Effect of Ocrelizumab on Neuroinflammation in Multiple Sclerosis as Measured by 11C-PBR28 MR-PET Imaging of Microglia Activation
Phase: PHASE4
Conditions: Multiple Sclerosis
Sponsor: Massachusetts General Hospital

CONFIDENTIAL 
 
This is a {Institution or Cooperative Group Name} document that 
contains confidential information.  It is intended solely for the recipient 
clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical 
investigations; any other proposed use requires written consent from 
{Institution or Cooperative Group Name}. 
 
Protocol:  Ocrelizumab {Institution or Cooperative Group Name} 
ML405452 
01Dec22 
 
PROTOCOL 
STUDY TITLE: 
Effect of Ocrelizumab on Neuroinflammation in 
Multiple Sclerosis as Measured by 11C-PBR28 
MR-PET Imaging of Microglia Activation  
STUDY DRUG: 
OCREVUS (ocrelizumab) 
 
SUPPORT PROVIDED BY: 
Genentech, Inc. 
 
INVESTIGATOR: 
Caterina Mainero, MD, PhD 
Tel: 617-7247746, Fax: 617-7267422, email: 
cmainero@.mgh.harvard.edu 
SUB-INVESTIGATORS: 
Jacob Sloane, MD 
Eric Klawiter, MD 
RESEARCH COORDINATOR: 
Lana Ruvinskaia, Tel: 617-7248823 
STUDY NUMBER: 
ML40542 
PROTOCOL VERSION/DATE: 
#15; July 5, 2023 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
2/P {Protocol Number} 
 
30032018 
 
 
TABLE OF CONTENTS 
1. ................................................................................................................................... INTRODUCTION
 ......................................................................................................................................................................... 5 
2. ......................................................................................................................................... OBJECTIVES
 ......................................................................................................................................................................... 5 
2.1 ............................................................................................................................. Primary Objectives
 ......................................................................................................................................................................... 6 
2.2 ....................................................................................................................... Secondary Objectives
 ......................................................................................................................................................................... 6 
3.1 .................................................................................................................. Description of the Study
 ......................................................................................................................................................................... 6 
3.2 ........................................................................................................... Rationale For Study Design
 ......................................................................................................................................................................... 9 
3.3 ........................................................................................................................... Outcome Measures
 ......................................................................................................................................................................... 9 
3.3.1 ........................................................................................................ Primary Outcome Measure
 ....................................................................................................................................................................... 10 
3.3.2 ............................................................................................... Secondary Outcome Measures
 ....................................................................................................................................................................... 10 
3.3.3 ..................................................................................... Ancillary Safety Outcome Measures
 ....................................................................................................................................................................... 10 
3.4 ............................................................................................................................................. Safety Plan
 ....................................................................................................................................................................... 10 
3.5 .................................................................................. Compliance with Laws and Regulations
 ....................................................................................................................................................................... 11 
4.0 ............................................................................................................ MaterIALS and METHODS
 ....................................................................................................................................................................... 11 
4.1 ................................................................................................................................................... Subjects
 ....................................................................................................................................................................... 11 
4.1.1 ............................................................................................................................ Subject Selection
 ....................................................................................................................................................................... 11 
4.1.2 .............................................................................................................................. Inclusion Criteria
 ....................................................................................................................................................................... 12 
4.1.3 ............................................................................................................................ Exclusion Criteria
 ....................................................................................................................................................................... 12 
4.2 ........................................................................................................................ STUDY TrEATMENT
 ....................................................................................................................................................................... 12 
4.3 ........................................................................................................................... Study Assessments
 ....................................................................................................................................................................... 12 
4.3.1 ............................................................................................... Assessments during Treatment
 ....................................................................................................................................................................... 13 
4.3.2 .............................................................................................................. Follow-Up Assessments
 ....................................................................................................................................................................... 13 
4.4 ....................................................................................................... Subject DISCONTINUATION
 ....................................................................................................................................................................... 13 
4.5 ........................................................................................................... Study DISCONTINUATION
 ....................................................................................................................................................................... 14 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
3/P {Protocol Number} 
 
30032018 
 
4.6 ............................................................................................................................. Statistical Methods
 ....................................................................................................................................................................... 14 
4.6.1 .................................................................................... Analysis of the Conduct of the Study
 ....................................................................................................................................................................... 14 
4.6.2 ...................................................................... Analysis of Treatment Group Comparability
 ....................................................................................................................................................................... 14 
4.6.3 ............................................................................................................................. Efficacy Analysis
 ....................................................................................................................................................................... 15 
4.6.4 ................................................................................................................................ Safety Analysis
 ....................................................................................................................................................................... 15 
4.6.5 ...................................................................................................................................... Missing Data
 ....................................................................................................................................................................... 15 
4.6.6 .................................................................................................. Determination of Sample Size
 ....................................................................................................................................................................... 15 
4.7 ................................................................................................................... Data Quality Assurance
 ....................................................................................................................................................................... 16 
5. .................................................................. SAFETY REPORTING OF ADVERSE EVENTS
 ....................................................................................................................................................................... 16 
Reporting of adverse events will be performed following IRB guidelines. . Error! 
Bookmark not defined. 
5.1   ASSESSMENT OF SAFETY ................................................................. 16 
5.2   METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES ...................................................................................... 18 
5.3   PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS ......................................................................................... 19 
6.1 ...................................................................................................................................... Study Initiation
 ....................................................................................................................................................................... 29 
6.2 ............................................................................................................................... Study Completion
 ....................................................................................................................................................................... 30 
6.3 ............................................................................................................................... Informed Consent
 ....................................................................................................................................................................... 30 
6.4 ............................................. Institutional Review Board or Ethics Committee Approval
 ....................................................................................................................................................................... 30 
6.5 .................................................................................................. Study Monitoring Requirements
 ....................................................................................................................................................................... 31 
6.6 ........................................................................................................................ DATA COLLECTION
 ....................................................................................................................................................................... 31 
6.7 .................................................................... Study Medication Accountability (if applicable)
 ....................................................................................................................................................................... 31 
6.8 ............................................................................................ Disclosure and publication of Data
 ....................................................................................................................................................................... 31 
6.9 ........................................................................................................................ Retention of Records
 ....................................................................................................................................................................... 32 
REFERENCES ...................................................................................................................................... 33 
SAFETY REPORTING FAX COVER SHEET ........................................................................ 34 
Genentech Supported Research .................................................................................................. 34 
 
 
 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
4/P {Protocol Number} 
 
30032018 
 
 
 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
5/P {Protocol Number} 
 
30032018 
 
1. 
INTRODUCTION 
Cortical demyelination and diffuse white matter (WM) axonal injury are well-
established neuropathological features of multiple sclerosis (MS), and main 
substrates of disease progression1.   
A series of neuropathological examinations of ex vivo progressive MS cases 
reported that cortical demyelination frequently appears to be topographically 
associated with meningeal ectopic inflammatory infiltrates of B cells, 
accompanied by profound cortical microglia activation2-4. The extent of meningeal 
inflammation correlated with microglia activation and the severity of 
demyelination in the underlying cortex.  These findings suggest that cortical 
demyelination in MS may be induced by soluble factors, produced within those B 
cell follicle-like structures, which then diffuse from the meninges into the cortex 
and trigger demyelination directly or indirectly through activation of microglia. 
Meningeal inflammation, in association with cortical demyelinating lesions, has 
also been described in biopsies at MS onset5. 
Neuropathological studies implicate that inflammation, through activation of 
microglia, may also represent a relevant pathogenic factor in the development of 
diffuse white matter (WM) axonal injury6. 
Ocrelizumab, a humanized monoclonal antibody targeting the CD20 marker in B 
cells, has been recently shown to have beneficial effects in relapsing-remitting 
MS (RRMS), but also in primary-progressive disease (PPMS) by significantly 
reducing new CNS inflammation, relapses, and progression in patients with 
gradually worsening disease7, 8. The efficacy of Ocrelizumab in MS challenges 
our understanding of MS disease-mechanisms, suggesting that B cells may have 
a main role in disease pathogenesis by contributing to propagate 
neuroinflammation within the MS CNS. It appears likely that functionally distinct B 
cells contribute to MS disease process through diverse mechanisms within the 
distinct disease compartments, and throughout stages of MS9. Peripheral pro-
inflammatory B cells play and important role in relapsing disease mechanisms10, 
whereas meningeal collections of B cells potentially participate in the 
maintenance and propagation of CNS-compartmentalized disease. 
Neuroinflammation by means of microglia/macrophages activation can be 
imaged in vivo on positron emission tomography (PET) using selective 
radiotracers that bind to the 18kDa translocator protein (TSPO), a protein that is 
upregulated in activated microglia/macrophages11. In a cross-sectional study, 
using simultaneous magnetic resonance-PET (MR-PET) imaging with 11C-
PBR28, a second-generation TSPO radiotracer, we demonstrated abnormally 
high TSPO expression, indicative of microglia/macrophages activation, across 
the brain of MS cases12. Relative to healthy controls, the greatest TSPO increase 
was found in the cortex and cortical lesions, thalamus, hippocampus, and normal 
appearing WM (NAWM). Additionally, in MS increased 11C-PBR28 binding in 
cortex, deep GM, and NAWM correlated with neurological disability and impaired 
cognitive performance. We have developed a method for estimating 11C-PBR28 
uptake that does not require arterial sampling and shows the same sensitivity as 
quantitative blood analysis to 11C-PBR28 changes in MS12, 13. 
 
 
2. 
OBJECTIVES 
In this study, we propose to evaluate, serially, functional and structural tissue 
changes in the cortex and WM of subjects with RRMS and progressive disease 
under Ocrelizumab using 11C-PBR28 MR-PET. The overall goal of the study is to 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
6/P {Protocol Number} 
 
30032018 
 
use advanced imaging protocols to determine the effect of ocrelizumab treatment 
on neuroinflammation as measured by microglia activation. 
 
2.1 
PRIMARY OBJECTIVES 
 
To assess whether treatment with Ocrelizumab in subjects with either RRMS or 
progressive MS is associated with decreased 11C-PBR28 binding in the 1) cortex, 
and 2) WM (lesions and normal appearing WM, NAWM), suggesting reduced 
neuroinflammation. 
 
2.2 
SECONDARY OBJECTIVES 
To assess whether changes in neuroinflammation under Ocrelizumab treatment, 
as measured by 11C-PBR28 uptake at either 12-month follow up relative to the 
baseline, are associated with changes in structural MR metrics of brain tissue 
damage including WM lesion load, cortical atrophy and demyelination in the 
cortex and in the NAWM as measured by magnetization transfer ratio (MTR). 
 
To explore whether changes in functional and structural imaging metrics under 
Ocrelizumab are associated with changes in clinical outcomes measures (EDSS, 
SDMT, MSFC). 
 
3.      STUDY DESIGN 
Open-label, serial longitudinal study on 24 MS patients (with RRMS or 
progressive MS1) fulfilling the inclusion/exclusion criteria detailed below. 
MS patients will be recruited through competitive enrollment at Massachusetts 
General Hospital (Dr. Eric Klawiter) and Beth Israel Medical Center (Dr. Jacob 
Sloane). Enrolled MS subjects will be scanned at MGH at baseline (pre-
treatment) and at 12-month after Ocrelizumab therapy on an integrated MR-PET 
scanner using 11C-PBR28 produced on site. 
 
3.1 
DESCRIPTION OF THE STUDY 
This is a prospective open-label study in which we will enroll 24 subjects with 
MS, including patients with a relapsing-remitting type of MS (RRMS), and  
subjects with a progressive type of MS (PMS). MS subjects fulfilling the inclusion 
criteria detailed below, and deemed by their referring clinician to be suitable for 
treatment with Ocrelizumab as part of their standard medical care, will be 
enrolled in the study. Women who are of childbearing potential and believe they 
may possibly be pregnant will not participate in the study.  
At the first visit, subjects will be screened and the study procedures will be 
explained to subjects in detail. Subjects will be asked to review the consent form, 
and any questions they may have will be answered.  
 
Screening visit and consenting 
Subjects who fulfill demographic and clinical inclusion criteria of the study will 
undergo routine clinical evaluations at baseline. MR contraindication screening 
will also be done to ensure that they meet also the basic imaging 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
7/P {Protocol Number} 
 
30032018 
 
inclusion/exclusion criteria for the study procedures. For the MR contraindication 
screening, the standard Martinos Center subject screening form will be 
administered. During screening, potential participants will be fully informed of the 
purpose and activities involved in the research study. Interested subjects will be 
scheduled for an in-person visit where written informed consent will be 
immediately obtained by a licensed physician investigator or a nurse practitioner, 
prior to initiating any of the study procedures. At the time the registered nurse 
practitioner obtains consent, each subject will be offered the option to speak with 
a physician investigator.  
Soon after consenting subjects will undergo a history and physical assessment, 
and blood drawing for TSPO genotyping. Subject screening visit and consenting 
may take place either on the same day or as a separate visit.  
 
PBR affinity test 
While 11C-PBR28 has the advantage of binding to the TSPO protein with a higher 
ratio of specific-to-nonspecific binding than 11C-PK11195, it also present a 
potential limitation, in that about 10% of human subjects show no binding to 
PBR2814. It has been demonstrated that a common polymorphism (rs6971) in the 
TSPO gene, which leads to an aminoacid substitution (Ala147Thr), predicts 
PBR28 binding affinity in human platelets15. Since the low-affinity binder 
phenotype is consistent across all tissues within the same subject, testing for the 
Ala147Thr polymorphism has been suggested to predict low affinity for 11C-
PBR28 in all organs, including the brain. Thus, all subjects considered for 
potential participation in a 11C-PBR28 scan will be genotyped for the Ala147Thr 
TSPO polymorphism. Venous blood (~10 ml) will be drawn into EDTA-containing 
tubes for Genomic DNA. 
High or Mixed affinity binders (Ala/Ala or Ala/Thr) will be considered eligible, 
whereas the Low affinity binders (Thr/Thr) will be considered ineligible for the 
study. 
 
MR-PET scan 
MR-PET imaging will be performed at baseline (pre-treatment) and at 12-month 
follow up after initiating therapy with Ocrelizumab. 
 
On the day of each MR-PET scan, before starting any imaging procedure, 
women of childbearing age will be tested for pregnancy using a blood pregnancy 
test. If the test performed comes back positive for pregnancy or the subject is 
breastfeeding, the subject will not undergo any of the PET procedures. 
 
Prior to radiotracer injection: 
1. 
The procedure will be explained to the subject and any questions he/she 
has about the procedure will be answered. 
2. 
Subject information such as height, weight will be obtained. 
3. 
All subjects will undergo a MR-PET scan using 11C-PBR28.  
4. 
Prior to injection of 11C-PBR28 patients will be asked to urinate to 
minimize the possibility that they will need to move during the scan. 
 
Radiotracer injection: 
1. 
Radiotracer injection may occur either outside or inside the MR-PET 
scanner. The subjects will be positioned on the MR-PET scanner table with their 
head in the center of the field of view; support devices under the back and/or legs 
will be used to enable the patient to comfortably maintain his/her position 
throughout the scan. 
2. 
~12 mCi of 11C-PBR28 will be injected and the time of injection will be 
recorded. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
8/P {Protocol Number} 
 
30032018 
 
 
Post-scan procedures: 
1. 
The subject will be asked to void again immediately after the scan and 
he/she will be counseled on the importance of continuing to drink fluids for 
several more hours.  This will increase urine flow rate, which will help minimize 
the radiation dose to the bladder wall. 
2. 
A detailed information sheet on post PET scan procedures will be given to 
the subject. 
 
Data acquisition: Subjects will be positioned in the BrainPET scanner and data 
acquisition may start after an intravenous bolus injection of 11C-PBR28 (~12mCi) 
to capture the 60-90 minutes after radiotracer administration. 
 During PET acquisition, the following MR protocols will be simultaneously 
acquired: 1) standard FLAIR protocols for WMLV estimation; 2) T1 anatomical 
images for Freesurfer cortical reconstruction and coregistration with MR-PET and 
7T data (~7 min); standard MTR protocols (~16 min).  
 
 
Data analysis: Standardized uptake value (SUV) maps of 11C-PBR28 uptake will 
be created for 60-90-minute PET frame and resampled at 1.25 mm isotropic 
voxels, as previously detailed12. Data in MS and in other neurological disorders 
show that 11C-PBR28 SUV can substitute for, and may even be more sensitive 
than absolute quantitation12, 16, 17. This method is expected to improve subject 
tolerability by allowing shorter scan time and not requiring arterial catheterization. 
In addition, the method allows smaller sample sizes for comparable statistical 
significance because of the relatively low variability of SUV. Scan-rescan 
reproducibility data in 5 healthy subjects at our Center demonstrate that 
quantification of 11C-PBR28 SUV normalized by a reference region (SUVR) has 
excellent stability over time, with mean±SD SUVR test-retest % change in all 
regions tested of 0.1±1.16, and with coefficient of variations across brain regions 
below 10%. 
Using a surface-based analysis, all subjects in this study will have acquired 3T 
anatomical and MTR maps to estimate intracortical MTR at 50% depth from the 
pial surface. With those 3T maps, specifically the relationship between the extent 
of microglia and/or macrophages activation and changes in MTR will be 
investigated. Decreases in MTR would suggest a reduction in cortical myelin 
content. Furthermore, this study will include whether changes in MTR in WM 
lesions or normal appearing WM (NAWM) is accompanied by changes in 
microglia/macrophages activation as measured by 11C-PBR28 MR-PET or 
whether these processes are unrelated.  
Finally, the relationship between radiographic measures from MR-PET studies 
and clinical outcome measures will be assessed.  
 
 
Clinical assessment.  
Clinical outcomes will be collected at baseline and at 12-month intervals. EDSS 
will be formally determined at baseline and 12 months as a descriptor of patient 
characteristics but not as an outcome measure. Clinical outcomes will include a 
modified MS Functional Composite (7 scores total) including the 25 foot walking 
time (25FT) and 6 minute walk (6MW) (2 scores), 9 Hole Peg Test (9HPT) (right 
and left separately; 2 scores), Symbol Digit modality test oral version (SDMT) (1 
scores) and the Sloane Low Contrast Sensitivity Chart (SLCC) at 2.5 % (OD and 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
9/P {Protocol Number} 
 
30032018 
 
OS separately; 2 scores). All tests will be administered 2 times prior to baseline 
to minimize learning effects and always administered under standardized testing 
conditions with scores discarded if unreliable (eg right hand in a cast would lead 
to discarding the RUE 9HPT score). Worsening will be defined as a > 15% 
change on the 25FT, 6MW or 9HPT or a decrease of > 5 points on the SDMT or 
> 3 points on the SLCC; sustained worsening will require persistence of this 
magnitude of change for at least 6 months. Worsening may be initiated in the 
setting of a relapse but will still require persistence to meet sustained disability 
criteria. Relapses will be defined as the development of new neurological 
symptoms lasting for at least 48 hours associated with new or worsening findings 
on examination in the absence of a febrile illness or other potential comorbid 
condition. 
 
3.2 
RATIONALE FOR STUDY DESIGN 
A large body of evidence shows that B cells play a main role in disease 
pathogenesis and progression in multiple sclerosis, both in the gray matter and in 
the WM. In the gray matter, the cortex is a main target of demyelination and 
neuroaxonal loss and this pattern of pathology is constantly associated with 
disease progression1. Neuropathological data demonstrate that cortical 
demyelination is largely driven by meningeal inflammation, often organized in 
lymphoid-like B-cell structures, through the activation of microglia2-4. Several 
studies also show that the extent and severity of cortical demyelination correlate 
with the degree of microglia activation. In the normal appearing WM, diffuse 
microglia activation is closely associated with axonal loss. Treatment with 
Ocrelizumab, a monoclonal antibody that targets the CD20 expressing B cells, 
has shown to be beneficial in RRMS and PMS by reducing CNS inflammation, 
relapses, and progression in patients with gradually worsening disease7, 8. 
Inflammation in the brain has been assessed, however, using traditional MRI 
methods including gadolinium enhancing lesions and new T2 lesions. These 
methods are insensitive to detect cortical inflammation, as well as the 
compartmentalized inflammation that typically characterizes progressive MS. 
Additionally, neuroinflammation by means of microglia/macrophages activation 
can be present in the absence of significant blood brain barrier abnormalities, or 
even precede them18. Here we propose to study the effects of Ocrelizumab 
treatment on neuroinflammation using a sensitive and reproducible method that 
we have implemented in our Lab. 
 
3.3 
OUTCOME MEASURES 
Make sure the primary and secondary outcome measures are consistent with the 
study design and objectives.  The items listed below should be considered when 
specifying the outcome measures; they should be discussed if necessary to 
justify the study design: 
• Appropriate timing in terms of follow-up.  The intervening length of time between 
assessments of response affects time outcomes and the statistical analysis. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
10/P {Protocol Number} 
 
30032018 
 
• Best measure of response (e.g., duration of response, incidence of toxicity, etc.) 
• Clinical applicability (e.g., consider whether the outcome measures are clinically 
meaningful and contribute to patient benefit) 
If necessary, explain why these outcome measures were chosen (i.e., medical 
justification) 
 
3.3.1 Primary Outcome Measure 
11C-PBR28 uptake measured as standardized uptake values (SUV, mean 
radioactivity/injected dose/weight) from the 60-90 minutes post-injection data) 
and normalized by a pseudoreference region (SUVR) as previously detailed. 
Tracer uptake will be assessed in 1) cortex; 2) WM lesions; 3) NAWM. 
3.3.2 Secondary Outcome Measures 
Cortical thickness. 
WM lesions. 
Cortical MTR. 
NAWM MTR. 
3.3.3 Ancillary Safety Outcome Measures 
NA 
3.4 
SAFETY PLAN 
Patients will be evaluated at each study visit for the duration of their participation 
in the study (see Section 4.5 and Appendix A, Study Flowchart). 
Ocrelizumab-related infusion reactions will be managed by the treating physician 
as detailed in Section 4.3.2 and according to recommended guidelines by the 
U.S. Food and Drug Administration (FDA) and Good Clinical Practices (GCPs), 
and as part of the patient standard clinical care. All laboratory analyses related to 
Ocrelizumab safety will also be conducted in patients as part of their standard 
medical care and supervised by their referring clinician.  
As part of this study, enrolled MS subjects will be asked to fill out a monthly 
questionnaire to report any new medical event or change in treatment. A 
designated investigator/clinical research coordinator in the study will review 
periodically the questionnaire with the referring clinician to record possible 
adverse events. 
 
MR-PET safety assessment: During the MR-PET scans subjects will lie 
motionless on the MR table, which will slide into the narrow tube of the MR-PET.  
Subjects will easily be able to hear and speak to the research staff throughout 
the scan. If they wish, they will be free to stop the examination at any time.  
The Siemens MR-PET system has also built in self-monitoring system that 
automatically shuts off if parameters exceed safe levels.  For backup protection 
technicians at the Martinos Center constantly monitor the subjects’ physiological 
signs and the quality of the raw data.  

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
11/P {Protocol Number} 
 
30032018 
 
We have a step-by-step checklist of the scan session and safety precautions that 
the research team follows for every subject. We will also ask patients about their 
comfort level throughout the session. 
 
The U.S. Food and Drug Administration (FDA) recently gave the regulatory 
clearance of a hybrid PET/MRI scanner in the U.S. Additionally, FDA considers 
investigations of MRI software and hardware operating within FDA specific 
parameters as non-significant risk device studies. All studies will adhere to these 
(non significant risk) FDA approved safety levels for the Siemens system. These 
system parameters include static magnetic field, time varying magnetic fields 
(dB/dt), specific absorption rate (SAR), and acoustic noise levels.  
The radiation exposure in this study will be ~ 3.7 mSv per PET scan.  If subjects 
have participated in other research studies in the past 12 months that have 
involved radiation exposure, they will be asked to inform the investigators or 
study staff (by placing a check mark on the consent form verifying that they have 
or have not been exposed to other radiation in the past 12 months).  If it is 
determined that their prior radiation exposure exceeds our current guidelines, it is 
possible that they will no be allowed to participate in this study. 
We will use 11C-PBR28 produced by the cyclotron/radiochemistry/radiopharmacy 
facility at the A. A. Martinos Center for Biomedical Imaging.  We will follow the 
safety standards approved by the Radiation Safety Committee for the use of 
radioligands. The IV injection will be administered either by a physician or by a 
trained technician. Should there be an adverse event, Dr. Mainero will be 
responsible for communicating with the IRB and Genentech within the stipulated 
time frame. 
 
The risks of neurological and neuropsychological testing are minimal. Patients 
with MS routinely undergo neuropsychological testing as part of standard clinical 
evaluation. As these tests evaluate higher cognitive processes such as executive 
functioning and memory, subjects may become anxious from self-perceived 
inability to successfully accomplish the tasks associated with the testing. 
Subjects will be advised prior to testing that the tasks are designed to be 
challenging. Appropriate referral to psychiatry/psychology will be provided if 
necessary.  
 
 
See Section 5 (Assessment of Safety) for complete details of the safety 
evaluation for this study. 
3.5 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration (FDA) Good Clinical Practices (GCPs), and local ethical and legal 
requirements. 
4.0 
MATERIALS AND METHODS 
4.1 
SUBJECTS 
 
4.1.1 Subject Selection 
24 subjects with either RRMS or PMS. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
12/P {Protocol Number} 
 
30032018 
 
 
4.1.2 Inclusion Criteria 
• Signed informed consent 
• RRMS and/or PMS subtype 
• Age between 18-65 years 
• EDSS between 0 and 7.0 
• Express at least one high-affinity (Ala147) allele of the TSPO receptor for PBR28 
 
4.1.3 Exclusion Criteria 
• Hypersensitivity to trial medications 
• History of life-threatening infusion reaction to Ocrelizumab 
• Acute or uncontrolled chronic medical condition 
• Impaired hearing 
• Claustrophobia 
• 300 lbs or greater (weight limit of MRI table) 
• Pregnancy or breastfeeding 
• Sensitivity to imaging agents 
• Contraindications to MRI 
• Use of benzodiazepines, topiramate, doxycycline, mynocicline. 
 
4.2 
STUDY TREATMENT   
Treatment will not be determined by the protocol and will be administered as per 
standard of care.  
 
 
4.3 
STUDY ASSESSMENTS 
Signed, IRB-approved informed consent must be obtained from patients prior to 
the pretreatment assessments.  Ensure that informed consent be obtained for 
both the any mandated testing or screening process for this protocol. 
The following are recommended evaluations: 
IRB-approved informed consent will be read and explained by Dr Mainero or by 
another co-investigator or study staff to patients during their first visit to the 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
13/P {Protocol Number} 
 
30032018 
 
Martinos Center.  We will train research assistant/technologist staff to pre-
consent subjects for the study. Those who choose to participate in the study will 
then meet with Dr Mainero or another co-investigator or study staff to receive a 
more detailed explanation about the study and the procedure.  Patients willing to 
participate in the study will sign the consent form in the presence of a licensed 
physician investigator or nurse practitioner. Consent form will explain the purpose 
of the study, the procedure, the risks and discomfort, and the possible benefits. It 
will also address the cost and payment issues, and guaranties confidentiality.   
Each subject recruited to the study will have a file kept in the Martinos Center. 
Each file will include a copy of the signed consent form. 
 
 
4.3.1 Assessments during Treatment 
The following are recommended evaluations: 
• EDSS at baseline and 12-month interval. EDSS will be formally 
determined at baseline and 12 months as a descriptor of patient 
characteristics but not as an outcome measure.  
 
• MS Functional Composite (7 scores total) including the 25 foot walking 
time (25FT) and 6 minute walk (6MW) (2 scores), 9 Hole Peg Test (9HPT) 
(right and left separately; 2 scores), Symbol Digit modality test oral version 
(SDMT) (1 scores) and the Sloane Low Contrast Sensitivity Chart (SLCC) 
at 2.5 % (OD and OS separately; 2 scores) at baseline and 12-month 
interval.  
 
4.3.2 Follow-Up Assessments 
We don’t plan to do any follow-up assessment once patients terminate the study 
or drop-off from the study for any given reason unless the reason for dropping-off 
is strictly related to potential issues arising from 11C-PBR28 MR-PET imaging. In 
these cases, follow-up will be followed according to standard IRB 
recommendations and guidelines. 
In cases where discontinuation is due to Ocrelizumab-related reasons, follow-up 
will be performed by the treating physician as part of their standard medical care. 
 
4.4 
SUBJECT DISCONTINUATION 
Subjects will be discontinued from the study in case any of the conditions listed in 
the exclusion criteria. We will evaluate on a case-by-case basis discontinuation 
of subjects starting treatment with any of the drugs listed in the exclusion criteria, 
as treatment of these drugs can be temporary and thereby not necessarily affect 
MR-PET assessments. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
14/P {Protocol Number} 
 
30032018 
 
4.5 
STUDY DISCONTINUATION 
Genentech, Study Center, and the Principal Investigator have the right to 
terminate this study at any time.  Reasons for terminating the study may include 
the following: 
• The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects 
• Subject enrollment is unsatisfactory. The enrollment time period will start only 
after all procedures and protocol will be IRB approved. 
• Data recording are inaccurate or incomplete 
• Study protocol not followed 
 
4.6 
STATISTICAL METHODS 
4.6.1 Analysis of the Conduct of the Study 
We will follow IRB guidelines to ensure that all study procedures are conducted 
appropriately. 
The principal investigator will have periodic meetings with all study staff to 
oversee any possible study deviation or violation to the protocol. We have a step-
by-step checklist of the scan session and safety precautions that the research 
team follows for every subject. We will also ask subjects about their comfort level 
throughout the session. 
Dr Mainero or another co-investigator will monitor all MR-PET scanning. Dr 
Mainero, the PI, and all other study staff (co-investigators and research 
technicians) are certified in the Partners Health Care System Human Subject 
Protection Education Requirements and are familiar with the procedures and 
steps necessary to report adverse events to the IRB committee 
 
4.6.2 Analysis of Treatment Group Comparability 
We will have only one treatment group (Ocrelizumab) in which we will assess 
neuroinflammation by means of 11C-PBR28 MR-PET imaging (SUVR) at 2 time 
points: 1) baseline, 2) 12-month follow up. 
At baseline, patient SUVR across different regions in WM and gray matter will be 
compared with brain SUVR data from a healthy control dataset obtained at the 
Martinos Center by using linear regression models and adjusting for age and 
PBR affinity. Group comparisons (baseline vs 12-month) will be carried out using 
region of interest analysis or voxelwise approaches by means of paired-test 
and/or ANOVA. In patients, regression models will be used to determine the 
relation between SUVR and structural MRI metrics (lesion load, MTR in NAWM 
and cortex), and adjusting for age and PBR affinity. Multivariate regression 
models will be also used to assess the relation between SUVR and EDSS at 
baseline and EDSS change at 1-year follow up, adjusting for PBR affinity. For 
evaluating changes/drug effects in the cortex and associations between cortical 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
15/P {Protocol Number} 
 
30032018 
 
SUVR and MRI or clinical metrics we will perform vertex-wise surface-based 
analyses by sampling SUVR maps at mid-cortical depth to reduce partial volume 
effects. Age and PBR affinity will be included as covariates of no interest when 
appropriate. 
 
 
4.6.3 Efficacy Analysis 
Not applicable 
 
4.6.4 Safety Analysis 
List all safety endpoints (i.e., endpoints relating to adverse events, laboratory 
assessments, physical examinations, vital signs, or any special safety 
assessments).  Variables relating to adverse events might include timing, 
severity, relationship to drug, relationship to therapy, outcome, effect on therapy, 
and degree of seriousness. 
Indicate the subject groups (usually all subjects) to be used in analyzing the 
safety variables. 
Unless specific safety questions have been included in the study objectives (and 
an appropriate sample size and study design have been established to permit 
answering those questions), it is usually sufficient to use descriptive procedures 
for summarizing safety data. 
 
4.6.5 Missing Data 
Data analysis will be conducted even in the case of missing data by considering 
separately each time point. We will consider missing data all the metrics that are 
not acquired within 3-months of the expected time point. 
 
4.6.6 Determination of Sample Size 
Quantification of 11C-PBR28 uptake shows excellent scan-rescan stability.  

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
16/P {Protocol Number} 
 
30032018 
 
  In 5 healthy controls (2 with high affinity binding, HAB, and 2 with mixed affinity binding, 
MAB for PBR28) we assessed the 3-month scan-rescan stability of 60-90 minutes11C-
PBR28 
SUVR 
quantification across all 
cortical regions sampled 
at mid-cortical depth (50% 
depth from pial surface).   
Results show excellent 
stability of these 
measures over time, with 
mean±SD SUVR test-
retest % change in all 
regions tested of 
0.1±1.16, and with 
coefficient of variations 
(COV) across cortical 
regions below 10%.  An 
example of test-retest 60-90 minutes SUVR in the fusiform gyrus and medial prefrontal 
cortex from 5 healthy subjects is illustrated in Fig. 1. 
11C-PBR28 uptake.  We found an increase in 11C-PBR28 uptake in cortical lesions of 
~26% in 13 RRMS and of ~29% in 14 SPMS12, and a variability in 11C-PBR28 uptake of 
~10% among subjects.  By assuming a variability among subjects of ~10-20%, we have 
a 90% power (significance level of 5%) to detect an absolute difference in 11C-PBR28 
uptake between MS and HC of ~15%. From scan-rescan changes in 11C-PBR28 uptake 
around ~1%, we anticipate to have a 90% power to detect at least a 1.5% longitudinal 
change of values over time. 
 
4.7 
DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of 
standard practices and procedures. 
 
5. 
SAFETY REPORTING OF ADVERSE EVENTS 
 
 
 
 
5.1   ASSESSMENT OF SAFETY 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events 
(AEs) and serious adverse events (SAEs) that are considered related to 
ocrelizumab per standard medical care protocol.  This includes all events of 
death, and any study specific issue of concern. 
Adverse Events 
Fig. 1.  Plots illustrate mean % signal change of test-retest 60-90 
minutes 11C-PBR28 SUVR in the fusiform gyrus and in the medial 
prefrontal cortex in 5 healthy controls that underwent 11C-PBR28 MR-

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
17/P {Protocol Number} 
 
30032018 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
• AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms 
associated with MS that were not present prior to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as radiotracer injection). 
• If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other 
protocol-mandated intervention. 
• Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
Serious Adverse Events 
• An AE should be classified as an SAE if the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results 
in substantial disruption of the subject’s ability to conduct normal life 
functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
• It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
18/P {Protocol Number} 
 
30032018 
 
 
5.2   METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES 
 
The investigator is responsible for ensuring that all AEs and SAEs that may be 
observed or reported during the study, are collected and reported to the FDA, 
appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND 
Safety Reports). 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained and initiation of study treatment and ends 30 days 
following the last administration of radiotracer and MR-PET or study 
discontinuation/termination, whichever is earlier. After this period, investigators 
should only report SAEs that are attributed to prior study treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, 
laboratory test, or other means will be reported appropriately. Each reported AE 
or SAE will be described by its duration (i.e., start and end dates), regulatory 
seriousness criteria if applicable, suspected relationship to the ocrelizumab (see 
following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, 
investigators should apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the ocrelizumab, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
AE follows a known pattern of response to the ocrelizumab; and/or the AE abates 
or resolves upon discontinuation of the ocrelizumab or dose reduction and, if 
applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the ocrelizumab (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
ocrelizumab administration (e.g., event diagnosed 2 days after first dose of 
ocrelizumab). 
 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
19/P {Protocol Number} 
 
30032018 
 
Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or 
current Investigator Brochure (I.B.) or not identified. This includes adverse events 
for which the specificity or severity is not consistent with the description in the P.I. 
or I.B. For example, under this definition, hepatic necrosis would be unexpected 
if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
For patients receiving combination therapy, causality will be assessed 
individually for each protocol-mandated therapy. 
 
5.3   PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
 
Eliciting Adverse Events 
 
A consistent methodology for eliciting AEs at all subject evaluation timepoints 
should be adopted. Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new/changed health problems since you were last 
here?”  
 
Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs. Avoid colloquialisms and abbreviations. 
 
a. 
Diagnosis vs. Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported 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, it is ok to report the information 
that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
 
b. 
Deaths 
 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 5.1.2), regardless of attribution, will be reported to the appropriate 
parties. When recording a death, the event or condition that caused or 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
20/P {Protocol Number} 
 
30032018 
 
contributed to the fatal outcome should be reported as the single medical 
concept. If the cause of death is unknown and cannot be ascertained at the time 
of reporting, report “Unexplained Death”. 
 
c. 
Preexisting Medical Conditions 
 
A preexisting medical condition is one that is present at the start of the study. 
Such conditions should be reported as medical and surgical history. A preexisting 
medical condition should be re-assessed throughout the trial and reported as an 
AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to convey the 
concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
 
d. 
Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE. For example, 
if a subject is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study. 
 
e. 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used 
for assessing adverse event severity. Below Table should be used for assessing 
severity for adverse events that are not specifically listed in the NCI CTCAE. 
 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
NCI CTCAE  
 
Grade  
 
 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age appropriate instrumental activities of daily livinga 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
21/P {Protocol Number} 
 
30032018 
 
3 
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or limiting 
self care activities of daily livingb,c.  
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to adverse eventd 
 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be 
found at:  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  
d. Grade 4 and 5 events must be reported as serious adverse events    
 
f. 
Pregnancy 
 
If a female subject becomes pregnant while receiving the study drug or within 6 
months after the last dose of study drug, or if the female partner of a male study 
subject becomes pregnant while the study subject is receiving the study drug or 
within 6 months after the last dose of study drug, a report should be completed 
and expeditiously submitted to Genentech, Inc. Follow-up to obtain the outcome 
of the pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported 
as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a 
female subject exposed to the study drug should be reported as an SAE. 
 
Additional information on any ocrelizumab-exposed pregnancy and infant will be 
requested by Genentech/Roche Drug Safety at specific time points (i.e. after 
having received the initial report, at the end of the second trimester, 2 weeks 
after the expected date of delivery, and at 3, 6, and 12 months of the infant’s life). 
 
g.   Post-Study Adverse Events The investigator must report any SAE they 
might become aware of occurring after a subject has completed or discontinued 
study participation if attributed to prior ocrelizumab exposure. If the investigator 
should become aware of the development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female subject who participated in the 
study, this should be reported as an SAE adequately to Genentech drug Safety 
during follow up period 
 
h.  Case Transmission Verification of Single Case Reports 
 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
22/P {Protocol Number} 
 
30032018 
 
The Sponsor agrees to conduct the Case Transmission verification to ensure that 
all single case reports have been adequately received by Genentech via The 
Sponsor emailing Genentech a Quarterly line-listing documenting single case 
reports sent by The Sponsor to Genentech in the preceding time period.  
 
The periodic line-listing will be exchanged within seven (7) calendar days of the 
end of the agreed time period. Confirmation of receipt should be received within 
the time period mutually agreed upon. 
                    
If discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall 
handle the matter on a case-by-case basis until satisfactory resolution.  The 
sponsor shall receive reconciliation guidance documents within the ‘Activation 
Package’. 
 
Following Case Transmission Verification, single case reports which have not 
been received by Genentech shall be forwarded by The Sponsor to Genentech 
within five (5) calendar days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report 
will be sent to Genentech 
 
i.   AEs of Special Interest (AESIs) 
 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern 
specific to the product, for which ongoing monitoring and rapid communication by 
the Investigator to the Sponsor is required. Such an event might require further 
investigation in order to characterize and understand it. Depending on the nature 
of the event, rapid communication by the trial Sponsor to other parties (e.g., 
Regulatory Authorities) may also be warranted. 
 
 
There are no ocrelizumab Events of Special Interest. 
 
Adverse events of special interest for this study may include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT 
or AST in combination with either an elevated bilirubin or clinical jaundice, 
as defined by Hy’s law: 
o Treatment-emergent ALT or AST > 3 x ULN in combination with 
total bilirubin > 2 x ULN 
o Treatment-emergent ALT or AST > 3 x ULN in combination with 
clinical jaundice 
• 
Data related to a suspected transmission of an infectious agent by the 
study drug (STIAMP), as defined below: 
o Any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible spongiform encephalopathy), pathogenic 
or non-pathogenic, is considered an infectious agent.  A 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
23/P {Protocol Number} 
 
30032018 
 
transmission of an infectious agent may be suspected from clinical 
symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected 
 
j. Exchange OF SINGLE CASE REPORTS  
 
The Sponsor will be responsible for collecting all protocol-defined Adverse 
Events (AEs)/Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), 
Special Situation Reports (including pregnancy reports) and Product Complaints 
(with or without an AE) originating from the Study for the Product.  
 
Investigators must report all the above mentioned single case reports adequately 
to Genentech within the timelines described below. The completed MedWatch or 
CIOMS I form or Genentech approved reporting forms should be faxed/emailed 
immediately upon completion to Genentech at the following contacts: 
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including 
pregnancy reports) and Product Complaints with an AE should be sent to: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should be reported to: 
PC Hotline Number: (800) 334-0290 
 
It is understood and agreed that the Sponsor will be responsible for the 
evaluation of AEs/SAEs, AESIs, Special Situation Reports (including pregnancy 
reports) and Product Complaints (with or without an AE) originating from the 
study.  
These single case reports will be exchanged between the parties as outlined 
below so that regulatory obligations are met. 
 
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy 
reports (including pregnancy occurring in the partner of a male study subject), 
other Special Situation Reports and Product Complaints (with or without an AE), 
where the patient has been exposed to the Genentech Product, will be sent on a 
MedWatch form or CIOMS I form or on Genentech approved reporting forms to  
Genentech Drug Safety. Transmission of these reports (initial and follow-up) will 
be either electronically or by fax and within the timelines specified below: 
 
SADRs 
Serious AE reports that are related to the Product shall be transmitted to 
Genentech within fifteen (15) calendar days of the awareness date. 
 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to 
Genentech within thirty (30) calendar days of the awareness date. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
24/P {Protocol Number} 
 
30032018 
 
 
AESIs 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the 
awareness date. 
 
Special Situation Reports 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per 
se, as defined herein, any reports of pregnancy (including pregnancy occurring in 
the partner of a male study subject), where the fetus may have been exposed to 
the Product, shall be transmitted to Genentech within thirty (30) calendar days of 
the awareness date. Pregnancies will be followed up until the outcome of the 
pregnancy is known, whenever possible, based upon due diligence taken to 
obtain the follow-up information. 
 
Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special 
Situations Reports should be collected even in the absence of an Adverse Event 
and transmitted to Genentech within thirty (30) calendar days: 
• 
Data related to the Product usage during breastfeeding 
• 
Data related to overdose, abuse, misuse or medication error (including 
potentially exposed or intercepted medication errors) 
• 
In addition, reasonable attempts should be made to obtain and submit the 
age or age group of the patient, in order to be able to identify potential 
safety signals specific to a particular population 
 
Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech 
within fifteen (15) calendar days of the awareness date. 
 
A Product Complaint is defined as 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 or clinical trial. 
 
 
MEDWATCH 3500A REPORTING GUIDELINES 
 
In addition to completing appropriate patient demographic (Section A) and 
suspect medication information (Section C & D), the report should include the 
following information within the Event Description (Section B.5) of the MedWatch 
3500A form: 
 
• 
Protocol number and title description  
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics (Section B.6) 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
25/P {Protocol Number} 
 
30032018 
 
• 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-Up Information 
 
• 
Additional information may be added to a previously submitted report by 
any of the following methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-
up 
• 
Adding supplemental summary information and submitting it as follow-up 
with the original MedWatch 3500A form 
• 
Summarizing new information and faxing it with a cover letter including 
patient identifiers (i.e. D.O.B. initial, patient number), protocol description 
and number, if assigned, brief adverse event description, and notation that 
additional or follow-up information is being submitted (The patient 
identifiers are important so that the new information is added to the correct 
initial report) 
 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download 
 
 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
Dr. Mainero as the Sponsor of the Study, will be responsible for the expedited 
reporting of safety reports originating from the study to the European Medicine 
Agency (EMA) through Eudravigilance Clinical Trial Module (EVCTM), where 
applicable. 
Dr. Mainero as the Sponsor of the Study, will be responsible for the preparation 
of six-monthly Suspected Unexpected Serious Adverse Reaction (SUSAR) 
reports and their submission to Investigators, Regulatory Authorities and the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), where 
applicable 
 
Dr. Mainero, as the PI of the Study, will be responsible for the expedited 
reporting of safety reports originating from the Study to the Regulatory Authorities 
(FDA) where it has been filed an IND in compliance with local regulations. 
 
The Sponsor will be responsible for the expedited reporting of safety reports 
originating from the Study to the Ethics Committees and Institutional Review 
Boards (IRB), where applicable. 
 
The Sponsor will be responsible for the distribution of safety information to its 
own investigators, where relevant, in accordance with local regulations. 
 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
26/P {Protocol Number} 
 
30032018 
 
 
Additional Reporting Requirements for IND Holders (if applicable):  
 
For Investigator-Initiated IND Studies, some additional reporting requirements for 
the FDA apply in accordance with the guidance set forth in 21 CFR § 
600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
 
The Investigator is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the Investigator to be possibly 
related to the use of ocrelizumab. An unexpected adverse event is one that is not 
already described in the ocrelizumab Investigator Brochure. Such reports are to 
be telephoned or faxed to the FDA and Genentech/Roche within 7 calendar days 
of first learning of the event. 
 
 
15 Calendar Day Written Report 
 
The Investigator is also required to notify the FDA and all participating 
investigators, in a written IND Safety Report, of any serious, unexpected AE that 
is considered reasonably or possibly related to the use of ocrelizumab. An 
unexpected adverse event is one that is not already described in the ocrelizumab 
investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR 
§ 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new 
report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to 
the FDA, Genentech/Roche, and all participating investigators within 15 calendar 
days of first learning of the event. The FDA prefers these reports on a MedWatch 
3500 form, but alternative formats are acceptable (e.g., summary letter). 
 
 
FDA fax number for IND Safety Reports: 
 
Fax: 1 (800) FDA 0178 
 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also 
be faxed to Genentech/Roche Drug Safety: 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
27/P {Protocol Number} 
 
30032018 
 
 
Fax: (650) 225-4682 or (650) 225-4630 
 
 
And The Sponsor will be responsible for the distribution of safety information to 
Site IRB: 
 
FAX (857) 282-5693 
Telephone (857) 282-1900 
 
For questions related to safety reporting, please contact Genentech/Roche Drug 
Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
 
 
 
AGGREGATE REPORTS  
 
 
IND ANNUAL REPORTS 
 
 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should 
be copied to Genentech 
 
Copies of such reports should be emailed to Genentech at:   
Genentech Drug Safety CTV mail box: ctvist_drugsafety@gene.com 
 
Other Reports  
 
The Sponsor will forward a copy of the Final Study Report to Genentech/Roche 
upon completion of the Study.  
 
 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. This includes all IND annual reports and the Clinical Study 
Report (final study report). Additionally, any literature articles that are a result of 
the study should be sent to Genentech. Copies of such reports should be mailed 
to the assigned Clinical Operations contact for the study: 
 
ocrelizumab-iis-d@gene.com 
 
And to Genentech Drug Safety CTV oversight mail box at: 
ctvist_drugsafety@gene.com 
 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
28/P {Protocol Number} 
 
30032018 
 
 
QUERIES 
 
Queries related to the Study will be answered by The Sponsor.  However, 
responses to all safety queries  from  regulatory  authorities  or  for publications 
will be discussed and coordinated between the Parties. The Parties agree that 
Genentech/Roche shall have the final say and control over safety queries relating 
to the Product. The Sponsor agrees that it shall not answer such queries from 
regulatory authorities and other sources relating to the Product independently but 
shall redirect such queries to Genentech/Roche. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses 
to urgent requests for information or review of data are met. The Parties will 
clearly indicate on the request the reason for urgency and the date by which a 
response is required. 
 
SAFETY CRISIS MANAGEMENT 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or 
regulatory actions that limit or restrict the way in which the Product is used, or 
where there is media involvement, the Party where the crisis originates will 
contact the other Party as soon as possible. 
 
The Parties agree that Genentech/Roche shall have the final say and control 
over safety crisis management issues relating to the Product. The Sponsor  
agrees that it shall not answer such queries from media and other sources 
relating to the Product but shall redirect such queries to Genentech/Roche. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
29/P {Protocol Number} 
 
30032018 
 
 
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT 
The Parties shall follow their own procedures for adherence to AE reporting timelines. 
Each Party shall monitor and, as applicable, request feedback from the other Party 
regarding AE 
report timeliness in accordance with its own procedures. The Parties agree to provide 
written 
responses in a timely manner to inquiries from the other Party regarding AE reports 
received 
outside the agreed upon Agreement timelines. If there is any detection of trends of 
increasing or 
persistent non-compliance to transmission timelines stipulated in this Agreement, both 
Parties 
agree to conduct ad hoc or institute a regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange 
timelines, with 
this Agreement, the Parties will jointly discuss and collaborate on clarifying and 
resolving the 
issues causing non-compliance. Every effort will be made by the non-compliant Party to 
solve the 
non-compliance issues and inform the other Party of the corrective and preventative 
actions taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, 
an audit 
under the provisions of this Agreement can be requested by either Party. The Parties 
will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the 
audit. The 
requesting Party will bear the cost of the audit. 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with 
Genentech or a Genentech representative: 
• Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any sub-investigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations. 
• Current curriculum vitae of the Principal Investigator 
• Written documentation of IRB approval of protocol and informed consent 
document 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
30/P {Protocol Number} 
 
30032018 
 
• A copy of the IRB-approved informed consent document 
• A signed Clinical Research Agreement 
 
6.2 
STUDY COMPLETION 
The following materials are requested by Genentech when a study is considered 
complete or terminated: 
• Any study report submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. This includes all IND annual reports and the Clinical Study 
Report (final study report). Additionally, any literature articles that are a result of 
the study should be sent to Genentech. Copies of such reports should be mailed 
to the assigned Clinical Operations contact for the study: 
• Email : ocrelizumab-iis-d@gene.com  
 
6.3 
INFORMED CONSENT 
The informed consent document must be signed by the subject or the subject’s 
legally authorized representative before his or her participation in the study.  The 
case history for each subject shall document that informed consent was obtained 
prior to participation in the study.  A copy of the informed consent document must 
be provided to the subject or the subject's legally authorized representative.  If 
applicable, it will be provided in a certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be 
available for verification by study monitors at any time. 
 
6.4 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL 
All study procedures of this protocol, the informed consent document, and 
relevant supporting information must be submitted to the IRB for review and must 
be approved before the study is initiated.  The study will be conducted in 
accordance with U.S. FDA, applicable national and local health authorities, and 
IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case the IRB must be updated at least once a year.  The 
Principal Investigator must also keep the IRB informed of any significant adverse 
events. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
31/P {Protocol Number} 
 
30032018 
 
Investigators are required to promptly notify their respective IRB of all adverse 
drug reactions that are both serious and unexpected.  This generally refers to 
serious adverse events that are not already identified in the Investigator Brochure 
and that are considered possibly or probably related to the molecule or study 
drug by the investigator.  Some IRBs may have other specific adverse event 
requirements that investigators are expected to adhere.  Investigators must 
immediately forward to their IRB any written safety report or update provided by 
Genentech (e.g., IND safety report, Investigator Brochure, safety amendments 
and updates, etc.). 
 
6.5 
STUDY MONITORING REQUIREMENTS 
NA 
 
6.6 
DATA COLLECTION 
Data collection will be carried on in the forms of imaging data and 
demographic/clinical data and/or questionnaire as detailed in the protocol. All 
data will be kept at the Martinos Center and accessible only to study 
investigators. 
 
6.7 
STUDY MEDICATION ACCOUNTABILITY (IF APPLICABLE) 
If study drug will be provided by Genentech, accurate records of all study drug 
dispensed from and returned to the study site should be recorded by using the 
institution’s drug inventory log. 
All expired, partially used or empty containers should be disposed of at the study 
site according to institutional standard operating procedure.   
 
6.8 
DISCLOSURE AND PUBLICATION OF DATA 
Subject medical information obtained by this study is confidential, and disclosure 
to third parties other than those noted below is prohibited. 
Upon the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or 
her welfare. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, 
Genentech, and the IRB for each study site, if appropriate. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
32/P {Protocol Number} 
 
30032018 
 
The results of this study may be published or presented at scientific meetings. 
The Sponsor will comply with the requirements for the publication of study 
results.   
Additionally, Section 801 of the Food and Drug Administration Amendments Act 
(FDAAA 801) (PDF) requires Responsible Parties to register and submit 
summary results of clinical trials with ClinicalTrials.gov. The law applies to certain 
clinical trials of drugs (including biological products) and medical devices. (refer 
to FDAAA 801 Requirements to learn about Responsible Party, Applicable 
Clinical Trials, and deadlines for registration and results submission) 
 
6.9 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for 2 years after marketing 
application approval.  If no application is filed, these records must be kept 
2 years after the investigation is discontinued and the U.S. FDA and the 
applicable national and local health authorities are notified.  Genentech will notify 
the Principal Investigator of these events. 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with U.S. FDA IND regulations and with the record 
retention policies of the relevant national and local health authorities. 

Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
33/P {Protocol Number} 
 
30032018 
 
REFERENCES 
 
1. 
Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neurites, 
apoptotic neurons, and reduced inflammation in cortical multiple sclerosis 
lesions. Ann Neurol. 2001 Sep;50(3):389-400. 
2. 
Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in 
secondary progressive multiple sclerosis associate with early onset of disease 
and severe cortical pathology. Brain. 2007 Apr;130(Pt 4):1089-104. 
3. 
Magliozzi R, Howell OW, Reeves C, et al. A Gradient of neuronal loss and 
meningeal inflammation in multiple sclerosis. Ann Neurol. 2010 Oct;68(4):477-93. 
4. 
Howell OW, Reeves CA, Nicholas R, et al. Meningeal inflammation is 
widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011 
Sep;134(Pt 9):2755-71. 
5. 
Lucchinetti CF, Popescu BF, Bunyan RF, et al. Inflammatory cortical 
demyelination in early multiple sclerosis. N Engl J Med. 2011 Dec 
8;365(23):2188-97. 
6. 
Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination 
and diffuse white matter injury in multiple sclerosis. Brain. 2005 Nov;128(Pt 
11):2705-12. 
7. 
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus Interferon Beta-
1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-34. 
8. 
Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus Placebo in 
Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-
20. 
9. 
Michel L, Touil H, Pikor NB, Gommerman JL, Prat A, Bar-Or A. B Cells in 
the Multiple Sclerosis Central Nervous System: Trafficking and Contribution to 
CNS-Compartmentalized Inflammation. Front Immunol. 2015;6:636. 
10. 
Li R, Rezk A, Miyazaki Y, et al. Proinflammatory GM-CSF-producing B 
cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015 Oct 
21;7(310):310ra166. 
11. 
Banati RB, Newcombe J, Gunn RN, et al. The peripheral benzodiazepine 
binding site in the brain in multiple sclerosis: quantitative in vivo imaging of 
microglia as a measure of disease activity. Brain. 2000 Nov;123 ( Pt 11):2321-37. 
12. 
Herranz E, Gianni C, Louapre C, et al. Neuroinflammatory component of 
gray matter pathology in multiple sclerosis. Ann Neurol. 2016 Nov;80(5):776-90. 
13. 
Herranz E, Hooker JM, Izquierdo-Garcia D, Loggia ML, Mainero C. Reply. 
Ann Neurol. 2016 Dec 29. 
14. 
Owen DR, Gunn RN, Rabiner EA, et al. Mixed-affinity binding in humans 
with 18-kDa translocator protein ligands. J Nucl Med. 2011 Jan;52(1):24-32. 
15. 
Owen DR, Yeo AJ, Gunn RN, et al. An 18-kDa translocator protein 
(TSPO) polymorphism explains differences in binding affinity of the PET 
radioligand PBR28. J Cereb Blood Flow Metab. 2012 Jan;32(1):1-5. 
16. 
Zurcher NR, Loggia ML, Lawson R, et al. Increased in vivo glial activation 
in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28. 
Neuroimage Clin. 2015;7:409-14. 
17. 
Loggia ML, Chonde DB, Akeju O, et al. Evidence for brain glial activation 
in chronic pain patients. Brain. 2015 Mar;138(Pt 3):604-15. 
18. 
Oh U, Fujita M, Ikonomidou VN, et al. Translocator protein PET imaging 
for glial activation in multiple sclerosis. J Neuroimmune Pharmacol.  
Sep;6(3):354-61. 
 
 

 
Protocol:  Ocrelizumab (Institution or Cooperative Group Name} 
34/P {Protocol Number} 
 
30032018 
 
APPENDIX B 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: Fax: 650-238-6067 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS 
COVER SHEET