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
95/Protocol MN42989, Version 3 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Desipramine 
ID 
0.51.0 
Dothiepin 
0.81.6 
0.2-1.5 
Doxepin 
ID 
0.01 
Imipramine 
ID 
0.13 
Nortriptyline 
ID 
0.53 
Others 
Moclobemide 
0.72 
1.6 
Probably safe. 
Antiemetics: 
Domperidone 
ID 
0.05 
Probably safe.  May increase milk secretion. 
Metoclopramide 
ID 
4.711.3 
Low dose or sporadic use probably safe.  May increase milk secretion. 
Antihistamines: 
Loratadine 
1.2 
0.7 
Probably safe.  No adverse effects reported in infants. 
Triprolidine 
0.53 
0.9 
Considered safe. 
Antipsychotics: 
Chlorpromazine 
ID 
0.2 
Probably safe.  May increase milk secretion.  Monitor infant for sedation, irritability etc. 
Flupenthixol 
ID 
0.50.8 
Haloperidol 
ID 
0.152.0 
Cardiovascular: 
Amiodarone 
ID 
37 
Avoid in breastfeeding. 
Atenolol 
2.34.5 
5.719.2 
Avoid in favor of antihypertensives with lower infant exposure. 
Captopril 
0.03 
0.014 
Considered safe. 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
96/Protocol MN42989, Version 3 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Digoxin 
0.60.9 
2.35.6 
Considered safe. 
Diltiazem 
0.98 
0.9 
Unlikely to be problematical in breastfeeding. 
Enalapril 
0.02 
 0.1 
Considered safe. 
Metoprolol 
2.8-3.6 
1.73.3 
Probably safe. 
Nadolol 
4.6 
5.1 
Consider choosing a beta-blocker with a lower infant dose, if feasible. 
Propranolol 
0.320.76 
0.20.9 
Probably safe. 
Quinapril 
0.12 
1.6 
Considered safe. 
Verapamil 
0.6 
0.140.84 
Considered safe. 
Sedatives/hypnotics: 
Clonazepam 
ID 
1.53.0 
Short-term use of low doses is probably safe. 
Diazepam 
0.16 
2.02.3 
Reasonable to breastfeed after a low single dose but potential for accumulation with 
prolonged use.  Sedation has been reported in breastfed infants. 
Lorazepam 
ID 
2.2 
Short-term use of low doses is probably safe. 
Midazolam 
0.16 
0.7 
Short-term use of low doses is probably safe. 
Nitrazepam 
ID 
ID 
Short-term use of low doses is probably safe.  Potential for accumulation with prolonged 
administration. 
Zopiclone 
0.5 
4.1 
Short-term use of low doses is probably safe. 
Social Drugs: 
Cannabis (THC) 
ID 
ID 
Avoid as long-term effects are unknown. 
Caffeine 
0.50.8 
0.621.0 
Low intake probably safe.  Restlessness and irritability documented.  Prolonged half-life 
(80100 hours) in neonates. 


Appendix 2:   Compatibility of Common Medications with Breastfeeding 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
97/Protocol MN42989, Version 3 
Drug 
M/PAUC 
% Maternal 
Dose 
Comments 
Ethanol 
0.9 
3-4 
Occasional low usage probably safe.  Chronic intake may be associated with impairment of 
psychomotor development.  Consider withholding breastfeeding for 12 hours per standard 
drink. 
Nicotine 
2.92 
ID 
Cigarette smoking should be avoided due to health hazards associated with smoking.  
Use of nicotine patches may be considered compatible with breastfeeding and is favored 
over smoking. 
Miscellaneous: 
Ethinyloestradiol 
ID 
0.3 
May suppress lactation. 
Levonorgestrel 
ID 
1.1 
Considered safe. 
Medroxyprogesterone 
ID0.72 
3.45.0 
Considered safe. 
Norethisterone 
ID0.26 
0.02-1.9 
Considered safe. 
Prednisone 
ID 
0.26 
Short courses of low doses ( 20 mg daily) are probably safe.  Note: there are insufficient 
data on other systemic corticosteroids (e.g., betamethasone, dexamethasone). 
Pseudoephedrine 
2.5 
4.0 
Low doses or sporadic use probably safe. 
Sulphasalazine 
ID 
1.27.0 
Avoid in infants with hyperbilirubinemia or G6PD deficiency. 
AUC  area under the concentration-time curves; G6PD  glucose-6-phosphate dehydrogenase; ID  insufficient data; M/PAUC  AUC of the drug 
in maternal milk and plasma; NSAID  nonsteroidal anti-inflammatory drug; THC  Tetrahydrocannabinol. 
Source:  Medsafe. URL: https://www.medsafe.govt.nz/profs/puarticles/lactation.htm. 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
98/Protocol MN42989, Version 3 
Appendix 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 John Cunningham 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 
 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
99/Protocol MN42989, 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 
(see 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 from Wattjes 2018.8 
 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
100/Protocol MN42989, 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 
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 
 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
101/Protocol MN42989, Version 3 
Table A3-2 Imaging characteristics of MS and PML1,6,7 (cont.) 
Parameters 
MS 
PML 
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; 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 
imaging, either because the JCV-induced disease progresses or because the 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
102/Protocol MN42989, Version 3 
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 
A3–3.1 
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; NTZ  natalizumab; ND  not done or equivocal result; 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 
 
A3–3.2 
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). 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
103/Protocol MN42989, Version 3 
 
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. 
 


Appendix 3:   Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
104/Protocol MN42989, 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 
105/Protocol MN42989, 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 wash-out 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 
106/Protocol MN42989, 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 
107/Protocol MN42989, Version 3 
Appendix 4  
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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 
108/Protocol MN42989, 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. 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 
 
3. PYRAMIDAL FSS 
0 
normal 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
109/Protocol MN42989, Version 3 
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 
110/Protocol MN42989, 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 
111/Protocol MN42989, 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. 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 
112/Protocol MN42989, Version 3 
A4–2 
EDSS BY TELEPHONE 
 
 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
113/Protocol MN42989, Version 3 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
114/Protocol MN42989, Version 3 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
115/Protocol MN42989, Version 3 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
116/Protocol MN42989, Version 3 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
117/Protocol MN42989, Version 3 
 


Appendix 4:   Expanded Disability Status Scale (EDSS) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
118/Protocol MN42989, Version 3 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
119/Protocol MN42989, Version 3 
Appendix 5  
Methods for Assessing and Recording Adverse Events 
A5–1 
Assessment of Severity of Adverse Events............................... 120 
A5–2 
Assessment of Causality of Adverse Events ............................. 120 
A5–3 
Procedures for recording Adverse Events................................. 121 
A5–3.1 
Infusion-Related Reactions ....................................................... 121 
A5–3.2 
Diagnosis versus Signs and Symptoms .................................... 121 
A5–3.3 
Adverse Events Occurring Secondary to Other Events ............ 121 
A5–3.4 
Persistent or Recurrent Adverse Events ................................... 122 
A5–3.5 
Abnormal Laboratory Values..................................................... 122 
A5–3.6 
Abnormal Vital Sign Values....................................................... 123 
A5–3.7 
Abnormal Liver Function Tests ................................................. 124 
A5–3.8 
Deaths ...................................................................................... 124 
A5–3.9 
Pre-existing Medical Conditions ................................................ 125 
A5–3.10 
Lack of Therapeutic Efficacy ..................................................... 125 
A5–3.11 
Hospitalisation or Prolonged Hospitalisation ............................. 125 
A5–3.12 
Overdoses, Misuses, Abuses, Off-Label Use, Occupational 
Exposure, or Medication Error .................................................. 126 
A5–3.13 
Quality Defects, Falsified Products and Product Complaints .... 126 
A5–3.14 
Drug Interactions ....................................................................... 126 
 


Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
120/Protocol MN42989, Version 3 
A5–1 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The adverse event severity grading scale for the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE; version 5.0) 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 (version 5.0), 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 
121/Protocol MN42989, 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 
122/Protocol MN42989, 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 
123/Protocol MN42989, 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 "hyperkalemia." 
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 AEs). 
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 
124/Protocol MN42989, 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 AEs). 
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 


Appendix 5:   Methods for Assessing and Recording Adverse Events 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
125/Protocol MN42989, Version 3 
the 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 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 
126/Protocol MN42989, 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 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). 
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 
127/Protocol MN42989, Version 3 
Appendix 6  
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 2 
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 
 
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, the Ages and Stages Questionnaire, version 3 (ASQ-3) age 
calculator2 can be used:  https://agesandstages.com/free-resources/asq-calculator/. 
Assessment of growth velocity at Months 2, 4, 6, 9, and 12 (as applicable and 
depending on the infant’s age at enrolment) 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 
post-natal care visits performed by e.g., the pediatrician. 
 
 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
128/Protocol MN42989, Version 3 
Appendix 7  
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 Published Protocol - MN42989 - OCREVUS - SOPRANINO - v3 - Glo
System identifier: RIM-CLIN-489536
Approval Task
Company Signatory
05-Jun-2023 12:55:42 GMT+0000
Approval Task
Deputy EU QPPV
05-Jun-2023 13:09:17 GMT+0000

SAP_001.pdf: 


STATISTICAL ANALYSIS PLAN APPROVAL 
 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE IV MULTICENTER, OPEN-LABEL STUDY 
EVALUATING B CELL LEVELS IN INFANTS OF LACTATING 
WOMEN WITH CIS OR MS RECEIVING OCRELIZUMAB – 
THE SOPRANINO STUDY 
PROTOCOL NUMBER: 
MN42989 
STUDY DRUG: 
Ocrelizumab (RO4964913) 
VERSION NUMBER: 
2 
IND NUMBER: 
100593 
EUDRACT NUMBER: 
2021-000063-79 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, MSc 
, PhD 
DATE FINAL: 
See electronic date stamp on the last page of this 
document 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
2 
 
TABLE OF CONTENTS 
1. 
BACKGROUND .............................................................................. 7 
2. 
STUDY DESIGN ............................................................................. 7 
2.1 
Protocol Synopsis ...................................................................... 9 
2.2 
Determination of Sample Size ................................................... 9 
2.3 
Analysis Timing .......................................................................... 9 
3. 
STUDY CONDUCT ....................................................................... 10 
3.1 
Randomization ......................................................................... 10 
3.2 
Independent Review Facility .................................................... 10 
3.3 
Data Monitoring ....................................................................... 10 
4. 
STATISTICAL METHODS ............................................................ 10 
4.1 
Analysis SETS ......................................................................... 11 
4.1.1 
Screened Set (Mothers) ........................................................... 11 
4.1.2 
Enrolled Set (Mothers) ............................................................. 11 
4.1.3 
Enrolled Set (Infants) ............................................................... 11 
4.1.4 
Full Analysis Set (Mothers) ...................................................... 11 
4.1.5 
Full Analysis Set (Infants) ........................................................ 11 
4.1.6 
Full Analysis Set (Mothers & Infants) ....................................... 11 
4.1.7 
Pharmacokinetic-Analysis Set (Mothers) ................................. 11 
4.1.8 
Pharmacokinetic-Analysis Set (Infants) ................................... 11 
4.1.9 
Safety Analysis Set (Mothers) .................................................. 11 
4.1.10 
Safety Analysis Set (Infants) .................................................... 11 
4.1.11 
Antibody Immune Response Analysis Set (Infants) ................. 12 
4.2 
Analysis of Study Conduct ....................................................... 12 
4.3 
Demographic and Baseline Characteristics ............................. 12 
4.3.1 
Mothers .................................................................................... 12 
4.3.2 
Infants ...................................................................................... 15 
4.4 
Primary endpoints Analysis...................................................... 16 
4.4.1 
Co-Primary Endpoints .............................................................. 16 
4.4.2 
Analytical Approach for Co-Primary Endpoints ........................ 18 
4.4.3 
Handling of Missing Data ......................................................... 19 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
3 
4.4.4 
Sensitivity Analysis for Primary Endpoint ................................. 19 
4.4.5 
Supplementary Analysis for Primary Endpoint ......................... 19 
4.4.6 
Subgroup Analyses for Primary Endpoints .............................. 19 
4.5 
Secondary Endpoints analyses ................................................ 19 
4.5.1 
B Cell Levels in Infants ............................................................ 19 
4.5.2 
Parameters to Evaluate the Transfer of Ocrelizumab into 
Breastmilk ................................................................................ 20 
4.5.3 
Relative Infant Dosage (RID) and Maximum Oral Daily 
Infant Dosage (MDID) .............................................................. 20 
4.5.4 
Infant Serum Concentration of Ocrelizumab ............................ 21 
4.5.5 
Infant Absolute Antibody Immune Response ........................... 21 
4.5.6 
Infant Positive Antibody Immune Response ............................ 22 
4.6 
Exploratory Endpoints .............................................................. 22 
4.6.1 
Infant Growth Velocity .............................................................. 22 
4.6.2 
Childhood Developmental Milestones ...................................... 23 
4.6.3 
Women’s Disease Activity........................................................ 24 
4.6.4 
Infant Evolution of B Cell Levels .............................................. 25 
4.6.5 
Feeding Schedule / Feeding Status ......................................... 25 
4.7 
Pharmacokinetic and Pharmacodynamic Analyses ................. 26 
4.8 
Safety Analyses ....................................................................... 26 
4.8.1 
Exposure of Study Medication ................................................. 26 
4.8.2 
Adverse Events ........................................................................ 27 
4.8.3 
Laboratory Data ....................................................................... 29 
4.8.3.1 
General Laboratory Evaluation and Reporting Conventions .... 30 
4.8.3.2 
Lymphocytes Evaluation .......................................................... 31 
4.8.3.3 
Serum Antibody Titers Evaluation ............................................ 31 
4.8.4 
Vital Signs ................................................................................ 31 
4.8.5 
Prior and Concomitant Medications ......................................... 31 
4.9 
Missing Data ............................................................................ 31 
4.10 
Interim Analyses ...................................................................... 31 
5. 
CHANGES TO PLANNED ANALYSIS .......................................... 32 
6. 
REFERENCES.............................................................................. 33 
 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
4 
LIST OF FIGURES 
Figure 1 
Overview of Study Design ............................................................. 8 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 34 
Appendix 2 
Schedule of Assessments: Screening Through the End of 
Treatment Period ........................................................................ 42 
Appendix 3 
B-Cell Reference Ranges by Week of Life:  Absolute and 
Percentage Counts ..................................................................... 52 
Appendix 4 
Age-Specific Reference Ranges for Absolute Count (n × 
106/L) of Lymphocyte Subsets .................................................... 53 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADID 
Average Oral Daily Infant Dosage 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AIRI 
Antibody Immune Response Analysis Set of Infants 
ALT 
Alanine Transaminase 
ASQ 
Ages and Stages Questionnaire 
AST 
Aspartate Transaminase 
ATC 
Atomic Therapeutic Chemical 
AUC 
Area Under the Milk Concentration-Time Curve 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CIS 
Clinically Isolated Syndrome 
CNS 
Central Nervous System 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMT 
Disease Modifying Therapy 
DTaP 
Diphtheria, Tetanus, and Pertussis 
eCRF 
Electronic Case Report Form 
EDSS 
Expanded Disability Status Scale 
FAS 
Full Analysis Set 
FASI 
Full Analysis Set Infants 
FASM 
Full Analysis Set Mothers 
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
Hib 
Hemophilus Influenzae type b 
ICE 
Intercurrent Event 
Ig 
Immunoglobulin 
IRR 
Infusion-Related Reaction 
IU 
International Unit 
LLN 
Lower Limit of Normal 
LMP 
Last Menstrual Period 
mAb 
Monoclonal Antibody 
MDID 
Maximum oral Daily Infant Dosage 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
Measles, Mumps, and Rubella 
MS 
Multiple Sclerosis 
NCI 
National Cancer Institute 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
6 
Abbreviation 
Definition 
NK 
Natural Killer 
PASI 
Pharmacokinetic Analysis Set Infants 
PASM 
Pharmacokinetic Analysis Set Mothers 
PCV-13 
13-Valent Pneumococcal Conjugate Vaccine 
PK 
Pharmacokinetic 
PPMS 
Primary Progressive Multiple Sclerosis 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RRMS 
Relapsing Remitting Multiple Sclerosis 
SAE 
Serious Adverse Event 
SAFI 
Safety Analysis Set of Infants 
SAFM 
Safety Analysis Set of Mothers 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SPMS 
Secondary Progressive Multiple Sclerosis 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
7 
1. 
BACKGROUND 
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and degenerative 
disease of the central nervous system (CNS) that affects approximately 1 million people 
in the United States (US) and 2.8 million worldwide. 
Ocrelizumab is a recombinant humanized monoclonal antibody (mAb) that selectively 
targets and eliminates CD20-expressing B cells, 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. 
Given the unmet need for women with MS who may wish to breastfeed but are at high 
risk of post-partum relapses, and given the available evidence of minimal transfer of 
rituximab into breastmilk, a dedicated prospective interventional study to specifically 
evaluate the transfer of ocrelizumab into breastmilk and the corresponding 
pharmacodynamic effects in infants is therefore required, and justified.  This study 
(SOPRANINO) is part of the Sponsor’s broader research effort to investigate the 
benefit-risk of exposure to ocrelizumab during pregnancy and lactation. 
2. 
STUDY DESIGN 
This is a prospective, multicenter, open-label study in lactating women with clinically 
isolated syndrome (CIS) or MS (in line with the locally approved indications) who 
decided together with their treating physician to continue on, or start treatment with, 
OCREVUS (ocrelizumab) post-partum despite ocrelizumab currently not being 
recommended during lactation. 
This study will enroll at least 10 women with CIS or MS who are breastfeeding or 
planning to breastfeed.  Laboratory and clinical assessments will be performed as 
described in the Schedule of Assessments presented in Appendix 2. 
The study will consist of the following periods: 
 
Screening period 
 
Treatment and sampling period 
 
Vaccination period 
 
Figure 1 presents an overview of the study design.  The schedule of assessments is 
provided in Appendix 2. 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
8 
Figure 1 Overview of Study Design 
 
Samples and visits at Days 14, 15 and 21 apply only to patients initiating treatment with 
ocrelizumab at 2  300 mg separated by a 14-day interval. 
ASQ-3  Ages and Stages Questionnaire, version 3; CIS  Clinically isolated syndrome; LMP  last 
menstrual period; MS  Multiple Sclerosis; OCR  Ocrelizumab. 
 
Study description:  In this prospective, multicenter, open-label study, lactating women with CIS 
or MS (in line with the locally approved indications) who decided together with their treating 
physician to continue on, or start treatment with, commercial ocrelizumab post-partum will enter a 
screening period, which may be started during the third trimester of pregnancy and continue 
until 24 weeks post-partum.  Women who have delivered a healthy term infant and made a 
decision to breastfeed their infant will be enrolled if they and their infants fulfil the respective 
eligibility criteria.  Women resuming treatment with ocrelizumab post-partum will be included only 
if the last exposure to ocrelizumab occurred more than 3 months before the LMP (i.e., women 
without potential fetal exposure).  In the 60-day ( 2 days) treatment and sampling period, 
women will receive the ocrelizumab dose regimen as per the locally-approved label, at any point 
between Week 2 and Week 24 post-partum.  The first dose of ocrelizumab may be administered 
as two 300-mg infusions separated by 14 days (for those initiating ocrelizumab) or as a single 
600-mg infusion (for those resuming ocrelizumab).  For women where a decision not to 
administer a second 300 mg infusion is taken after enrolment, continuation in the study will be 
allowed.  Women referred by healthcare professionals to participate in the trial may receive 
ocrelizumab treatment at their neurologist’s site as part of their standard of care treatment.  
Laboratory and clinical assessments will be performed at the designated visits. 
 
Women will collect their breastmilk samples over several time points up to 60 ( 2) days 
after the first post-partum ocrelizumab infusion, reserving 5 mL at each sampling point 
for analysis of ocrelizumab concentrations.  Infant blood samples will be collected at Day 
30 ( 2 days) after the first post-partum ocrelizumab infusion (regardless of whether 
women receive a 600 mg or a 2  300 mg dose).  Infant blood samples may be collected 
at home by a visiting nurse, if not collected at the clinical site during a study visit.  In the 
vaccination period, infants will continue to 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 for example, the pediatrician as part of routine postnatal care, may also be used).  
Infant laboratory assessments will be performed 1 month ( 30 days) after the first dose 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
9 
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, to evaluate whether infants are able to mount humoral 
immune responses to clinically-relevant vaccines, and for measurement of B-cell levels.  
A structured telephone interview will be conducted by site personnel post-partum 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 mother 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.  Women who decide to 
discontinue the study (this includes discontinuation of either the mother or the infant) will 
be invited to attend an early study discontinuation visit as soon as possible (this visit 
may be conducted virtually or by telephone). 
Further details of the procedures during each period can be found in the protocol. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1 – please refer here for the list of objectives and 
corresponding endpoints.  For additional details, see the Schedule of Assessments in 
Appendix 2. 
2.2 
DETERMINATION OF SAMPLE SIZE 
There is no formal sample size calculation, as no confirmatory hypothesis testing is 
planned.  The primary analysis will be descriptive.  The study will include at least 
10 women with CIS or MS (in line with the locally approved indications) who are 
breastfeeding or planning to breastfeed. 
With 10 infants, a precision (width of the two-sided 95% CI) of 0.443 is expected if one 
event is observed (defined as B cells below the lower limit of normal [LLN]) and a 
precision of 0.531 if two events are observed in the study.  If no event is observed during 
the study, there is a 95% confidence that the event rate is below 0.31. 
2.3 
ANALYSIS TIMING 
The primary analysis will be conducted after the last breastmilk sample collection at the 
end of the 60-day Treatment and Sampling Period. 
The full analysis, including analysis of the vaccination response in infants, will be 
conducted at the end of the 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 Measles Mumps and Rubella (MMR) vaccine, or at month 13 of age 
[+30 days] if MMR vaccine is not planned to be administered) for the last infant. 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MN42989 
10 
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. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION  
No randomization, treatment assignment or blinding is planned. 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable to this study. 
3.3 
DATA MONITORING 
There is no Independent Data Monitoring Committee (IDMC) planned for this study. 
4. 
STATISTICAL METHODS 
The analysis of this open-label study will be primarily based on descriptive statistical 
methods.  Unless otherwise specified, statistical tests will be exploratory in nature. 
Corresponding 95% confidence interval (CI) will be presented as appropriate.  No 
correction for multiple testing will be applied. 
For continuous variables, descriptive statistics (e.g., number of patients [n], mean, 
standard deviation [SD], median, 25th and 75th percentiles, minimum, maximum) will be 
calculated and summarized. 
For categorical variables, the number and percentage in each category will be displayed. 
Unless specified otherwise, values at the mother’s first ocrelizumab infusion visit (which 
may take place any time between Week 2 and Week 24 post-partum) will be considered 
as baseline for all analyses. For analyses in the infant, date of birth will be considered as 
baseline. 
Note that the protocol’s Schedule of Assessments (see Appendix 2) defines the day of 
first post-partum ocrelizumab administration as Day 0, whereas per the Clinical Data 
Interchange Standards Consortium (CDISC) standards the analysis defines it as Day 1, 
i.e., Study Day  Date of assessment – Day of first post-partum ocrelizumab dose + 1.  
Study day will be defined in the footnotes of outputs as appropriate.  The primary 
analysis time point will be described as the “Day 30 Visit” to highlight that it refers to the 
visit label defined in the protocol rather than the derived study day for analysis, since in 
this case the derived Study Day  31. 
The analyses outlined in this Statistical Analysis Plan (SAP) supersede those specified 
in the protocol. 


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4.1 
ANALYSIS SETS 
4.1.1 
Screened Set (Mothers) 
All mothers who had informed consent signed. 
4.1.2 
Enrolled Set (Mothers) 
All mothers who were enrolled into the study. 
4.1.3 
Enrolled Set (Infants) 
All infants who were enrolled into the study. 
4.1.4 
Full Analysis Set (Mothers) 
The full analysis set of mothers (Full Analysis Set Mothers [FASM]) will include all 
enrolled mothers who receive any post-partum dose of ocrelizumab. 
4.1.5 
Full Analysis Set (Infants) 
The full analysis set of infants (FASI) will include all the infants of women in the FASM 
population. 
4.1.6 
Full Analysis Set (Mothers & Infants) 
The full analysis set (FAS) will include the combined population of infants and mothers in 
the FASI and FASM respectively. 
4.1.7 
Pharmacokinetic-Analysis Set (Mothers) 
The pharmacokinetic (PK) analysis set of mothers (PASM) will include all women in the 
FASM with a sufficient number of ocrelizumab concentration samples from breastmilk to 
allow calculation of PK parameters.  This analysis set will be used to estimate the PK 
parameters of ocrelizumab in the breastmilk of lactating women with CIS or MS receiving 
ocrelizumab post-partum. 
4.1.8 
Pharmacokinetic-Analysis Set (Infants) 
The PK analysis set of infants (PASI) will include all infants in the FASI with a serum 
sample to allow measurement of ocrelizumab concentration.  This analysis set will be 
used to estimate the serum concentration of ocrelizumab in the infant due to 
ocrelizumab transfer from the mother to the infant via breastmilk. 
4.1.9 
Safety Analysis Set (Mothers) 
The safety analysis set of mothers (SAFM) will be the same as the FASM. 
4.1.10 
Safety Analysis Set (Infants) 
The safety analysis set of infants (SAFI) will be the same as the FASI. 


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4.1.11 
Antibody Immune Response Analysis Set (Infants) 
The antibody immune response analysis set of infants (AIRI) will include all infants in the 
SAFI for whom any serum titers of antibody immune response to vaccinations are 
available.  This analysis set will be used to analyze humoral immune responses to 
common childhood immunizations. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Patient disposition information will be summarized separately for the mother and infant, 
as: the reason and number of screen failures (mother only), the number enrolled, in the 
respective FAS population, in the respective safety analysis set (SAF) population, 
completed the treatment and sampling period, discontinued from treatment and sampling 
period and the reasons for discontinuation, completed the vaccination period, 
discontinued study and the reasons for study discontinuation. 
Disposition information will be listed for mother/infant pairs in a single combined listing. 
Mothers and infants who discontinued from the treatment and sampling period will be 
listed including reasons for discontinuation. 
Time on study (weeks) will be summarized for mothers and infants, and calculated as: 
(date of last assessment* – date of mother’s 1st post-partum ocrelizumab dose + 1) / 7. 
* Date of last assessment for a subject is defined as the maximum of study 
completion/discontinuation date and the latest recorded date in all CRF and non-CRF data. 
 
Major protocol deviations, including deviations of inclusion/exclusion criteria, will be 
summarized in the FAS of mother/infant pairs. 
The number enrolled by site and country will be summarized in the enrolled population of 
mother/infant pairs.  
4.3 
Demographic and Baseline Characteristics 
4.3.1 
Mothers 
The following demographic, MS history, baseline disease characteristics of mothers will 
be summarized and listed in the FASM, unless otherwise stated: 
Demographic and Baseline Characteristics 
 
Age at screening (years) as continuous and categorical (18 to  30, >30 
to  35, >35 to  40, >40) 
 
Self-reported race and ethnicity 
 
Height (cm), weight (kg), and Body Mass Index (BMI: kg/m²) 
 
Smoking history (never, current, former) 
 
If previous smoker, time (years) since last use 


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 
Alcohol use history (never, current, former) 
 
If previous user of alcohol, time (years) since last use 
 
Number of weeks post-partum 
 
Fertility status (listing only) 
 
Multiple Sclerosis History 
 
Medical condition (Relapsing Remitting Multiple Sclerosis [RRMS], Secondary 
Progressive Multiple Sclerosis [SPMS], Primary Progressive Multiple Sclerosis 
[PPMS], CIS) 
 
Duration (years) since onset of MS symptoms and its category (  3 years, >3 
to   5 years, >5 years to   10 years, >10 years to  15 years, > 15 years) 
 
Duration (years) since MS diagnosis and its category (  3 years, >3 to 
 5 years, >5 years to  10 years, >10 years to  15 years, > 15 years) 
 
Expanded Disability Status Scale (EDSS) details up to 1 year prior to 
pregnancy  
 
Number of EDSS assessments and its category (0, 1,   2) 
 
Most recent EDSS score 
 
Change in EDSS score from last pre-baseline measurement (up to 1 year 
before LMP) to baseline 
 
Multiple Sclerosis History - Relapse 
 
Number of relapses up to 1 year prior to pregnancy and its category (0, 1, 2, 3 
and    4) 
 
Women with relapses up to 1 year prior to pregnancy (Yes, No) 
 
Duration (months) since last onset of MS relapse prior to enrollment and its 
category ( 6 months,   6 and  12 months,   12 and  18 months,   18 months) 
 
If the date of the relapse is completely missing or if only the year is available, the patient 
will be excluded from the analysis as appropriate.  If the day is missing but the month is 
available, it will be imputed to the first day of the month. 
Multiple Sclerosis History - Prior Disease Modifying Therapies Use 
 
Number of Disease Modifying Therapies (DMTs) used prior to pregnancy (1, 2, 
3 and >3) 
 
Type of DMTs used prior to pregnancy 
 
Number of DMTs used during pregnancy (1, 2, 3 and   3) 
 
Type of DMTs used during pregnancy 
 
Number of DMTs used post-partum but before baseline (1, 2, 3 and >3) 


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 
Type of DMTs used post-partum but before baseline 
 
Number of patients by the most recent DMT 
 
Reason for discontinuing most recent DMT 
 
Duration of the most recent DMT as continuous and categorical (6 months, >6 
and   12 months, >12 and 24 months, >24 months) 
 
Time (months) from last DMT to LMP prior to study 
 
Time (months) from last DMT to first ocrelizumab prior to study 
 
Multiple Sclerosis History - Prior Ocrelizumab Use 
 
Received ocrelizumab prior to the study (Yes, No) 
 
Duration (months) of ocrelizumab therapy prior to enrolment 
 
Duration of ocrelizumab therapy prior to enrolment ( 6 months, >6 and 
 12 months, >12 and   24 months, >24 months) 
 
Time (months) between last ocrelizumab infusion and the last menstrual period 
(LMP) (3 to  6 months, >6- to  9 months, >9 to  12 months, >12 months) 
 
Time (months) between delivery and first post-partum ocrelizumab infusion 
 
Baseline Disease Characteristics 
 
Baseline EDSS continuous 
 
Baseline EDSS distribution: count and percent of patients corresponding to 
each observed score of EDSS at baseline 
 
For those who underwent neurological examination at baseline, any new 
clinically significant abnormalities since last exam (Yes, No) 
 
Type of abnormality for those with clinically significant abnormalities since last 
exam (disability progression independent of relapse, MS relapse, signs or 
symptoms suggestive of Progressive Multifocal Leukoencephalopathy, Other) 
 
Obstetric and Gynecological History 
 
History of previous pregnancies (Yes/No) 
 
Number of previous pregnancies (1, 2, 3, 4, >4) 
 
Previous pregnancy outcome (Full term live birth, preterm live birth, 
spontaneous abortion, still birth, therapeutic abortion, elective abortion, ectopic 
pregnancy, unknown) 
 
History of obstetrical complications during previous pregnancies (Yes/No) 
 
Medical History 
Medical history of the mother will be summarized in the SAFM by SOC and PT. For each 
previous and concurrent medical history recorded medical history (MH), the term entered 


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by the investigator describing the event (the “reported term”) will be assigned a 
standardized term (the “Preferred Term” [PT]) and assigned to a superclass term (the 
“System Organ Class” [SOC]) on the basis of the MedDRA World Health Organization 
(WHO) dictionary of terms. 
Vaccination History 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and non-
SARS-CoV-2 vaccination history will be summarised in the SAFM overall and split by the 
period prior to infant’s birth and before/after LMP and after infant’s birth.  Where time 
period cannot be determined due to completely or partially missing date, it will be 
imputed to before infant’s birth. 
SARS-CoV-2 vaccination history will also be listed in the SAFM, including the following: 
 
Manufacturer name (first, second and, if applicable third dose and any booster 
dose(s)) (Pfizer/BioNTech Covid-19 vaccine, Moderna Covid-19 vaccine, Astra 
Zeneca Covid-19 vaccine, Johnson & Johnson Covid-19 vaccine, Other) 
 
Type of vaccine for each dose (mRNA vaccine, Viral Vector Vaccine, 
Inactivated Vaccine, Other) 
 
Timepoint of last COVID-19 vaccination prior to enrollment (>6 months before 
pregnancy,   6 months before pregnancy, 1st trimester, 2nd trimester, 3rd 
trimester,  6 months post-partum, >6 months post-partum) 
Other vaccination history (vaccines other than SARS-CoV-2) will also be listed in the 
SAFM. 
4.3.2 
Infants 
The following baseline characteristics of infants will be summarized and listed in the 
FASI, unless otherwise stated: 
Characteristics at Birth 
 
Details of birth (vaginal delivery, vaginal delivery - forceps/vacuum instrumental, 
cesarean – scheduled, cesarean – emergency) 
 
Gestational age (weeks) 
 
Sex (male, female) 
 
Weight (kg) 
 
Length (cm) 
 
Head circumference (cm) 
 
Apgar score – 1 minute 
 
Apgar score – 5 minute 
 
Apgar score – 10 minute 


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 
Congenital anomalies 
 
Characteristics at Screening 
 
Age (weeks) 
 
Sex (male, female) 
 
Weight-for-Age percentile categories 
 
Length/Height-for-Age percentile categories 
 
Head Circumference-for-Age percentile categories 
Characteristics at Baseline 
 
Sex (male, female) 
 
Age (weeks) 
 
Exposure via breastmilk (months) 
 
Medical History 
Medical history of the infant will be summarized in the SAFI by System Organ Class 
(SOC) and preferred term (PT), following the same approach as previously described for 
medical history of the mother. 
Vaccination Detail 
Vaccination details of the infant will be listed in the SAFI. 
4.4 
PRIMARY ENDPOINTS ANALYSIS 
4.4.1 
Co-Primary Endpoints 
The co-primary endpoints are: 
1. 
Proportion of infants with B cell levels (CD19+ cells, absolute counts in blood) 
below the LLN, measured at Day 30 Visit after the mother’s first ocrelizumab 
post-partum infusion 
2. 
Estimated average oral daily infant dosage (ADID), calculated as the 
ocrelizumab average milk concentration over 60 days multiplied by an 
estimated infant milk intake of 150 mL/kg/day. 
The estimand of the proportion of infants with B cell levels below the LLN is defined as: 
 
Population: All infants of women in the FASM population who have B cell levels 
measured at Day 30 Visit after the mother’s first ocrelizumab post-partum 
infusion (FASI) 


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 
Variable: Proportion of infants with B cell level (CD19+ cells, absolute counts in 
blood) below the age-adjusted LLN, measured at Day 30 Visit after the mother’s 
first ocrelizumab post-partum infusion. 
 
Treatment: Commercial ocrelizumab of the mother (potential exposure via 
breastmilk). 
 
Handling of Intercurrent Events (ICEs): 
1. 
Incomplete dosing, including delayed second (300 mg) ocrelizumab 
infusion: all the B cell data will be included in the analysis. 
2. 
Infant did not receive any breastmilk before B cell measurement during the 
entire 30-day period after the mother’s first ocrelizumab post-partum 
infusion: B cell data will be excluded from the analysis. 
3. 
Mother used other DMT during breastfeeding before B cell measurement 
on Day 30 Visit post ocrelizumab infusion 1: B cell data will be excluded 
from the analysis. 
4. 
Mother used other medication before B cell measurement on Day 30 Visit 
post ocrelizumab infusion 1 that is not allowed by protocol during 
breastfeeding: B cell data will be excluded from the analysis. 
5. 
Infant’s blood sample collected before assessment window (i.e. before day 
28, which is before Analysis Study Day 29): Data will be excluded from the 
analysis. 
6. 
Infant’s blood sample collected after the assessment window: B cell data 
might be included or excluded depending on the cause of the delay and 
schedule of delayed visit: 
i. Delayed due to operational reason and sample is collected more 
than 8 days after the assessment window (i.e. > Day 40, which 
is > Analysis Study Day 41): B cell data will be excluded. 
ii. Delay due to illness of infant: sample collected between 32 days 
and 40 days while infant has an illness /or recovered from an 
illness (which is between Analysis Study Days 33 and 41): B cell 
data will be excluded on a case-by-case basis if the illness is likely 
to confound the B cell data. 
7. 
Infant's blood sample collected while infant has an illness: B cell data will 
be excluded on a case-by-case basis if the illness is likely to confound the 
B cell data.  
B-cell reference ranges by week of life (absolute and percentage counts) are 
defined by Borriello et al. 2022 (Appendix 3).  B cell data being confounded with 
illness will be determined by clinical team in a blinded manner before conducting 
the primary analysis.  


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 
Population-level summary: The number and proportion of infants with B cell 
levels below LLN will be reported with the two-sided Clopper-Pearson 95% CI; 
no formal statistical testing will be done. 
The estimand of the ADID in breastmilk is defined as: 
 
Population: All women in the FASM population who provide any breastmilk 
samples (PASM). 
 
Variable: Average oral daily infant dosage (ADID), calculated as the arithmetic 
mean of the mother’s daily ocrelizumab milk concentration over 60 days post 
ocrelizumab infusion 1 multiplied by an estimated infant milk intake of 
150 mL/kg/day.  For example, arithmetic mean of the mother’s daily ocrelizumab 
breastmilk concentration over 60 days (A)  20 ng/mL, assumed fixed daily milk 
intake (B)   150 ml/kg, observed weight of infant at Day 30 visit (C)   3kg. 
Average oral Daily Infant Dosage (ADID)   A x B x C  20 ng/mL x 150 mL/kg x 
3kg  9,000 ng  0.009 mg  9 g. 
 
Treatment: Commercial ocrelizumab. 
 
Handling of Intercurrent Events (ICEs): 
1. 
Incomplete dosing, including delayed second (300 mg) ocrelizumab 
infusion: all the ADID data will be collected and included in the analysis.  
No adjustments based on actual dose will be made. 
2. 
Mother used other DMT during breastfeeding: ADID data will be included. 
3. 
Mother used other medication not allowed by protocol during 
breastfeeding: ADID data will be included in the analysis. 
4. 
Mother has mastitis infection during the sample collection period: ADID 
data will be included from milk samples obtained from the non-infected 
breast (in case of bilateral mastitis, breastmilk sampling will be interrupted 
until the infection resolves). 
 
 
Population-level summary: Summary statistics together with two-sided 95% CI for 
the mean will be reported; no formal statistical testing will be done. 
 
4.4.2 
Analytical Approach for Co-Primary Endpoints 
The number and proportion of infants with B cell levels below the LLN at Day 30 after the 
mother’s first ocrelizumab post-partum infusion will be presented in the FASI, including 
Clopper Pearson 95% CI.  A corresponding listing will be presented for B cell levels 
(absolute count) at Day 30, including whether any ICEs led to exclusion of subject’s data 
from the analysis. 
Summary statistics for the ADID will be presented in the PASM, including 95% CIs for 
the mean based on the t-distribution.  Average oral daily infant dosage will be calculated 


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over all days for which measurements are available, assuming any missing assessments 
are missing at random.  Breastmilk ocrelizumab concentrations below the limit of 
quantification (BLQ) will be imputed to zero for the calculation of summary statistics.  A 
corresponding listing will be presented, including whether any ICEs led to exclusion of 
subject’s data from the analysis. 
4.4.3 
Handling of Missing Data 
No data will be imputed unless otherwise stated.  Every effort will be made to ensure all 
samples with all supporting information are collected for B cell measurement. 
4.4.4 
Sensitivity Analysis for Primary Endpoint 
For the primary endpoint of the proportion of infants with B cell levels below the LLN, 
measured at Day 30 after the mother’s first ocrelizumab post-partum infusion, a 
sensitivity analyses will be performed including those samples collected outside the 
assessment window as well as those taken while infant has an illness. 
4.4.5 
Supplementary Analysis for Primary Endpoint 
No supplementary analyses are planned for the estimation of proportion of infants with 
B cell levels below the LLN. 
For the estimation of ADID in the breastmilk, the following supplementary analyses may 
be performed: 
 
ADID will only be calculated in cases where the complete dose of ocrelizumab 
was administered. Any subjects experiencing ICE 1 (incomplete dosing) will 
therefore be excluded from this supplementary analysis. 
 
4.4.6 
Subgroup Analyses for Primary Endpoints 
Subgroup analyses will be performed for the primary endpoint of the proportion of infants 
with B cell levels (CD19+ cells, absolute counts in blood) below the LLN, measured at 
Day 30 after the mother’s first ocrelizumab post-partum infusion.  Analysis will be 
presented for the following subgroups: 
 
The first dose of ocrelizumab post-partum (1x600mg, 2x300mg) 
 
Type of feed (breast milk, partial breast milk/infant formula) 
 
4.5 
SECONDARY ENDPOINTS ANALYSES 
4.5.1 
B Cell Levels in Infants 
B cell levels (CD19+ cells, absolute counts and percentage of lymphocytes) in infants at 
Day 30 after the mother’s first ocrelizumab post-partum infusion will be summarized 
descriptively in the FASI, irrespective of the occurrence of any ICEs identified for the 
primary endpoint. 


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4.5.2 
Parameters to Evaluate the Transfer of Ocrelizumab into 
Breastmilk 
The area under the milk concentration-time curve (AUC) of ocrelizumab in mature 
breastmilk (i.e., milk produced after Day 14 post-partum) over 60 days after the first 
post-partum ocrelizumab infusion will be calculated using the following time points 
depending on the dosing schedule: 
 
If receiving 1x600 mg: before infusion and at 24 hours (Day 1), 7 days, 30 days 
and 60 days post-infusion 
 
If receiving 2x300 mg: before infusion 1 and at 24 hours (Day 1), 7 days, 
14 days, 15 days (24 hours after infusion 2), 21 days, 30 days and 60 days 
post-infusion 1 
 
Summary statistics will be presented in the PASM for the following PK parameters of 
ocrelizumab in the breastmilk measured over 60 days after the mother’s first postpartum 
ocrelizumab infusion, irrespective of the occurrence of any ICEs identified for the primary 
endpoint: 
 
Area under the milk concentration-time curve of ocrelizumab in mature 
breastmilk (AUC) 
 
Average ocrelizumab milk concentration (Cmean) 
 
Peak ocrelizumab milk concentration (Cmax) 
 
Time to reach peak milk concentration (tmax, days) 
 
Summary statistics for each parameter will be presented in the PASM, irrespective of the 
occurrence of any ICEs identified for the primary endpoint.  A corresponding listing will 
be produced.  
For summary stats of all PK parameters other than AUC, concentrations reported as 
BLQ are set to zero.  For AUC calculation, BLQ values before the first measurable 
concentration are set to zero, and to missing after the last measurable concentration. 
Other PK and exposure parameters may be calculated and summarized as appropriate, 
based on the data obtained. 
Subject-level plots of the concentration of ocrelizumab in breastmilk over time will be 
produced in the PASM. 
4.5.3 
Relative Infant Dosage (RID) and Maximum Oral Daily Infant 
Dosage (MDID) 
The estimated maximum oral daily infant dosage (MDID) will be calculated at the subject 
level as the peak ocrelizumab milk concentration measured over 60 days after the 
mother’s first post-partum ocrelizumab infusion multiplied by an estimated infant milk 
intake of 150 mL/kg/day. 


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The average relative infant dose (RID, %) over 60 days will be calculated as the ADID 
(g) divided by the average maternal dosage (g) over 60 days multiplied by 100.  
i.e., 
Average Oral Daily Infant Dosage (ADID) (A) = 9 g 
Average maternal dosage over 60 days (B) = total dose / 60 = 600 mg / 60 = 10 mg = 
10,000 g 
Average RID (%) based on ADID = (A / B) x 100 = (9 / 10,000) x 100 = 0.09% 
The maximum RID (%) will also be calculated, where MDID is substituted for ADID in the 
formula above, i.e.  
Maximum RID (%) = (MDID / Average maternal dosage over 60 days) x 100 
Breastmilk ocrelizumab concentrations reported as BLQ will be imputed to zero for the 
calculation of summary statistics. 
Summary statistics for MDID, average RID and maximum RID will be presented in the 
PASM, irrespective of the occurrence of any ICEs identified for the primary endpoint. 
The analysis will be repeated for the following subgroups: 
 
The first dose of ocrelizumab post-partum (1x600mg, 2x300mg) 
 
4.5.4 
Infant Serum Concentration of Ocrelizumab 
To evaluate whether there is transfer of ocrelizumab from the mother to the infant via 
breastmilk, serum concentrations of ocrelizumab in the infant are measured 30 days 
after the mother’s first ocrelizumab post-partum infusion. 
Ocrelizumab concentrations reported as BLQ will be imputed to zero for the calculation 
of summary statistics. 
Summary statistics for the serum concentration of ocrelizumab in the infant will be 
presented in the PASI, and a corresponding listing produced. 
4.5.5 
Infant Absolute Antibody Immune Response 
The infant’s antibody (immunoglobulin [IgG]) immune response to common childhood 
immunizations with full or partial doses given prior to 1 year may include (but is not 
limited to) responses to MMR, diphtheria, tetanus, and pertussis (DTaP), Hemophilus 
influenzae type b (Hib), hepatitis B virus (HBV) and 13-valent pneumococcal conjugate 
vaccine (PCV-13), measured 1 month after the first or second dose of MMR vaccine or 
at Month 13 of age (+30 days) in case MMR vaccine is not planned to be administered. 


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Summary statistics for each serum IgG antibody titer will be presented in the AIRI, and a 
corresponding listing produced.  Results for MMR titers and other vaccine induced 
antibodies will be summarized together irrespective of whether or not the infant received 
MMR vaccine. Listings will include whether or not the mother switched to another DMT 
regardless of timing. 
4.5.6 
Infant Positive Antibody Immune Response 
The number and proportion of infants with positive humoral response (seroprotective 
titers as defined for the individual vaccine) will be presented for each IgG antibody titer in 
the AIRI population.  Analysis will be presented by total as well as by women not 
switching to another DMT vs switching to another DMT regardless of timing. 
A corresponding listing will be produced. 
Seroprotective titers are defined for each vaccine in the table below: 
Vaccine test 
Seroprotective Titer 
Bordetella pertussis antibodies, IgG 
> 1.04 COI 
Haemophilus influenzae B, IgG 
≥ 0.15 g/mL 
Anti-Diphtheria IgG(-70)CL 
≥ 0.01 IU/mL 
Anti-Tetanus Toxoid IgG(-70)RUO 
≥ 0.01 IU/mL 
13 Valent anti-pneumococcal antibody panel 
≥ 0.35 g/mL 
Anti-Measles Vir IgG(-70)CL 
≥ 120 mIU/mL 
Anti-MumpsAT Vir iGG(-70)CL 
≥ 17 U/mL 
Anti-Rub Vir IgG(-70)RUOCL 
≥ 10 IU/mL 
Anti-HBs 
≥ 10 mIU/mL 
COI  Cut-off Index; IU  International Unit IgG  immunoglobulin G. 
Source: Storsaeter et al. 1998; EMA 2015. 
 
For Tetanus and Diphtheria, a sensitivity analysis will be conducted using a 
seroprotective threshold of   0.1 International Unit (IU)/mL for infants receiving a 4th 
dose at least one month prior to the titer assessment.  The   0.01 IU/mL threshold will 
still be used for those only receiving 3 doses.  
4.6 
EXPLORATORY ENDPOINTS 
4.6.1 
Infant Growth Velocity 
Infant growth velocity will be assessed by recording the infant’s weight (kg), height (cm) 
and head circumference (cm) at birth, and Months 2, 4, 6, 9, and 12.  Analysis will be 
based on the SAFI and includes: 
 
Actual values and change from baseline (defined as at birth) for weight, 
length/height, head circumference, and growth velocity (defined as the change 


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from baseline divided by the number of months since baseline) will be 
summarized at each age time-point (birth, and Months 2, 4, 6, 9 and 12).  
 
The weight-for-age, length/height-for-age, and head circumference-for-age 
percentiles and change from baseline percentiles at each time-point will be 
summarized.  
 
The number and percentage of infants in the 3rd, 5th, 10th, 25th, 50th, 
and >50th percentile of the WHO growth charts will be presented for weight-for-
age, length/height-for-age, and head circumference-for-age percentiles at each 
age time point.  The number and percentage of infants within 10th-90th 
percentile, and 3rd-97th percentile of the WHO growth charts will also be 
presented.  
 
Shift tables will be presented for each parameter to compare the change from 
infant’s percentile at baseline (   3rd, >3rd -   5th, >5th -   10th, >10th 
-   25th, >25th -  50th, >50th) to each age time-point (WHO 2006; WHO 2007; 
WHO 2017).  
 
Mean percentiles for weight-for age, length/height-for-age, and head 
circumference-for-age and corresponding 90% CIs will be plotted over time.  
 
Individual growth charts will be presented for each infant.  This chart will 
present the weight, length/height, and head circumference-for-age for the infant 
over time, including reference lines for the 3rd, 25th, 50th, 75th, 90th and 97th 
percentiles for weight-for-age, length/height-for-age, and head circumference-
for-age from WHO growth charts. Separate plots will be produced for each 
infant. Combined plots will also be produced for males and females separately, 
to show the trajectories of each infant on the same page. 
 
All observed assessments will be included in the analysis; no imputation for missing 
assessments will be performed.  Analyses will also be presented for the following 
subgroups: 
 
Type of feed: exclusive breast milk since birth to month 6 vs others (including 
complementary feeding [breastmilk + formula milk, in various proportions] and 
formula feeding [no breast milk]). 
 
All infant growth velocity data will be listed. 
4.6.2 
Childhood Developmental Milestones 
The infant’s developmental milestones will be assessed using the Ages and Stages 
Questionnaire version 3 (ASQ-3), in the domains of communication, gross motor, fine 
motor, problem solving, and personal-social at months 2, 4, 6, 9, and 12. 
The total score for each domain will be summarized by visit using summary statistics in 
the SAFI. 


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In addition, the number and percentage of infants with abnormal scores (Yes/No) will be 
presented in the SAFI, as per cut-offs below transcribed from the ASQ-3 User’s guide: 
ASQ-3 
questionnaire 
Area 
Communication 
Gross Motor 
Fine Motor 
Problem Solving 
Personal-
Social 
Month 2 
22.77 
41.84 
30.16 
24.62 
33.71 
Month 4 
34.60 
38.41 
29.62 
34.98 
33.16 
Month 6 
29.65 
22.25 
25.14 
27.72 
25.34 
Month 9 
13.97 
17.82 
31.32 
28.72 
18.91 
Month 12 
15.64 
21.49 
34.50 
27.32 
21.73 
ASQ-3  Ages and Stages Questionnaire version 3. 
 
Values below the respective cut-off will be classified as abnormal (i.e., further 
assessment with a professional may be needed). 
A corresponding listing will be produced. 
Only questionnaires assigned to the correct time point will be included in the main 
analysis.  If the wrong questionnaire is used for some time points in >20% infants, a 
sensitivity analysis will be performed with these data included. 
4.6.3 
Women’s Disease Activity 
To assess disease activity in women the EDSS score, a neurological examination and 
potential relapses are collected at baseline, early discontinuation and unscheduled visits 
if applicable.  This will be summarized as follows in the FASM:  
 
Relapse: 
o 
Number of relapses before/during pregnancy (defined by LMP) and after 
pregnancy (defined as after birth) will be summarized in 3-month intervals  
o 
Number and percentage of women in each category (0, 1, 2, 3 and   4) in 
3-month intervals of before/during/after pregnancy 
o 
Among women who received their last ocrelizumab within 12 months 
before the LMP:  
▪ 
Number of relapses between 6-9 months after last ocrelizumab dose 
before Baseline  
▪ 
Number of relapses in the 3 months after the first post-partum 
ocrelizumab dose. 
o 
Annualized relapse rate and 95% CI may also be presented in 3-month 
intervals if warranted by the number of data points 


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 
Presence of any clinically significant abnormalities from the neurological 
examination (Yes, No) 
 
Type of neurological abnormality (disability progression independent of relapse, 
MS relapse, signs or symptoms suggestive of Progressive Multifocal 
Leukoencephalopathy, Other) 
 
Corresponding listings will be produced for relapses, EDSS, neurological examination 
findings. 
4.6.4 
Infant Evolution of B Cell Levels  
To evaluate the evolution of B cell levels over the first year of life, B cell levels (CD19+ 
cell, absolute counts and percentage of lymphocytes) are collected in the infant at 
Day 30 Visit and 1 month after the first dose of MMR vaccine or at Month 13 of age if 
MMR vaccine is not planned to be administered. 
Summary statistics for the mean absolute values and percentage change from Day 30 
will be presented at each visit (Day 30, 1 month after first MMR vaccine, Month 13 of 
age if MMR vaccine is not administered) for absolute CD19+ cell counts and percentage 
of lymphocytes based on the FASI, irrespective of the occurrence of any ICEs identified 
for the primary endpoint. 
The proportion of infants with CD19+ B cell levels below LLN, and summary statistics for 
the result, will be presented by visit (Day 30, Month 13). 
Subject profile plots (one line per infant) will be used to display the trajectory of CD19+ 
cell levels (absolute counts and percentage of lymphocytes) over time in the FASI.  The 
Y axis will be the absolute cell count or percentage of lymphocytes, and the X axis will 
be age in weeks.  Lines will be plotted based on the actual age (i.e., not pooled into age 
categories).  The age-specific LLN and ULN (see Appendix 3) for CD19+ cell counts and 
percentage of lymphocytes will be overlayed. 
All B cell data collected will be listed.  This listing will flag cases where absolute cell 
counts at each visit fall below the age-specific LLN for CD19+ (based on Borriello et al. 
2022 [see Appendix 3]), and for CD3, CD4, CD9 and CD16+56 (based on Tosato et al. 
2015 [see Appendix 4]). 
4.6.5 
Feeding Schedule / Feeding Status 
The following Feeding Schedule Diary data will be presented by Study Day in the FASM 
(noting that Study Days 13, 14, 15, 16, 20, 21 and 22 should only be completed for 
subjects who receive 2  300 mg ocrelizumab infusions in 2 separate visits): 
 
Number and proportion with each type of feed (breastmilk, partial 
breastmilk/infant formula, other feeds such as baby food) 
 
Mean number of breastmilk feeds 
 
Mean number of formula milk feeds 


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 
Mean number of other feeds (baby food) 
 
After the 60-day sample period, woman may switch to another DMT and continue to 
breastfeed, this will be summarized as follows in the FASM: 
 
Number and proportion with each type of feed (breastmilk, partial 
breastmilk/infant formula, other feeds such as baby food) at Months 2, 4, 6, 9, 
and 12, by whether or not they switched to another DMT, regardless of timing 
 
A corresponding listing will be produced. 
4.7 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Pharmacokinetic and pharmacodynamic (B cells) analyses for ocrelizumab in the 
breastmilk and serum are described elsewhere for the primary and secondary endpoints 
(see Sections 4.4 and 4.5). 
4.8 
SAFETY ANALYSES 
The safety outcome measures to be analyzed comprise the following: incidence and 
nature of all adverse events (AEs), including findings on vital sign measurements, 
neurological examinations, clinical laboratory tests, and concomitant medications. 
All safety analyses will be conducted on applicable data collected from the first post-
partum ocrelizumab infusion until the end of the study.  The safety analysis will be 
performed on the SAFM and infants (SAFI) separately. 
4.8.1 
Exposure of Study Medication 
Definitions 
Dose: Ocrelizumab dose is given as one infusion or two infusions administered 2 weeks 
apart.  Patients will be considered to have received a Dose of treatment if at least part of 
one infusion of that Dose (either Day 1 or Day 15 for dual infusions) was given. 
Treatment duration (in weeks) for a woman will be calculated as follows: 
[(Date of last contact*  Date of first post-partum dose) 1] / 7 
*Earliest  1) date of last OCR dose plus risk window of 6 months (182 days)  
2) date of death 
3) clinical cut-off date 
Exposure Analysis 
The following measures of exposure of ocrelizumab will be summarized in the SAFM 
using descriptive statistics: 
 
Number of patients completing each dose type (Dose 1, full dose; Dose 1 split 
dose #1; Dose 1, split dose #2) 
 
Treatment duration (weeks) 


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 
Number of doses received (Day 1 and Day 15 infusions are considered as one 
dose) 
 
Total cumulative dose (mg) 
 
A corresponding listing will be produced. 
The analysis of exposure to ocrelizumab in infants (as measured via concentration in the 
breastmilk, and also directly from serum samples) is described previously as part of the 
primary and secondary endpoints. 
4.8.2 
Adverse Events 
All summaries of AEs will be based on the respective safety population for mothers and 
infants, and will include AEs occurring between the mother’s first post-partum ocrelizumab 
infusion and the end of the study.  Only treatment-emergent AEs (TEAEs) will be analyzed 
and the terms TEAE and AE will be used interchangeably. 
For each recorded adverse event (AE), the term entered by the investigator describing the 
event (the “reported term”) will be assigned a standardized term (the “Preferred Term” 
[PT]) and assigned to a superclass term (the “System Organ Class” [SOC]) on the basis 
of the Medical Dictionary for Regulatory Activities (MedDRA) WHO dictionary of terms 
version 27.1. 
Definitions 
Treatment-emergent adverse event (TEAE): AEs with an observed or imputed date of 
onset on or after the start date of trial treatment.  If the onset date of the AE is prior to the 
day of first dose, the AE will be considered treatment-emergent only if the most extreme 
intensity is greater than the initial intensity (i.e., the intensity for a given AE increases and 
its end date is on or after the date of the first dose).  An AE with a completely missing, 
non-imputed start date will be assumed to be treatment emergent unless the AE has a 
complete, non-imputed end date that is prior to the date of the first dose. 
Imputation of incomplete date: in order to evaluate if an AE is treatment-emergent, 
incomplete dates will be imputed as follows: 
o If the start date is incomplete:  
 
If the day is missing, impute to 01, or to the day of first dose of 
ocrelizumab if the month and year is the same as the dosing date. 
 
If the month is missing, impute to January, or to the month of first 
dose of ocrelizumab if the year is the same as the year of dosing. 
 
If the date is completely missing, then the date will remain missing 
o If the end date is incomplete:  
 
If the day is missing, impute to the last day of the month 
 
If the month is missing, impute to December 
 
If the date is completely missing, then the date will be missing  
 


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If the imputed start date of an AE is post first dose, it is considered treatment emergent. 
If the imputed start date of an AE is prior first dose, it is considered non-treatment 
emergent. 
In case of a missing start date and an (imputed) end date prior to first dose, the AE is 
considered non-treatment emergent. 
Otherwise, the AE is considered treatment emergent. 
Serious Adverse Events (SAEs): all SAEs including serious MS relapses and serious 
Infusion Related Reactions (IRRs). 
Output Conventions 
All analyses of AE data will be performed using the PTs unless otherwise specified. 
For all summary tables, the AEs will be sorted by SOC (in decreasing order of overall 
incidence) and then by PT (in decreasing order of overall incidence).  At each level of 
summarization (at least one event, SOC and PT), patients reporting more than one AE will 
be counted only once.  For TEAEs by grade (intensity), the highest grade will be reported. 
All AE summaries will be based on TEAEs only. 
The following summary tables will be generated for mothers and infants separately: 
o Overview summary table of TEAEs, including: total number of subjects with at 
least one AE, total number of AEs, total number of SAEs, total number of deaths, 
total number withdrawn from study due to an AE, and total number of subjects 
with at least one: 
 
AE with fatal outcome 
 
SAE 
 
SAE leading to withdrawal from treatment (“Drug Withdrawn” for the 
“Action taken with ocrelizumab due to SAE/AE” field in the “Adverse 
Event/IRR” electronic Case Report Form [eCRF] form) (mothers only) 
 
SAE leading to dose modification/interruption (mothers only) 
 
Related SAE 
 
AE leading to withdrawal from treatment (mothers only) 
 
AE leading to dose modification/interruption (mothers only) 
 
Related AE 
 
Related AE leading to withdrawal from treatment (mothers only) 
 
Related AE leading to dose modification/interruption (mothers only) 
 
AE of Grade   3 
 
Infusion related reaction (IRR) (mothers only) 
 
Serious IRR (mothers only) 


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 
Infections (using the MedDRA SOC of ‘Infections and Infestations’) 
 
Serious infections 
 
Serious infections leading to withdrawal from treatment (mothers only) 
o TEAEs, by SOC and PT 
o Serious TEAEs, by SOC and PT 
o TEAEs, by Highest NCI CTCAE Grade  
o Infections, by Type and PT (identified using the Orelizumab specific Adverse 
Events Glossary of Terms) 
o IRRs, by Highest National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) grade (mothers only) 
o Infusion Related Reactions by Time of Event (During Infusion, within 24 hours after 
end of infusion) Overall and by post-partum Infusion (Dose 1 full dose, Dose 1 split 
dose 1, Dose 1 split dose 2, Dose 2) (mothers only) 
o Adverse Events of Special Interest (AESI, mothers only): 
 
Cases of potential medicine-induced liver injury that include an elevated 
alanine transaminase (ALT) or aspartate transaminase (AST) in 
combination with either an elevated bilirubin or clinical jaundice, as defined 
by Hy's law and in the protocol. 
 
Suspected transmission of an infectious agent by the study medicine, as 
defined in the protocol. 
 
All SAEs, AESIs, AEs leading to withdrawal, infections, and deaths occurring during the 
study will be listed.  For all of these listings, mothers/infants pairs will be presented ‘next 
in line’ as one row after the other in the same listing, rather than as two separate listings. 
4.8.3 
Laboratory Data 
Laboratory assessments (performed in central laboratory, except for urinalysis) will 
include the following: 
 
Hematology (Mother): hemoglobin, hematocrit, quantitative platelet count, red blood 
cell [RBC] count, white blood cell [WBC] absolute or/and differential count 
[neutrophils, eosinophils, lymphocytes, monocytes, basophils]. 
 
Serum chemistry (Mother): potassium, sodium, chloride, random glucose, AST, 
ALT, gamma-glutamyl transpeptidase [GGT], total bilirubin and creatinine. 
 
Urinalysis (Mother): 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 (Mother): Women with positive screening tests for HBV, 
determined by a positive hepatitis B surface antigen (HBsAg) result (current 


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infection) or positive hepatitis B core antibody (HBcAb) titers (previous infection) will 
be excluded. Women with documented history of HBV vaccination or positive HBsAb 
titers are eligible. 
 
Serum immunoglobulin (Ig) concentration (Mother): Quantitative measurement 
for IgG, IgM and IgA levels. 
 
Serum titers (IgG) of antibody immune responses to vaccinations (Infant): May 
include but not be limited to MMR, DTaP, Hib, HBV and PCV-13; 1 month 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. 
 
Lymphocyte subtypes (Mother & Infant): Blood samples will be collected to 
measure B-cell counts (CD19+ and B-cell subsets** [see below]), T-cell counts 
(CD3+, CD4+, CD8+), and natural killer (NK) cell counts (CD16+CD56+).  
**B-cell subsets: 
Naïve 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-, CD38bright  
Plasmablasts/Plasma cells: CD45+, CD19+, CD27+, CD38bright 
 
4.8.3.1 
General Laboratory Evaluation and Reporting Conventions 
All laboratory assessments in the mother (hematology, serum chemistry, urinalysis, 
Hepatitis B virus serology, serum immunoglobulin concentration) will be summarized in 
the SAFM or listed when applicable. 
Absolute value and change from baseline at each visit will be summarized using standard 
unit.  The baseline value for laboratory assessments summarized in mothers will be the 
last value prior to the first dose of study medication.  When laboratory data are presented 
over time, these laboratory values will be time-windowed into a common visit structure.  If 
multiple values of the same laboratory parameter occur within the same time window, the 
worst value for that parameter will be presented in the summary table. 
Unless specified otherwise, any laboratory parameters which are below the BLQ will be 
listed, for summaries a value of the LLQ/2 will be imputed.  Values above the upper limit 
of quantification will be summarized at the upper limit of quantification. 
For hematology and serum chemistry, the number and percentage of patients with 
normal/abnormal laboratory outcomes based on normal laboratory ranges will be 
summarized for each parameter and visit. For urinalysis, the number and percentage 
with each test result category will be reported for each parameter and visit. 
Corresponding patient-level listings will be produced for the following in the SAFM: 
hematology, serum immunoglobin concentration, laboratory abnormalities for 
hematology, laboratory abnormalities for serum chemistry, laboratory abnormalities for 
urinalysis. 


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4.8.3.2 
Lymphocytes Evaluation 
All lymphocytes parameters in the infants (with the exception of CD19+ cells already 
covered in the primary and secondary endpoint analyses) will be summarized using 
absolute count and change from baseline values at each visit.  All lymphocytes 
parameters in the mothers at screening will be summarized. 
Corresponding listings will also be produced for lymphocyte parameters in infants and 
mothers. 
Parameters may also be displayed graphically over time, as appropriate. 
4.8.3.3 
Serum Antibody Titers Evaluation 
The secondary endpoint analysis of serum titers (IgG) of antibody immune responses to 
vaccinations in the infant is described in Section 4.5.5. 
4.8.4 
Vital Signs 
The actual value and change from Baseline at each visit will be summarized for the 
following vital signs parameters in mothers: systolic blood pressure (mmHg), diastolic 
blood pressure (mmHg), pulse rate (beats/min), temperature (ºC). 
4.8.5 
Prior and Concomitant Medications 
Prior (defined as treatment ended before mother’s first dose of study drug) and 
Concomitant medications (defined as treatment used at any time since mother’s first 
dose of study drug) will be summarized, for mothers and infants separately, by 
frequency tables according to the Anatomic Therapeutic Chemical (ATC) classification 
system using the WHO Drug dictionary. 
Pre-infusion prophylactic treatment will be summarized by medication class in mothers, 
by frequency tables according to the ATC classification system using the WHO Drug 
dictionary. 
Corresponding listings will also be produced. 
4.9 
MISSING DATA 
All methods for handling missing data and associated sensitivity analyses are described 
above, section by section, for each endpoint.  If not otherwise specified, missing values 
are not imputed. 
4.10 
INTERIM ANALYSES 
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. 


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5. 
CHANGES TO PLANNED ANALYSIS 
The following list documents changes between the protocol-defined statistical analyses 
and those presented in the SAP: 
1. The protocol refers to the PASM as the Primary Analysis Set Mother.  This definition 
was corrected in the SAP to Pharmacokinetic Analysis Set Mother. 


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6. 
REFERENCES 
Borriello F, Pasquarelli N, Law L, et al. Normal B cell ranges in infants: A systematic 
review and meta-analysis. J Allergy Clin Immunology 2022; 150(5):1216-24. 
doi:https://doi.org/10.1016/j.jaci.2022.06.006. 
European Medicines Agency. Assessment report: Vaxelis. December 2015. Available 
from: https://www.ema.europa.eu/en/documents/assessment-report/vaxelis-epar-
public-assessment-report_en.pdf 
Storsaeter J, Hallander HO, Gustafsson LP, et al. Levels of anti-pertussis antibodies 
related to protection after household exposure to Bordetella pertussis. Vaccine 
1998;16:1907-16. 
Tosato F, Bucciol G, Pantano G, et al. Lymphocytes subsets reference values in 
childhood. Cytometry 2015; 87: 81-85. doi.org/10.1002/cyto.a.22520 
WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, 
weight-for-height: Methods and development. Geneva: World Health Organization, 
2006. 
WHO Multicentre Growth Reference Study Group: WHO Child Growth Standards: Head 
circumference-for-age: Methods and development. Geneva: World Health 
Organization, 2007. 
World Health Organization. The immunological basis for immunization series: module 4: 
pertussis. World Health Organization 2017: 
https://apps.who.int/iris/handle/10665/259388. License: CC BY-NC-SA 3.0 IGO 


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Appendix 1 Protocol Synopsis 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY EVALUATING 
B-CELL LEVELS IN INFANTS OF LACTATING WOMEN WITH CIS 
OR MS RECEIVING OCRELIZUMAB – THE SOPRANINO STUDY 
PROTOCOL NUMBER: 
MN42989 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2021-000063-79 
IND NUMBER: 
100593 
NCT NUMBER: 
NCT04998851 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
Phase IV 
INDICATION: 
Multiple Sclerosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics of ocrelizumab in the breastmilk of lactating 
women with clinically isolated syndrome (CIS) or multiple sclerosis (MS) [in line with the locally 
approved indications] treated with ocrelizumab, by assessing the concentration of ocrelizumab 
in mature breastmilk, as well as the corresponding exposure and pharmacodynamic effects 
(blood B-cell levels) in the infants.  Specific objectives and corresponding endpoints for the 
study are outlined below. 
Objectives 
Corresponding Endpoints 
Co-Primary Outcome Measure 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum present with B-cell 
depletion 
 
Proportion of infants with B-cell levels 
(CD19  cells, absolute counts in blood) below 
the LLN, measured at Day 30 after the mother’s 
first ocrelizumab postpartum infusion 
 
To evaluate the exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated ADID, calculated as the ocrelizumab 
average milk concentration over 60 days 
post-ocrelizumab infusion 1 multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
Secondary Outcome Measures 
 
To evaluate B-cell levels in 
infants of lactating women with 
CIS or MS receiving 
ocrelizumab postpartum 
 
B-cell levels (CD19  cells, absolute counts and 
percentage of lymphocytes) measured at 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 


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Objectives 
Corresponding Endpoints 
Secondary Outcome Measures (cont.) 
 
To evaluate transfer of 
ocrelizumab into breastmilk of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
AUC of ocrelizumab in mature breastmilk 
(i.e., milk produced after Day 14 postpartum) 
over 60 days after the first postpartum 
ocrelizumab infusion using the following time 
points: 
– 
If receiving 1  600 mg: before infusion and 
at 24 hours (Day 1), Day 7, Day 30 and Day 
60 post-infusion 
– 
If receiving 2  300 mg: before infusion 1 
and at 24 hours (Day 1), Day 7, Day 14, 
Day 15 (24 hours after infusion 2), Day 21, 
Day 30, and Day 60 post-infusion 1 
 
Average and peak ocrelizumab milk 
concentration as well as time to reach peak milk 
concentration, measured over 60 days after the 
mother’s first postpartum ocrelizumab infusion 
 
To evaluate the relative and 
maximum exposure to 
ocrelizumab in infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Estimated MDID calculated as the peak 
ocrelizumab milk concentration multiplied by an 
estimated infant milk intake of 150 mL/kg/day 
measured over 60 days after the mother’s first 
postpartum ocrelizumab infusion 
 
Average RID over 60 days, calculated as the 
ADID (mg/kg/day) divided by the maternal 
dosage (mg/kg/day) multiplied by 100 
Note:  Other pharmacokinetic and exposure 
parameters may be calculated as appropriate, 
based on the data obtained 
 
To evaluate whether there is 
transfer of ocrelizumab from the 
mother to the infant via 
breastmilk  
 
Serum concentration of ocrelizumab in the 
infant measured at Day 30 after the mother’s 
first ocrelizumab postpartum infusion 
 
To evaluate whether infants of 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 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 MMR, diphtheria, tetanus, 
pertussis, Hib, HBV, and PCV-13 
 
Proportion of infants with positive humoral 
response (seroprotective titers; as defined for 
the individual vaccine) to vaccines 
Safety Objectives 
 
To evaluate the safety of 
ocrelizumab in lactating women 
with CIS or MS receiving 
ocrelizumab postpartum and in 
their respective infants 
 
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 
 


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Objectives 
Corresponding Endpoints 
Exploratory Objectives 
 
To evaluate infant’s growth 
velocity and developmental 
milestones in the first year of life 
 
Assessment of growth velocity based on 
age-adjusted length, weight, head 
circumference, using monthly 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 measure disease activity in 
lactating women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Number of MS relapses during the postpartum 
period (clinical relapses) 
 
Mean change in the EDSS score from last 
pre-baseline measurement (up to 1 year before 
LMP) to baseline 
 
To evaluate the evolution of 
B-cell levels over the first year 
of life in infants of lactating 
women with CIS or MS 
receiving ocrelizumab 
postpartum 
 
Trajectory (absolute and percentage changes) 
of B-cells (CD19  cells) in the infant from 
Day 30 after the mother’s first ocrelizumab 
postpartum infusion 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 
ADID  average oral daily infant dosage; ASQ-3  Ages and Stages Questionnaire version 3; 
AUC  area under the milk concentration-time curve; CIS  clinically isolated syndrome; 
EDSS  Expanded Disability Status Scale; HBV  hepatitis B virus; Hib  Hemophilus influenzae 
type b; LLN  lower limit of normal; LMP  last menstrual period; MDID  maximum oral daily 
infant dosage; MMR  measles, mumps, and rubella MS  multiple sclerosis; PCV-
13  13-pneumococcal conjugate vaccine; RID    relative infant dose; WHO  World Health 
Organization. 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a prospective, multicenter, open-label study in lactating women with CIS or MS (in line 
with the locally approved indications) who decided together with their treating physician to 
continue on, or start treatment with, OCREVUS (ocrelizumab) postpartum despite ocrelizumab 
currently not being recommended during lactation. 
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 at least 10 women with CIS or MS who are breastfeeding or planning to 
breastfeed. 


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The study will consist of the following periods: 
 
Screening period:  After providing written informed consent, women will enter a screening 
period for eligibility assessments.  Considering that decisions on initiating or resuming 
treatment with a disease-modifying therapy (DMT) in the postpartum period are usually 
taken before or during pregnancy, screening may be conducted at any time from the third 
trimester until 24 weeks postpartum.  Final inclusion will only take place for women who 
have delivered a healthy term infant and have made a decision to breastfeed their infant 
despite ongoing ocrelizumab treatment.  General health and medical history of the infant 
will also be reviewed for eligibility. 
Women resuming treatment with ocrelizumab postpartum will be included only if the last 
exposure to ocrelizumab occurred more than 3 months before the last menstrual period 
(LMP) (i.e., women without potential fetal exposure) to exclude any interference between 
fetal exposure and exposure via lactation. 
 
Treatment and sampling period:  Women fulfilling the inclusion/exclusion criteria will receive 
the ocrelizumab dose regimen as per the locally approved label.  The first dose of 
ocrelizumab may be administered at any point between Week 2 and Week 24 postpartum, 
as an initial split dose of two 300 mg infusions (in 250 mL 0.9% sodium chloride) separated 
by 14 days or as a single 600 mg infusion (in 500 mL 0.9% sodium chloride) according to 
the local prescribing information.  For women where a decision not to administer a second 
300 mg infusion is taken after enrolment, continuation in the study will be allowed.  Dosing 
and treatment duration are at the discretion of the physicians, in accordance with local 
clinical practice and local labeling (U.S. Prescribing Information [USPI]; Summary of 
Product Characteristics [SmPC]).  If women did not experience a serious infusion-related 
reaction (IRR) with any previous ocrelizumab infusion, a shorter (2-hour) infusion can be 
administered for subsequent 600 mg doses (Summary of Product Characteristics [SmPC], 
United States Prescribing Information [USPI]).  Women referred by healthcare professionals 
(HCPs) to participate in the trial may receive ocrelizumab treatment at their neurologist’s 
site as part of their standard of care treatment. 
Maternal breastmilk samples will be collected over several time points up to 60 ( 2) days 
after the first postpartum ocrelizumab infusion at approximately the same time of day, 
although flexibility is allowed on collection timings to accommodate the mother and infant 
feeding schedule.  The only exception is the first (Day 1) post-infusion breastmilk sample 
and, in women who received a 2  300 mg dose, the second (Day 15) post-infusion 
breastmilk sample, which should be collected 24 hours after the midpoint of the infusion.  
On days of collection, milk should be expressed from both breasts until completely emptied 
using an electric breast pump.  The milk from each breast is then mixed and a sample 
(volume  5 mL) is removed for analysis.  The infant can be bottle-fed the remaining 
expressed milk.  If the infant is not usually fed using a bottle, milk may be expressed from 
one breast only.  If the mother presents with unilateral mastitis, milk should only be 
expressed from the unaffected breast, until the infection resolves.  If mastitis presents 
bilaterally (rare), breastmilk collection should be stopped until the infection resolves. 
The infant blood sample will be collected at Day 30 ( 2 days) of lactation after the first 
ocrelizumab infusion administered postpartum, i.e., regardless of whether women receive a 
600 mg or a 2  300 mg dose.  Blood samples may be collected at home by a visiting nurse, 
or at the hospital as part of study visits.  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). 
A structured telephone interview will be conducted by site personnel every 2 weeks in the 
treatment and sampling period, for a general review, and to identify and collect information 
on any changes in the woman’s and infant’s health status (including the occurrence of 
MS relapses in the mother and use of and 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. 


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 Vaccination period:  After the 60-day ( 2 days) treatment and sampling period, infants will 
continue to be followed-up for growth (age-adjusted length, weight, head circumference) 
and developmental milestones up to 12 months of age.  Growth charts (following the World 
Health Organization 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 post-natal care, may also be used. 
Infant laboratory assessments will be performed 1 month ( 30 days) after the first or 
second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13 of age 
( 30 days), in case MMR vaccine is not planned to be administered, to evaluate whether 
infants are able to mount humoral immune responses to clinically relevant vaccines, and for 
measurement of B-cell levels.  In case the mother decides to switch to another DMT or to 
stop DMT after the 60-day treatment and sampling period, the infant blood sample will still 
be collected. 
A structured telephone interview will be conducted by site personnel postpartum every 
3 months in the vaccination period (in-between ocrelizumab infusions) for a general review, 
and to identify and collect information on any changes in the woman’s and infant’s health 
status (including the occurrence of MS relapses in the mother and use of and 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 visit. 
 
Discontinuation:  Women who decide to discontinue the study (this includes discontinuation 
of either the mother or the infant; this does not apply to treatment discontinuation) will be 
invited to attend an early study discontinuation visit (which may be conducted remotely, 
i.e., virtually or by telephone) as soon as possible.  Depending on the timing of 
discontinuation, the following is recommended: 
Discontinuation before the infant blood draw at 30 ( 2) days post-infusion 1:  Collection 
of infant outcomes in the first year of life as per standard pharmacovigilance procedures 
– 
If the mother remains on treatment with ocrelizumab and decides to stop 
participating at 30 ( 2) days after the first postpartum ocrelizumab infusion, 
attempts to collect the infant sample at 30 ( 2) days should be made before 
discontinuation. 
– 
If the mother switches to another DMT, the infant sample at 30 ( 2) days should 
not be collected. 
Discontinuation after the infant blood draw at 30 ( 2) days post-infusion 1:  Collection 
of infant outcomes in the first year of life as per standard pharmacovigilance 
procedures. 
 
NUMBER OF WOMEN 
This study will enroll at least 10 women with CIS or MS (in line with the locally approved 
indications) who are breastfeeding or planning to breastfeed. 
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.  
The primary analysis will be conducted at the end of the Treatment and Sampling Period 
(Day 60 [ 2 days]). 
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 3 years.  This includes an enrolment period of approximately 
21 months and a woman’s participation period of 16 months. 


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TARGET POPULATION 
INCLUSION CRITERIA 
The following criteria must be met for study entry: 
 
An Informed Consent Form (ICF) for participation of the maternal subject and her infant 
(for collection of blood, infant demographic 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 
 
Woman is able and willing to comply with the study protocol, according to the judgment of 
the investigator, in particular: 
– 
Woman is willing to breastfeed (either exclusively, or with formula supplementation) for 
at least 60 days after the first postpartum ocrelizumab infusion (this decision is to be 
taken prior to and independent from study participation) 
– 
Woman is willing to provide breastmilk samples before and after their first and, 
if applicable, second postpartum ocrelizumab infusion 
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. 
 
Woman is between 18 and 40 years of age at screening 
 
Woman has a diagnosis of MS or CIS (in line with the locally approved indications) 
 
Woman has delivered a healthy term singleton infant ( 37 weeks gestation)  
 
Infant is between 224 weeks of age at the time of the mother’s first postpartum dose of 
ocrelizumab 
 
For women who received commercial ocrelizumab (OCREVUS) before enrolment: 
documentation that last exposure to ocrelizumab occurred more than 3 months before the 
LMP (i.e., excluded a potential fetal exposure) and was given at the approved dose of 
2  300 mg or 1  600 mg 
 
Woman agrees to use acceptable contraceptive methods or alternative methods during the 
study as described below and, if applicable, upon study treatment discontinuation, as 
defined by the local prescribing information 
– 
The following contraceptive methods are considered acceptable (failure rate  1% 
[Clinical Trial Facilitation Group (CTFG)]):  progestogen-only oral hormonal 
contraception, where inhibition of ovulation is not the primary mode of action; male or 
female condom with or without spermicide; cap, diaphragm, or sponge with spermicide; 
combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier method). 
Birth control methods that are highly effective (i.e., failure rate  1% [CTFG]) may also be 
used but are not required, and include: oral, intravaginal or transdermal combined hormonal 
contraception associated with inhibition of ovulation [unless not recommended or 
contraindicated during breastfeeding];  oral, injectable or implantable progestogen-only 
hormonal contraception associated with inhibition of ovulation; intrauterine device; 
intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; 
sexual abstinence. 
Note:  lactational amenorrhea method can be used to ensure adequate protection from an 
unplanned pregnancy, and the following three criteria must be met: 1) amenorrhea; 2) fully 
or nearly fully breastfeeding (no interval of  46 hours between breastfeeds); and 
3)  6 months postpartum.  If any of the three listed criteria change at any stage during the 
study, an alternative or additional method of acceptable contraception is required. 
 


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EXCLUSION CRITERIA 
Mothers/infants who meet any of the following criteria will be excluded from study entry: 
Exclusions related to the mother 
 
Hypersensitivity to ocrelizumab or to any of its excipients 
 
Woman received last dose of ocrelizumab  3 months before the LMP or during pregnancy 
(i.e., there was a potential fetal exposure to ocrelizumab) 
 
Active infections (note: the woman may be included once the infection is treated and is 
resolved; women with bilateral mastitis infection should not have samples collected until the 
infection is completely resolved) 
 
Prior or current history of primary or secondary immunodeficiency, or woman in an 
otherwise severely immunocompromised state.  Woman may be re-screened and included 
if condition resolves 
 
Woman 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 high risk of breast malignancies 
undergoing prophylactic treatment with drugs such as tamoxifen are excluded  
 
Woman has history of breast implants, breast augmentation, breast reduction surgery or 
mastectomy 
 
Woman has prior or current history of chronic alcohol abuse or drug abuse 
 
Woman has any medical, obstetrical or psychiatric condition that, in the opinion of the 
investigator, would compromise the woman's ability to participate in this study 
 
Treatment with a DMT for CIS or MS during pregnancy and/or first weeks postpartum, with 
the exception of formulations of interferon-beta, glatiramer acetate or pulsed corticosteroids 
 
Drugs known to transfer to the breastmilk and with established or potential deleterious 
effects for the infant, including but not limited to aspirin (risk of Reye’s syndrome), 
tetracyclines or fluoroquinolones 
 
Treatment with any investigational agent within 6 months or five half-lives of the 
investigational drug (whichever is longer) prior to the LMP, unless the investigational agent 
is ocrelizumab administered  3 months prior to the LMP in the context of a study or registry 
sponsored by Roche 
 
Exclusions related to the infant 
 
Infant is  24 weeks of age at the time of the mother’s first postpartum dose of ocrelizumab 
 
Infant has any abnormality that may interfere with breastfeeding or milk absorption, 
including but not limited to cleft palate and/or lip, congenital diaphragmatic hernia and 
esophageal atresia 
 
Infant has an active infection.  Infant may be included once the infection resolves 
 
Infant has any other medical condition or abnormality that, in the opinion of the investigator, 
could compromise the infant’s ability to participate in this study, including interference with 
the interpretation of study results 
 
Infant has any other medical condition or abnormality that, in the opinion of the investigator, 
could compromise the infant’s ability to participate in this study, including interference with 
the interpretation of study results 
 
Infant has at least one documented brief resolved unexplained event (BRUE), as defined by 
the 2016 Guidelines of the American Academy of Pediatrics 
 
Exclusions related to laboratory findings 
 
Mother with any abnormal screening laboratory value that is clinically relevant should 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. 


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 
Mother 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 (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. 
 
STUDY TREATMENT 
The study treatment is commercial ocrelizumab. 
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 IRRs.  Premedication with an antipyretic (e.g., paracetamol) may also 
be considered prior to each ocrelizumab infusion 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary analysis will be conducted on the full analysis set (all women who meet the 
eligibility criteria and received any postpartum dose of ocrelizumab) and infants of women in the 
full analysis set.  The analysis will be performed after the last breastmilk sample collection at the 
end of the 60-day treatment and sampling period. 
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 estimated average 
oral daily infant dosage will be analyzed using descriptive statistics.  Mean, corresponding 
95% CI, standard deviation, and other statistics will be presented. 
More details about missing data handling, as well as sensitivity analyses based on alternative 
imputation approaches, will be specified in the statistical analysis plan. 
DETERMINATION OF SAMPLE SIZE 
The study will include at least 10 women with CIS or MS (in line with the locally approved 
indications) who are breastfeeding or planning to breastfeed.   
With 10 infants, a precision (width of the two-sided 95% CI) of 0.443 is expected if one event is 
observed (defined as B-cells below the LLN) and a precision of 0.531 if two events are 
observed in the study.  If no event is observed during the study, there is a 95% confidence that 
the event rate is below 0.31. 
 
 














 
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APGAR  appearance, pulse, grimace, activity, and respiration; ASQ-3  Ages and Stages Questionnaire, version 3; BRUE  brief resolved 
unexplained event; 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; HCPs  Healthcare professionals; Hib  Hemophilus influenzae type b; ICF  Informed 
Consent Form; IRR    infusion-related reaction; 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; SmPC    Summary of Product Characteristics; 
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 telephone interview will not be conducted in a week where there will be an on-site visit). 
 
a Visits 2a, 3a and 4a are only applicable for women who will be receiving the first ocrelizumab dose as two 300 mg infusions. 
b The length of the screening period is variable and depends on local timings for performing some of the eligibility assessments.  It is possible that 
visit 1 (screening) is completed in one day or over several days/weeks.  Screening may be started during the third trimester of pregnancy and 
continue until 24 weeks postpartum. 
c Samples 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 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. 
d The following diagnoses are accepted:  MS or CIS (in line with the locally approved indications). 
e 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. 
f 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 baseline visit.  Demographic data will include age, self-reported race/ethnicity, and level of education.  Clinically 
significant diseases and/or surgeries and concomitant medication should also be recorded throughout the study.  Information on vaccinations 
administered to the mother during the study will be collected under concomitant medications. 
g Documentation of start of ocrelizumab (OCREVUS) therapy and date and dose of last ocrelizumab infusion prior to enrolment.  
Ocrelizumab-related information to be collected only in women who received commercial ocrelizumab prior to enrolment. 
h A complete physical examination should be performed at the screening and baseline visits and at all visits during the treatment period (results 
from examinations done as part of routine care at subject’s HCPs [obstetrician/gynecologist, pediatrician, neurologist of referred subjects] 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. 
i Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be 
recorded throughout the treatment period.  To reduce the burden of visits to mothers, results from neurological examinations done as part of 


 
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routine care may be used.  For patients referred to the investigator, results from routine visits at the woman’s neurologist may be used. 
j Women should record the volume of pumped breastmilk and indicate date and time for collection as well as whether breastmilk was pumped 
from one or both breasts.  For sampling on Day 0 (baseline), the sample should be taken before the infusion. For 24 hours post-infusion (Day 1 
and Day 15), samples are collected based on the midpoint of infusion.  For example, if the infusion began at 8 am and ended at 10 a.m., the 24-
hour sample collection would occur at 9 a.m. on the day after the infusion.  With the exception of the 24-hour (Day 1; and [for women who 
received a 2  300 mg dose] Day 15) post-infusion breastmilk collection time points, flexibility is allowed on collection timing to accommodate the 
mother and the infant feeding schedule.  If the mother presents with unilateral mastitis, milk should only be expressed from the unaffected 
breast, until the infection resolves.  If mastitis presents bilaterally (rare), breastmilk collection should be stopped until the infection resolves. 
k Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute or/and differential count (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils), and quantitative platelet count.  Chemistry will include potassium, sodium, chloride, random glucose, AST, ALT, GGT, 
creatinine, total bilirubin.  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. 
l 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. 
m 
Blood samples will be collected to measure B-cell counts (CD19   and B-cell subsets [Table 2 of the Study Protocol version 3]),T-cell counts 
(CD3 , CD4 , and CD8  ), and NK cell counts (CD16+CD56+). 
n 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. 
o In line with the dose regimen in the local label, the first dose of ocrelizumab may be administered as an initial split dose of two 300 mg infusions 
(in 250 mL 0.9% sodium chloride) separated by 14 days, or as a single 600 mg infusion (in 500 mL 0.9% sodium chloride), at any point between 
Week 2 and 24 postpartum.  For women where a decision not to administer a second 300 mg infusion is taken after enrolment, continuation in 
the study will be allowed.  Dosing and treatment duration are at the discretion of the physicians, in accordance with local cl inical practice and 
local labeling (USPI; SmPC).  If women did not experience a serious IRR with any previous ocrelizumab infusion, a shorter (2-hour) infusion can 
be administered for subsequent 600 mg doses.  Women referred by HCPs to participate in the trial may receive ocrelizumab treatment at their 
neurologist’s site as part of their standard of care treatment. 
p General health and medical history for infants includes screening for the following (infants should be excluded from the study if any are present): 
age  24 weeks of age at the time of the mother’s first postpartum dose of ocrelizumab; any abnormality that may interfere with breastfeeding or 
milk absorption, including but not limited to cleft palate and/or lip, congenital diaphragmatic hernia and esophageal atresia; an active infection 
(the infant may be included once the infection resolves); at least one documented BRUE, as defined by the 2016 Guidelines of the American 
Academy of Pediatrics. 
q These will include: mode of delivery (vaginal delivery, instrumental delivery, scheduled or urgent cesarean section); APGAR score (1 min, 5 min, 
10 min); gestational age at birth; infant’s measurements (weight, length, head circumference); and congenital malformations. 


 
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r During the treatment and sampling period, women should record the number of breastmilk feeds and/or feeds with formula milk 
(supplementation) on the day of the sample collection and the previous and following day, i.e., day of collection  1 day.  During the vaccination 
period, women 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, at Months 2, 4, 6, 9, and 12, as applicable and depending on 
the infant’s age at enrolment. 
s 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 as applicable and depending on the infant’s age at enrolment (see Appendix 6 of the Study Protocol 
version 3 for details of time windows of infant growth velocity and child developmental milestone assessments). 
t Growth charts (according to the WHO Child Growth Standards; WHO 2022) will be used, as well as absolute values; other standard 
measurements recorded by e.g., the pediatrician as part of routine post-natal care may also be used).  Infant growth will be captured at Months 
2, 4, 6, 9, and 12 (see Appendix 6 of the Study Protocol version 3 for details of time windows of infant growth velocity and child developmental 
milestone assessments). 
u Including documentation of past or current medications as well as clinically significant pediatric disease/abnormality.  Changes to concomitant 
medication given to the infant should be recorded throughout the study. 
v Documentation of vaccinations administered to the infant will be collected throughout the study. 
w  Infant sampling at Day 30 ( 2 days) post-infusion 1 and at 1 month ( 30 days) after first or second dose of MMR, or Month 13 of age in case 
MMR vaccine is not planned to be administered ( 30 days) may be conducted via in-home nurse visits or at the hospital as part of study visits.  
CD19  B-cell level at Day 30 ( 2 days) post-infusion 1 represents the co-primary endpoint measurement. 
x If the infant’s B-cell levels are found to be below LLN, repeat analyses may be done at unscheduled visits at the discretion of the investigator 
(in consultation with the Sponsor). 
y 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 sample at 
Day 30 ( 2 days) post-infusion 1, (1) safety laboratory samples [scheduled or unscheduled and performed at the discretion of the investigator] 
(2) lymphocyte subtypes sample for B-cell counts (CD19 ) and T-cell counts (CD3 , CD4 , and CD8  ), and NK cell counts (CD16+CD56+). 
(3) serum ocrelizumab concentration; for the Month 13 of age/1 month after first/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 ) and T-cell counts (CD3 , CD4 , and CD8  ), and NK cell counts (CD16+CD56+). 
z For 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, all efforts will be made to collect samples.  However, if they cannot be collected, it will not be considered a protocol deviation. 
aa Serum anti-vaccine antibody (IgG) titers will be measured to vaccines administered as per local practice over the first year of life (which include 
MMR, diphtheria, tetanus, pertussis, Hib, HBV and PCV-13); 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. 


 
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Statistical Analysis Plan MN42989 
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bb 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 
13/1 month after first or second MMR dose. 
cc A structured telephone interview will be conducted by site personnel postpartum every 2 weeks during the treatment and sampling period and 
every 3 months during the vaccination period (in-between ocrelizumab infusions) for a general review, and to identify and collect information on 
any changes in the woman’s and infant’s health status (including the occurrence of MS relapses in the mother 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. 
dd Adverse events in both mother and infant will be reported throughout the study as per standard pharmacovigilance procedures.  Adverse events 
will also be captured at screening for women who received ocrelizumab before pregnancy. 
ee Documentation of premedication is not required. 


 
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Statistical Analysis Plan MN42989 
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Appendix 3 B-Cell Reference Ranges by Week of Life:  Absolute 
and Percentage Counts 
 
Extracted Borriello et al. 2022. 


 
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Statistical Analysis Plan MN42989 
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Appendix 4 Age-Specific Reference Ranges for Absolute Count 
(n × 106/L) of Lymphocyte Subsets  
Subsets 
Age group 
(months) 
Lower Limit of Normal 
(90th Percentile) 
CD3+  
0 to < 3 
3180 
 
3 to < 12 
2284 
 
12 to < 24 
2542 
CD4+ 
0 to < 3 
2330 
 
3 to < 12 
1523 
 
12 to < 24 
1573 
CD8+ 
0 to < 3 
712 
 
3 to < 12 
524 
 
12 to < 24 
656 
CD16+56 
0 to < 3 
201 
 
3 to < 12 
230 
 
12 to < 24 
186 
 
Extracted from Tosato et. al. 2015. 


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