Conditions: Radiologically Isolated Syndrome Multiple Sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 4 study in which eligible patients with RADIOLOGICALLY ISOLATED SYNDROME (RIS) (as defined by meeting 2017 McDonald criteria for DIS) will be randomized 1:1 to receive ocrelizumab treatment or placebo (standard of care).

Detailed description:
This study is designed to investigate the treatment effect of ocrelizumab compared with placebo on clinical and radiological outcomes in patients with RIS (i.e., asymptomatic CNS lesions fulfilling the 2017 McDonald criteria for DIS), as well as neuroimaging, serologic, immunologic and other exploratory biomarkers of MS disease biology in order to improve the understanding of B cell biology in early disease pathophysiology, characterize the emergence of CNS autoimmunity, and the mechanism of action of ocrelizumab in this population.

Arms:
arm 1: Three courses of ocrelizumab will be administered over the course of the study. arm 2: Three courses of placebo will be administered over the course of the study.

Interventions: intervention 1: Ocrelizumab intervention 2: Placebo
Intervention descriptions: intervention 1: The first course of ocrelizumab will be administered as two 300 mg infusions at Week 0 (Day 1) and Week 2 (Day 15), with the subsequent second- and third-courses given as a single 600 mg infusion at Weeks 24 and 48. intervention 2: Placebo will be administered at Week 0 (Day 1) and Week 2 (Day 15), with the subsequent second- and third-courses given at Weeks 24 and 48.

Protocol document:
Prot_SAP_000.pdf: 
OCRELIZUMABYale University 
Protocol ML42790, Version 2.0 
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 PROTOCOL 
TITLE: 
A PHASE 4, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO ASSESS THE EFFICACY OF 
OCRELIZUMAB IN PATIENTS WITH 
RADIOLOGICALLY ISOLATED SYNDROME 
STUDY NUMBER: 
ML42790 
VERSION NUMBER: 
2.0 
TEST PRODUCTS: 
Ocrelizumab (RO4964913) (OCREVUS®) 
INDICATION: 
Prevention of clinical multiple sclerosis in individuals 
with radiologically isolated disease. 
IND Number 
153801 
IND Holder 
Erin Longbrake, MD, PhD 
INVESTIGATOR: 
Erin Longbrake, MD, PhD 
PO Box 208018, New Haven, CT 06520 
Telephone:  203-287-6100 
Fax:  203-287-6101 
E-mail:  erin.longbrake@yale.edu 
SUPPORT PROVIDED 
BY: 
Genentech, Inc. 
 
PROTOCOL DATE: 
22 December 2022 
 
 
 
 
 
 
 
 


TABLE OF CONTENTS 
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PROTOCOL HISTORY 
 
Version 
Date 
2.0 
22 Dec 2022 
1.4 
05 July 2022 
1.3 
25 April 2022 
1.2 
20 July 2021 
1.1 
08 February 2021 
1.0 
19 November 2020 
 
 
BACKGROUND .................................................................................................. 11 
Background on Multiple Sclerosis ............................................................... 11 
Background on RADIOLOGICALLY ISOLATED SYNDROME ................... 12 
Background on OCRELIZUMAB ................................................................. 14 
Study Rationale and Benefit-Risk Assessment ........................................... 15 
OBJECTIVES AND ENDPOINTS ....................................................................... 18 
Primary Objective(s).................................................................................... 18 
Primary Efficacy Objective ....................................................................... 18 
Secondary Objective(s) ............................................................................... 18 
Secondary Efficacy Objective .................................................................. 18 
Exploratory Efficacy Objectives ............................................................... 18 
Safety Objectives ........................................................................................ 20 
STUDY DESIGN ................................................................................................. 20 
Description of the Study .............................................................................. 20 
End of Study and Length of Study .............................................................. 23 
Rationale for Study Design ......................................................................... 24 
Rationale for Ocrelizumab Dose and Schedule ....................................... 24 


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Rationale for Patient Population and Use of 2017 McDonald 
Criteria ..................................................................................................... 24 
Rationale for Control Group ..................................................................... 25 
Rationale for Biomarker Assessments ..................................................... 25 
MATERIALS AND METHODS ............................................................................ 27 
Patients 
27 
Inclusion Criteria ...................................................................................... 27 
Exclusion Criteria ..................................................................................... 28 
Method of Treatment Assignment and Blinding .......................................... 31 
Treatment Assignment ............................................................................. 31 
Blinding .................................................................................................... 32 
Study Treatment ......................................................................................... 33 
Study Treatment Formulation, Packaging, and Handling ......................... 33 
Ocrelizumab and Placebo .................................................................. 33 
NonInvestigational Medicinal Products ............................................... 34 
Study Treatment Dosage, Administration, and Compliance..................... 34 
Ocrelizumab and Placebo .................................................................. 34 
Premedications ................................................................................... 35 
ReTreatment Criteria for Ocrelizumab ................................................ 35 
Investigational Medicinal Product Accountability ..................................... 36 
Continued Access to Ocrelizumab ........................................................... 36 
Concomitant Therapy .................................................................................. 36 
Treatment of First Clinical Neurologic Event ............................................ 37 
Treatment of Radiologic Event ................................................................. 37 
Prohibited Therapy .................................................................................. 38 
Immunizations .......................................................................................... 38 
Study Assessments..................................................................................... 39 
Informed Consent Forms and Screening Log .......................................... 39 
Overview of Clinical Visits ........................................................................ 40 
Delayed Dosing Visit ................................................................................ 40 
Unscheduled Visits .................................................................................. 40 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................................... 41 


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Physical Examinations ............................................................................. 41 
Vital Signs ................................................................................................ 41 
Neurological Examination ........................................................................ 42 
Brain and Cervical Spine Magnetic Resonance Imaging ......................... 42 
Assessment of Disability:  Expanded Disability Status Scale ................... 43 
Symbol Digit Modalities Test .................................................................... 44 
Assessment of Neurologic Event ............................................................. 44 
Laboratory, Biomarker, and Other Biological Samples ............................ 45 
Hepatitis Screening and Liver Function Monitoring .................................. 48 
Patient-Reported Outcomes .................................................................... 49 
Data Collection Methods for Clinical Outcome 
Assessments ...................................................................................... 49 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) ................................ 50 
Optional Lumbar Punctures ..................................................................... 51 
Optional Samples for Immune Cell Network Sub-study ........................... 51 
Optional Samples for Research Biosample Repository ........................... 53 
Sample Collection............................................................................... 53 
Confidentiality ..................................................................................... 54 
Consent to Participate in the Research Biosample 
Repository .......................................................................................... 54 
Withdrawal from the Research Biosample Repository ........................ 55 
Monitoring and Oversight ................................................................... 55 
Treatment, Patient, and Study Discontinuation ........................................... 56 
Study Treatment Discontinuation ............................................................. 56 
Patient Discontinuation from the Study .................................................... 56 
Study Discontinuation .............................................................................. 57 
Site Discontinuation ................................................................................. 57 
ASSESSMENT OF SAFETY .............................................................................. 58 
Safety Plan 58 
Risks Associated with Ocrelizumab ......................................................... 58 
Identified Risks and Adverse Drug Reactions .................................... 58 
Potential Risks .................................................................................... 61 


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Risks Associated with Corticosteroids ..................................................... 62 
Risks Associated with Antihistamines ...................................................... 62 
Management of Patients Who Experience Adverse Events ..................... 62 
Dose Modifications ............................................................................. 62 
Treatment Interruption ........................................................................ 62 
Management Guidelines InfusionRelated Reactions .......................... 62 
Safety Parameters and Definitions .............................................................. 63 
Adverse Events ........................................................................................ 63 
Serious Adverse Events ........................................................................... 63 
Adverse Events of Special Interest .......................................................... 64 
Methods and Timing for Assessing and Recording Safety 
Variables ................................................................................ 64 
Adverse Event Reporting Period .............................................................. 65 
Assessment of Adverse Events ............................................................... 65 
Procedures for Eliciting, Recording, and Reporting Adverse 
Events.................................................................................... 66 
Eliciting Adverse Event Information ......................................................... 66 
Specific Instructions for Recording Adverse Events ................................ 66 
Diagnosis versus Signs and Symptoms ............................................. 66 
Deaths ................................................................................................ 66 
Preexisting Medical Conditions .......................................................... 66 
Hospitalizations for Medical or Surgical Procedures .......................... 66 
Assessment of Severity of Adverse Events ........................................ 67 
Assessment of Causality of Adverse Events ............................................ 67 
Pregnancies ....................................................................................... 67 
Other Special Situations Reports ....................................................... 68 
Product complaints ............................................................................. 68 
Post-Study Adverse Events ................................................................ 68 
Adverse Event Reporting ............................................................................ 68 
Reporting Requirements For Adverse Events Originating 
From Patient Reported Outcomes ........................................................... 71 
MedWatch 3500A Reporting Guidelines .................................................. 71 
Follow-up Information ......................................................................... 71 


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Reporting to Regulatory Authorities, Ethics Committees and 
Investigators ............................................................................................ 72 
Aggregate Reports ...................................................................................... 73 
Study Close-Out .......................................................................................... 74 
STATISTICAL CONSIDERATIONS .................................................................... 76 
Determination of Sample Size ..................................................................... 76 
Summaries of Conduct of Study ................................................................. 77 
Summaries of Treatment Group Comparability ........................................... 77 
Efficacy Analyses ........................................................................................ 77 
Primary Efficacy Endpoint ........................................................................ 77 
Secondary Efficacy Endpoints ................................................................. 78 
Exploratory Efficacy Endpoints ................................................................ 79 
Safety Analyses .......................................................................................... 79 
Biomarker Analyses .................................................................................... 79 
Interim Analyses ......................................................................................... 80 
Data  Quality Assurance ............................................................................. 80 
INVESTIGATOR REQUIREMENTS ................................................................... 81 
Retention of Records .................................................................................. 81 
Study Medical Monitoring Requirements..................................................... 82 
Study Medication Accountability ................................................................. 82 
Data Collection ............................................................................................ 83 
ETHICAL CONSIDERATIONS ........................................................................... 83 
Compliance with Laws and Regulations...................................................... 83 
Informed Consent ....................................................................................... 83 
Institutional Review Board or Ethics Committee ......................................... 83 
Confidentiality ............................................................................................. 84 
REFERENCES ................................................................................................... 85 
 
 
 
LIST OF TABLES 
Table 1  Diagnostic Criteria for Dissemination in Space ..................................... 12 


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Table 2  Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE .......................................................................................... 67 
 
 
LIST OF APPENDICES 
Appendix 1  Schedule of Activities ...................................................................... 93 
Appendix 2  Immune Cell Network Sub-study .................................................... 99 
Appendix 4  Registry of First Degree Family Members with MS ....................... 103 
Appendix 6  New York Heart Association Classification of 
Functional Cardiac Capacity ............................................................................. 107 
Appendix 7  Progressive Multifocal Leukoencephalopathy:  Guidance for 
Diagnosis of Progressive Multifocal Leukoencephalopathy .............................. 109 
Appendix 8  2017 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis ........................................................................................................... 115 
Appendix 9  Pregnancy Outcome and Infant Health Information on First 
Year of Life ....................................................................................................... 117 
Appendix 10  Neuro-QOL ................................................................................. 125 
Appendix 11  Safety Reporting Fax Cover Sheet………………………….136 




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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
β-hCG 
beta subunit human chorionic gonadotropin 
CI 
confidence interval 
CNS 
central nervous system 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DIS 
dissemination in space 
DMT 
disease-modifying therapy 
DSS 
disease status scale 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EDSS 
Expanded Disability Status Scale 
Gd 
gadolinium 
FS 
Functional Systems 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HepCAb 
hepatitis C antibody 
IFN-β 
interferon beta 
Ig 
immunoglobulin 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IV 
intravenous 
IxRS 
interactive voice/web response system 
LLN 
lower limit of normal 
LPLV 
last patient, last visit 
LP 
lumbar puncture 
MMRM 
mixed model with repeated measure 
MRI 
magnetic resonance image  
MS 
multiple sclerosis 
NfL 
neurofilament light (chain) 
OCB 
oligoclonal bands 
PCR 
polymerase chain reaction 
PML 
progressive multifocal leukoencephalopathy 


 
 
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PPMS 
primary progressive multiple sclerosis 
PRO 
patient reported outcome 
RIS 
radiologically isolated syndrome 
RMS 
relapsing multiple sclerosis 
RRMS 
relapsing-remitting multiple sclerosis 
scRNAseq 
single-cell RNA sequencing  
SPMS 
secondary progressive multiple sclerosis 
 
 
 


 
 
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BACKGROUND 
BACKGROUND ON MULTIPLE SCLEROSIS 
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and degenerative 
disease of the CNS that affects approximately 2.3 million people worldwide 
(Tullman et al. 2013 MSIF 2013).  While MS is a global disease, its prevalence is highest 
in North America and Europe (140 and 108 per 100,000 people, respectively) 
(MSIF 2013).  A recent study by leading experts, launched and supported by the 
National MS Society, estimates that in 2017 nearly 1 million adults (up to 913,925) were 
living with MS in the United States.  This is more than twice the previously reported 
estimates (Wallin et al. 2019). MS primarily affects young adults, with nearly 80% of 
patients having an age of onset (i.e. initial clinical presentation to a physician) between 
20 and 40 years (Tullman 2013).  Overall, there is a strong gender bias:  MS is 
approximately twice as prevalent in women as in men, except in individuals with the 
primary-progressive form of the disease, where there is no gender prevalence difference 
(MSIF 2013; Tullman 2013).  Reasons for these observed differences are unclear.  
However, once progression begins, it continues at similar rates in women and men 
(Leray et al. 2010).  
MS can be subcategorized into three major phenotypic disease patterns, including 
relapsing-remitting MS (RRMS), primary-progressive MS (PPMS) and secondary 
progressive MS (SPMS).  In approximately 85% of patients, MS begins as a relapsing, 
episodic disorder with gradual complete or incomplete recovery (i.e., RRMS).  Over time, 
and if left untreated, the majority of these patients transition to a secondary-progressive 
form characterized by worsening neurologic disability, either with or without occasional 
super-imposed relapses (i.e., active- or non-active SPMS, respectively).  Patients 
accumulate disability as a result of incomplete recovery from acute relapses and/or 
gradual often insidious disease progression (Tullman 2013).  The term ‘relapsing 
multiple sclerosis (RMS)’ applies to those patients with either RRMS or SPMS who 
continue to suffer relapses (i.e. active-SPMS).  Nonetheless, overwhelming evidence 
suggests that neuroinflammation is present throughout all clinical courses of MS 
(Frischer et al. 2009).  Differences between disease phenotypes may be due to the 
differential contribution of inflammatory and neurodegenerative processes to the 
pathology of CNS damage over time (Frischer et al. 2009, 2015). Therefore, patients 
with MS regardless of subtype and stage, share a common underlying inflammatory 
pathophysiology that therefore constitutes a common therapeutic target. 
Although the exact etiology of MS remains largely unknown, there is consensus that MS 
is an autoimmune disease driven by aberrant functioning of both the adaptive and innate 
immune system in genetically susceptible individuals.  Considerable evidence suggests 
that early intervention with disease modifying therapies (DMT) is beneficial for MS 


 
 
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patients and is associated with more favorable long-term outcomes. Significant 
advances have been made in the identification of biomarkers and risk-factors that lead to 
earlier and thus more accurate diagnosis of MS. Magnetic resonance imaging (MRI) is 
among one of the most valuable biomarkers for MS diagnosis. An unintended 
consequence of widespread use of MRI by the medical community has been incidental 
findings of CNS abnormalities that are consistent with inflammatory or demyelinating 
lesions. This has augmented the overall awareness of MRI findings suggestive of MS, 
particularly in individuals who are otherwise asymptomatic and clinically “normal,” but 
are nevertheless at increased risk of developing clinical CNS demyelinating disease.  
BACKGROUND ON RADIOLOGICALLY ISOLATED SYNDROME 
The term ‘radiologically isolated syndrome’ (RIS) was first introduced in 2009 by Okuda 
and colleagues to describe the presence of these incidentally identified CNS white 
matter anomalies that were typical of inflammatory demyelinating disease in subjects 
with no present or past symptoms suggestive of MS (Okuda et al. 2009). The diagnostic 
criteria for RIS proposed by Okuda et al. requires a heavy lesion burden, strictly defining 
the morphology, size, location, number, and distribution of lesions fulfilling at least three 
out of four Barkhoff criteria for dissemination in space (DIS) in order to differentiate those 
at highest-risk for developing MS (Table 1). In addition, the Okuda criteria also include 
an indication for MRI other than suspected MS, and exclude other disease entities that 
could better account for the observed paraclinical anomalies. Approximately one-third of 
patients with RIS will experience a first acute or progressive clinical event related to CNS 
demyelination within 5 years, while two-thirds of patients with RIS show radiologic 
progression with a median of 2.7 years (Lebrun et al. 2008; Granberg et al 2013; 
Okuda et al. 2014, and Yamout 2017).  Several factors have been associated with 
conversion to MS in RIS patients, including younger age (<40), sex (male) and the 
presence of spinal cord or infratentorial brain lesions (Okuda et al. 2011; Etemadifar et 
al. 2014; Okuda et al. 2014; Makhani 2017;Thouvenot et al. 2019).  Abnormal 
cerebrospinal fluid (CSF) findings, including the presence of oligoclonal bands (OCBs) 
and/or elevated IgG index, have also been suggested as potential risk factors for clinical 
conversion (Nakamura et al. 2014; Gastaldi 2017; Matute-Blanch et al. 2018; and 
Makhani et al. 2019).   
Table 1 
Diagnostic Criteria for Dissemination in Space 
Okuda Diagnostic Criteria for RIS 
2017 McDonald Diagnostic Criteria for MS 
The presence of incidentally identified CNS 
white matter anomalies meeting the following 
MRI criteria: 
≥1 T2-hyperintense lesions characteristic of 
MS in ≥2 of 4 CNS areas  
Periventricular 
Cortical or juxtacortical 
Infratentorial brain regions 


 
 
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Ovoid, well-circumscribed, and homogeneous 
foci with or without involvement of the corpus 
callosum 
T2 hyperintensities measuring >3mm and 
fulfilling ≥3 of 4 Barkhof criteria for DIS 
≥9 lesions or ≥1 Gd+ lesion  
≥3 periventricular lesions  
≥1 juxtacortical lesion  
≥1 infratentorial lesion 
Spinal cord 
CNS=central nervous system; Gd=gadolinium; MRI=magnetic resonance imaging; MS=multiple 
sclerosis; RIS=radiologically isolated syndrome 
 
Pathological changes and degenerative processes occur very early in MS, even years 
before clinical signs surface. In this regard, studies have demonstrated a close 
association between RIS and MS since the initial formal description in 2009.  Therefore, 
it has been suggested that RIS represents a preclinical phase of MS (Siva et al. 2009; 
Amato et al. 2012; and Boyko 2019).  Similar lesion loads and brain atrophy have been 
demonstrated in RIS and patients with well-established MS (De Stefano et al. 2011; 
Amato et al. 2012).  Patients with RIS have subclinical cognitive impairment (Hakiki et al. 
2008; Lebrun et al. 2010; Amato et al. 2012; Cortese et al. 2016; and Labiano-
Fontcuberta et al. 2016), inflammation (Lebrun 2009; Rossi et al. 2015; and Bjornevik et 
al. 2019) and CNS pathology (Stromillo et al. 2013) similar to that described in patients 
with MS.  Furthermore, other non-descript neurologic symptoms that do not yet surpass 
the clinical threshold often present in patients at high-risk for developing MS (e.g., 
anxiety, depression, migraine, lower cognitive performance, etc.). It is widely recognized 
that this early preclinical and prodromal phase of disease may go unnoticed for many 
years prior to the clinical manifestation of MS (Cortese et al. 2016; Wijnands et al. 2017; 
Disanto 2018; Bjornevik et al. 2019, Wijnands et al. 2019; Zhao et al. 2020).  This is 
accompanied by increased health care utilization in the years preceding MS diagnosis 
(Wijnands et al. 2017; Disanto et al. 2018; Wijnands et al. 2019a; Wijannds et al 2019b).  
Serum neurofilament light chain (NfL), a biomarker of neuroaxonal injury, has been 
found to be elevated years before the clinical onset of MS (Bjornevik et al. 2019), further 
indicating not only that a preclinical and prodromal phase of MS exists, but also that 
subclinical tissue damage is already occurring during this early stage of disease.  
While Okuda criteria have now been widely used to study RIS, they require a higher 
burden of radiologic disease than modern diagnostic criteria for MS. The 2017 McDonald 
criteria are used in clinical practice to identify MS. This iteration of the McDonald criteria 


 
 
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has allowed earlier identification of MS, requiring as few as two CNS lesions among 
patients presenting with a first clinical symptom of disease (Thompson et al. 2018). 
 
BACKGROUND ON OCRELIZUMAB 
Ocrelizumab is a recombinant humanized, glycosylated, monoclonal IgG1 antibody that 
selectively targets and depletes CD20-expressing B cells, while preserving the capacity 
of B-cell reconstitution and preexisting humoral immunity.  CD20 is a B-cell surface 
molecule that is restricted in expression to pre−B cells and mature B cells but is not 
expressed earlier in the development of B cells (Banchereau and Rousset 1992).  Based 
on the results of ocrelizumab Phase III studies in patient populations with relapsing MS 
(RMS) and PPMS, ocrelizumab was approved by the US Food and Drug Administration 
(FDA) on 28 March 2017 for the treatment of adult patients with RMS and PPMS and by 
the European Medicines Agency (EMA) on 12 January 2018 for patients with active 
relapsing forms of MS defined by clinical or imaging features and for patients with early 
PPMS in terms of disease duration and level of disability, and with imaging features 
characteristic of inflammatory activity.  
Two identical randomized, active-controlled studies (OPERA I [Study WA21092] and 
OPERA II [Study WA21093]) have demonstrated superior efficacy outcomes versus 
interferon β-1a in patients with RMS (Hauser et al. 2017); one randomized placebo-
controlled study (ORATORIO [Study WA25046]) has demonstrated superior efficacy in 
PPMS versus placebo (Montalban et al. 2017).  Results of these studies show that 
depletion of CD20+ B cells leads to a significant impact on a broad range of clinical 
measures of disease, including disability progression, in addition to an impact on 
magnetic resonance imaging (MRI) outcomes related to disease progression and 
reflective of neural tissue loss, thus further supporting the hypothesis that B cells are 
central to the pathogenesis of both RMS and PPMS.  Ocrelizumab has demonstrated a 
favorable safety profile in patients with RMS and PPMS (Hauser et al. 2017; Montalban 
et al. 2017).  The proportion of patients with adverse events was similar in patients 
treated with ocrelizumab compared with interferon β-1a (both 83.3%) or placebo 
(95.1% vs. 90.0%).  The proportion of patients experiencing a serious adverse event 
was similar between ocrelizumab and the comparator groups (in RMS: 6.9% 
[ocrelizumab] and 8.7% [interferon β-1a]; in PPMS: 20.4% [ocrelizumab] and 
22.2% [placebo]).  
Refer to the Ocrelizumab Investigator's Brochure and/or local prescribing information for 
details on nonclinical and clinical studies of ocrelizumab. 


 
 
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STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
This study is designed to investigate the treatment effect of ocrelizumab compared with 
placebo on clinical and radiological outcomes in patients with RIS (i.e., asymptomatic 
CNS lesions fulfilling the 2017 McDonald criteria for DIS), as well as neuroimaging, 
serologic, immunologic and other exploratory biomarkers of MS disease biology in order 
to improve the understanding of B cell biology in early disease pathophysiology, 
characterize the emergence of CNS autoimmunity, and the mechanism of action of 
ocrelizumab in this population.   
In general, DMTs have been demonstrated to be more effective when utilized at the 
onset of disease (Comi et al. 2001 and 2009; Leist et al. 2014; Miller 2014).  Multiple 
randomized clinical studies have supported the benefit of treatment early in the course of 
disease, demonstrating that early initiation of DMT after a first event in patients with CIS 
significantly delays the time to a second clinical attack and reduces the accumulation of 
new MRI lesions (Comi et al. 2001 and 2009; Goodin 2009; Leist et al. 2014; Miller 
2014).  Yet despite this evidence supporting the benefit of early DMT use, it is reported 
that most clinicians adopt a “wait-and-watch” approach for RIS, periodically monitoring 
patients and delaying treatment until the emergence of clinical symptoms (Sellner et al. 
2010; Alshamrani 2017).  Delaying treatment in at-risk RIS patients could result in 
irreversible CNS damage and permanent disability, even despite repair and 
compensatory mechanisms that might account for the lack of obvious clinical symptoms 
(Akbar et al. 2016; Labiano-Fontcuberta 2017; Okuda 2017; and Makhani et al. 2018).  
Furthermore, it has been reported that subjects with RIS evolve to PPMS with a similar 
frequency as that observed in the general MS population, providing further evidence that 
RIS represents a preclinical stage of disease that is biologically part of the MS spectrum 
(McDonnel et al. 2003; Kantarci et al. 2016). In this regard, patients with RIS have been 
demonstrated to have evidence of early axonal loss (Stromillo et al. 2012, 2013; 
Azevedo et al. 2015), brain atrophy (De Stefano et al. 2011, Labiano-Fontcuberta et al. 
2016a; Labiano-Fontcuberta et al. 2016b; Alcaide-Leon et al. 2018), and subclinical 
inflammatory disease, including elevated serum NfL (Bonzano et al. 2013; Disanto et al. 
2016; Knier et al. 2016; Malute-Blanch et al. 2018), and IL-8 (Rossi et al. 2015), as well 
as retinal nerve fiber layer thinning (Vural et al. 2020) as observed by OCT. Cognitive 
deficits, such as impaired information processing speed (Achiron et al; 2003; Lebrun et 
al. 2010; Amato et al. 2012; D’Anna et al. 2014; Labiano-Fontcuberta et al. 2016; 
Menascu et al. 2019), and increased anxiety and depression have also been noted in 
patients with RIS (Labiano-Fontcuberta et al. 2015). These changes, often subtle, may 
be missed during routine neurological assessments and can significantly impact quality 
of life even if physical functioning remains intact (Glanz et al. 2010). 
Despite a pathophysiologic rationale for treatment, limited data exist on the use of DMT 
in RIS.  Randomized, clinical trials are needed to provide evidence for the benefit: risk of 


 
 
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intervening therapeutically at this stage of disease (Okuda et al. 2015; Lebrun et al. 
2016).  The results of the first randomized clinical trial in RIS have recently been relased: 
ongoing use of the MS medication dimethyl fumarate reduced the chances of RIS 
patients converting to clinical MS (Okuda et al. 2022). No changes to the drug’s label 
have been made, however, and dimethyl fumarate will require continuous use for 
ongoing efficacy. It is not clear that a lifelong immunotherapy will be an acceptable 
method for treating RIS. Early intervention in the RIS population with short-term use of 
ocrelizumab, a high efficacy DMT, provides the unique opportunity to address this unmet 
need.   
The Phase III program of ocrelizumab comprised three pivotal Phase III studies that 
evaluated ocrelizumab 600 mg administered as an IV infusion at a fixed-interval 
schedule every 24 weeks, which demonstrated favorable benefit-risk profile in RMS and 
PPMS.  Together, these data derived from a total of 2381 patients demonstrated that 
selective depletion of CD20+ B cells leads to a significant impact on a broad range of 
clinical measures of disease, including relapse rate, MRI outcomes and disability 
progression.  
Data from the ocrelizumab development program support the hypothesis that B cells are 
central to the pathogenesis of MS. B cells play a significant role in the pathophysiology 
of MS at all stages of disease (Hauser et al. 2017; Montalban et al. 2017; Sabatino 
2019; Lassmann 2019).  B cells are involved in cytokine regulation and antigen 
presentation to T cells, myeloid cell activation, and are also the source of intrathecal 
antibody production, including clonally expanded IgG bands (oligoclonal bands [OCB]) 
detected in the CSF of approximately 90% of MS patients (Dobson et al. 2013; Li 2018).  
Ectopic lymphoid follicles rich with B cell aggregates can be found in the meninges of 
MS patients and are associated with cortical demyelination and neuroaxonal damage 
(Magliozzi et al. 2007 and 2010; Howell et al. 2011).  Recent studies investigating the 
role of B cells in the early stages of MS (i.e., CIS) have revealed that markers of B cell 
activation and antigen-driven responses within the CSF predict conversion to clinically 
definite MS and correlate with MRI activity, onset of relapses and future disability 
progression (Serafini et al. 2004; Imrell et al. 2009; Joseph et al. 2009; Sellebjerg et al. 
2009; Brettschneider et al. 2010; Magliozzi et al. 2010; Howell et al. 2011; Kalinowska-
Łyszczarz et al. 2011; Khademi et al. 2011; Disanto et al. 2012; Dobson et al. 2013).  
Furthermore, in RIS it has been observed that B cells are skewed toward a 
proinflammatory phenotype and produce less of the immunoregulatory cytokine IL-10.  
This was associated with the emergence of disease activity and poor prognosis 
(Guerrier et al. 2018).   These data along with the profound clinical benefit of 
ocrelizumab on suppressing disease activity and disability progression in RMS and 
PPMS, underscore the central role of B cells in the immunopathophysiology of MS.  
Given the remarkable success of ocrelizumab on clinical outcomes in MS, the question 
arises as to whether treatment in radiologically isolated disease might provide an even 


 
 
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more favorable therapeutic benefit than in patients with established disease.  Early 
intervention in this population with ocrelizumab, a high efficacy DMT, provides the 
unique opportunity to address this unmet need.  Ocrelizumab is particularly attractive for 
use in RIS patients at high-risk for developing MS because of (1) its well-characterized 
safety profile, (2) administration and dosing schedule, and (3) that it targets peripheral B 
cells that eventually migrate into the CNS and drive compartmentalized CNS 
inflammation (i.e., CNS leukocyte recruitment, focal demyelinated lesions, intrathecal 
antibody production with OCBs, etc.).  The B cell profile that reconstitutes after anti-
CD20 depletion exhibits a naïve phenotype that produce high levels of IL-10 (Duddy et 
al. 2007; Bar-Or et al. 2010; Barr et al. 2012; Li et al. 2015; Longbrake 2016; Li 2018) 
and less proinflammatory cytokines (i.e., IL-6, TNF, GM-CSF, and LT). This suggests 
that B cell depletion may alter immunoregulatory networks and restore the 
proinflammatory to anti-inflammatory imbalance that contributes to long lasting impact on 
MS disease activity and disability progression. Whether therapeutic intervention with 
ocrelizumab during RIS “functionally-resets” the immune system and thereby leads to 
durable improvement of long-term outcomes and the delay or prevention of the clinical 
manifestation of MS is unknown.  
Administering three courses of ocrelizumab permits the interrogation of the 
immunodynamics surrounding the emergence of CNS autoimmunity and the 
reconstitution of the immune system following anti-CD20 B cell depletion. Understanding 
the effect of B cell depletion in RIS will provide invaluable insight into MS pathogenesis 
as well as the mechanism of action of ocrelizumab, both of which remain poorly 
understood. 
While this study is the first clinical trial investigating the use of ocrelizumab in patients 
with RIS, ocrelizumab is well established as a standard of care, high efficacy disease-
modifying therapy for the treatment of patients with RMS (including CIS, RRMS, SPMS) 
and PPMS; with a favorable safety profile in over 130,000 patients worldwide since its 
US FDA approval in 2017.  Therefore, the benefits versus the risks for individual 
participants treated with ocrelizumab for study-related procedures are considered 
acceptable. 
 


 
 
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OBJECTIVES AND ENDPOINTS 
PRIMARY OBJECTIVE(S) 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the treatment effect of 
ocrelizumab compared with placebo on delaying the time to development of new 
radiologic or clinical evidence of MS. 
Primary Efficacy Endpoint: 
Time to development of first new radiologic (e.g., new or enlarging T2 lesions, T1 
gadolinium-enhancing lesions consistent with MS) or clinical evidence of MS (i.e., 
neurological event resulting from CNS demyelination, as evidenced by acute or 
progressive clinical syndrome consistent with MS). 
A detailed description of the primary endpoints and estimands are provided in Section 
6.4.1.  
SECONDARY OBJECTIVE(S)  
Secondary Efficacy Objective 
The secondary objectives for this study are to understand the treatment effect of 
ocrelizumab compared with placebo on clinical, neuroimaging and serum neurofilament 
light (NfL) biomarkers that are associated with disease activity, and with the clinical 
response to ocrelizumab.   
Secondary Efficacy Endpoints: 
Cumulative number of new or enlarging T2 lesions identified at Weeks 48, 104 and 208 
Change in T2-lesion volume from Baseline to Weeks 48, 104 and 208 
Cumulative number of new T1 gadolinium-enhancing lesions identified at Weeks 48, 104 
and 208 
Change from Baseline to Weeks 48, 104 and 208 in total brain volume 
Change from Baseline to Weeks 48, 104 and 208 in total spinal cord volume  
Change from Baseline to Weeks 48, 104 and 208 in serum NfL (sNfL)  
 
Exploratory Efficacy Objectives 
The exploratory objectives for this study are to evaluate inflammatory, 
neurodegenerative, and exploratory biomarkers of disease activity in the blood and 
cerebrospinal fluid (CSF) and their correlations with radiologic, clinical and patient 
reported outcomes.  
Exploratory Efficacy Endpoints: 


 
 
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Change from Baseline to Weeks 48, 104 and 208 in white matter volume, gray matter 
volume, and thalamic volume 
Change from Baseline to Weeks 48, 104 and 208 in spinal cord white and gray matter 
volume 
Change from Baseline to Week 104 and 208 in CSF immune cell populations frequency 
and phenotype 
Change from Baseline to Week 104 and 208 in CSF NfL levels 
Percent change in the presence of CSF oligoclonal bands (OCB) from Baseline to 
Weeks 104 and 208 
Percent change in normalization of CSF IgG index from Baseline to Weeks 104 and 208 
Change from Baseline to Weeks 104 and 208 in CSF biomarkers (i.e., CSF Weeks 104 
and 208 only), including CXCL13, BAFF (B cell activating factor), TNF, IL-6, IL-10, IL-17, 
interferon-gamma, IL-4, IL-23, IL-8, soluble CD27 (sCD27), genetic risk factors (HLA-
DRB1*15:01) or other emerging exploratory markers of disease biology as appropriate 
Change from Baseline to Weeks 48, 104, and 208 in slowly evolving lesions (SEL) 
Change from Baseline to Weeks 24, 48, 72, 104, 130, 156, 182 and 208 in peripheral 
blood immune cell population frequency and phenotype, including B cells, T cells and 
innate immune cells (monocyte, macrophage, neutrophils, natural killer cells, etc.)  
Change from Baseline to Weeks 24, 48, 72, 104, 130, 156, 182 and 208 in peripheral 
blood biomarkers, including CXCL13, BAFF (B cell activating factor), TNF, IL-6, IL-10, 
IL-17, interferon-gamma, IL-4, IL-23, IL-8, soluble CD27 (sCD27), genetic risk factors 
(e.g., HLA-DRB1*15:01) or other emerging exploratory markers of disease biology as 
appropriate 
Change from Baseline to Weeks 24, 48, 72, 104, 130, 156, 182 and 208 in patient 
reported outcomes, including quality of life, fatigue, depression, and disability, as 
measured by Neuro-QoL™ 
Change from Baseline to Weeks 24, 48, 72, 104, 130, 156, 182 and 208 in cognitive 
function and information processing speed as measured by symbol digit modality test 
(SDMT)  
Correlation between changes in compartment-specific biomarkers of disease biology 
with radiologic and/or clinical disease outcomes 
Correlation between changes in patient reported outcomes, including SDMT, and 
radiologic and/or clinical disease outcomes  
Correlation between changes in compartment-specific immune cell subsets with 
radiologic and/or clinical disease outcomes.  
Correlation between changes in NfL levels and radiologic and/or clinical disease 
outcomes 
Correlation between changes in CSF abnormalities (OCB and IgG index) and radiologic 
and/or clinical disease outcomes  
 
 


 
 
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SAFETY OBJECTIVES 
The safety objectives for this study are to evaluate the safety of ocrelizumab compared 
with placebo on the basis of the following endpoints: 
Nature, frequency, severity, and timing of adverse events 
Vital signs, physical findings, and clinical laboratory results during and following study 
drug administration 
Adverse events related to biomarker sample collection  
 
STUDY DESIGN 
DESCRIPTION OF THE STUDY 
This study includes a main study for all patients enrolled and one optional sub-study: an 
Immune Cell Network sub-study.  The following is a description of the main study.  A 
schedule of activities (SOA) for the main study is provided in Appendix 1.  For details on 
the Immune Cell Network sub-study, please refer to 


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Appendix 2. For the sub-study schema, please refer to Appendix 3 
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 4 study in 
which eligible patients with RIS (as defined by meeting 2017 McDonald criteria for DIS) 
will be randomized 1:1 to receive ocrelizumab treatment or placebo (standard of care).  
Three courses of ocrelizumab or placebo will be administered over the course of the 
study.  The first course of ocrelizumab will be administered as two 300 mg infusions at  
Week 0 (Day 1) and Week 2 (Day 15), with the subsequent second- and third-courses 
given as a single 600 mg infusion at Weeks 24 and 48.  Placebo will be administered at 
the same timepoints.  Screening will occur over a 45-day period.   
All participants must have had CSF analysis at baseline.  For those who have had 
lumbar puncture and CSF analysis prior to screening for this study, historical results (for 
oligoclonal banding) will be accepted as long as original source documentation can be 
provided. Optional CSF (baseline, weeks 104 and 208, with paired blood) can still be 
contributed to the study. For those who have not had prior CSF analysis, lumbar 
puncture and CSF analysis will be required at baseline with two optional follow-up 
lumbar punctures post-baseline (Weeks 104 and 208). Refer to Figure 1 
Study 
Schema. 
The double-blind phase will be considered complete when the results of the primary 
analysis are disclosed and the study becomes unblinded to sites.  If the projected 
number of radiological or clinical events (21) has not been reached when the last patient 
completes 4 years in the double-blind phase because of slower than anticipated event 
rates, the double-blind phase may be extended until the required number of events have 
occurred.  After the primary analysis is complete, patients will remain in the study and be 
followed for a minimum total of 3 years after treatment.  
As the primary analysis is event driven, the study duration in the double-blind phase will 
vary for each patient.  
The study population will consist of patients with RIS, defined as individuals with 
magnetic resonance imaging (MRI) anomalies within the CNS that are typical of CNS 
inflammatory demyelinating disease, yet lacking symptomatic clinical features 
suggestive of MS. To more closely approximate real-world practice and facilitate early 
diagnosis, MRI anomalies will be required to meet dissemination in space criteria as 
defined by the 2017 McDonald diagnostic criteria for MS. Male and female patients aged 
18−55 with a diagnosis of RIS in accordance with the McDonald 2017 criteria for DIS at 
screening will be eligible for this study.   
As RIS is typically identified incidentally, first-degree family members of individuals with 
MS will be pre-screened for possible recruitment into this study.  These relatives are at 
increased risk for RIS, with an estimated 3%−10% of clinically unaffected siblings having 
lesions highly suggestive of demyelination.  After obtaining written consent, pre-


 
 
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screening MRIs will be offered to such high-risk individuals and those who meet 
radiologic criteria will be eligible for the full study.  Patients already diagnosed with RIS 
are also eligible for this study. Any known RIS patients whose MRIs have remained 
stable for 5 years or more will be excluded. 
While younger age (<37) represents a significant predictor for the development of a first 
clinical event in RIS patients, RIS is often not diagnosed until later; indeed, in the recent 
ARISE clinical trial of RIS, the average age at diagnosis was around 44 years old 
(Okuda et al, 2022). Moreover, the ARISE trial found recruitment to be difficult and 
ultimately needed to end the study early for this reason. In order to effectively recruit for 
the CELLO trial, we will use the age range of 18-55, aligning with the phase 3 
ocrelizumab trials in multiple sclerosis as well as the recent published study of RIS. 
Pre-screened first degree family members who do not meet the McDonald 2017 criteria 
for DIS will be eligible to participate in a registry (Appendix 4).  These individuals will 
have annual phone check-ins over the course of the total study duration to assess 
patient reported outcomes (Neuro-QoL; see Appendix 10) and healthcare utilization 
including neurologic or other autoimmune diagnoses, symptoms, medications (i.e., 
prescriptions, over-the-counter, supplements, etc.), number of emergency department 
visits, hospitalizations, office visits/physician encounters (i.e., specialists), etc.   
Re-screening in general is not allowed, however patients enrolled in the registry may 
qualify for a re-screening opportunity at the discretion of the investigator. For more 
details on the registry of first-degree family members of patients with MS, see 
Appendix 4. 
In the case of a clinical neurologic event consistent with CNS demyelination, the patient 
should have an unscheduled visit and a full assessment, as detailed in the SOA.  Upon 
confirmation of a clinical relapse, the patient will be discontinued from the study and 
should start commercially available DMT, including ocrelizumab, at the discretion of the 
treating physician. In the event of radiologic progression, in which a new lesion 
suggestive of MS develops, the choice to continue or discontinue from the study in order 
to initiate treatment is at the discretion of the treating physician.  
Treatment may be stopped at any time due to lack of clinical benefit, unacceptable 
toxicity, withdrawal of consent, patient or physician decision to discontinue treatment, 
death, or if the sponsor decides to close the trial, whichever occurs first.  
An external, independent DMC (iDMC) will periodically review safety data throughout the 
study until the primary analysis is performed.  Following unblinding, iDMC involvement in 
safety monitoring is no longer needed.  Analyses required for the iDMC data review will 
be performed as described in the iDMC Charter.   


 
 
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All patients enrolled into the main study will be evaluated for safety throughout the study.  
In the case of early termination, the patient will be asked to return for an early 
termination visit.   
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator's discretion.  The investigator will record reasons for screen failure in the 
screening log. Family members who undergo radiologic pre-screening and do not have 
lesions meeting DIS criteria are not considered screen failures and will be enrolled in the 
family registry. 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1. 
Figure 1 Study Schema 
 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV), 
occurs or the date at which the last data point required for statistical analysis or safety 
follow-up is received from the last patient, whichever occurs later.  The end of the study 
is expected to occur 48 months/4 years after the last patient is enrolled. 
In addition, the Sponsor and/or Collaborator (Genentech) may decide to terminate the 
study at any time. 


 
 
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The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6−7 years. 
RATIONALE FOR STUDY DESIGN 
Rationale for Ocrelizumab Dose and Schedule 
Consistent with the USPI, the ocrelizumab dose administered in this study is 600 mg 
every 24 weeks.  Three-courses of ocrelizumab or placebo will be administered over the 
course of the study.  The first dose of ocrelizumab will be administered as two 300 mg IV 
infusions on Week 0 (Day 1) and Week 2 (Day 15), with the subsequent second- and 
third-courses given as a single 600 mg infusion at Weeks 24 and 48.  Study drug for 
patients randomized to the placebo group will be administered analogously to those 
receiving ocrelizumab.  Patients will then be followed in the clinical trial for 3 years.  
Administering three-courses of ocrelizumab permits the interrogation of the 
immunodynamics surrounding the emergence of CNS autoimmunity and the 
reconstitution of the immune system following anti-CD20 B cell depletion with 
ocrelizumab. Understanding the effect of B cell depletion in RIS using this treatment 
paradigm will provide invaluable insight into the onset of MS, as well as the mechanism 
of action of ocrelizumab, both of which remain poorly understood. 
Rationale for Patient Population and Use of 2017 McDonald Criteria 
When considering the pathophysiology of MS, and the increased emphasis placed on 
earlier identification of MS in order to initiate appropriate treatment early, it has been 
recommended that identical MRI criteria for DIS should be applied for the diagnosis of 
RIS and MS (De Stefano et al 2018; Flippi et al 2016). The original criteria for RIS 
required a fairly heavy lesion burden, whereas it has been suggested that RIS diagnostic 
criteria should instead reflect the 2017 McDonald criteria for DIS, which are routinely 
used for the clinical diagnosis of MS (Table 1). The McDonald criteria were revised in 
2017 to increase sensitivity while promoting more rapid diagnosis of MS. In contrast to 
Okuda criteria, the McDonald criteria require fewer lesions and instead focus on lesion 
location rather than lesion count for the assessment of DIS, which facilitates 
interpretation and use in scenarios suggestive of MS. Therefore, the McDonald 2017 
criteria for DIS represent the “real-world” criteria used routinely in everyday practice to 
establish MS diagnosis and share comparable sensitivity in detecting RIS, perhaps at 
even earlier stages of pathology. Patients meeting McDonald 2017 criteria for DIS can 
be confirmed to have MS at the time of their first clinical symptoms of disease. Early 
recognition of the disease provides the best window for treatment intervention. Thus, 
utilizing the 2017 McDonald criteria for DIS to establish RIS in this study may have 
clinical and research implications, not only in establishing an earlier window of 
opportunity to identify, diagnose and treat, but also in advancing the understanding of 
the onset and pathogenesis of disease.  


 
 
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Rationale for Control Group  
To date, there are no expert guidelines on the management of RIS.  The standard of 
care for RIS patients is active monitoring with periodical clinical and radiological follow-
up every 6−12 months. This is in accordance with the MAGNIMS consensus 
recommendation published in 2018.  Given that no standard of care therapy exists for 
the treatment of RIS, a placebo-control is considered to be appropriate for this trial.  
Rationale for Biomarker Assessments 
There is a paucity of evidence-based guidelines on the management of RIS and of 
factors that stratify risk for clinical MS in this population. Therefore, the discovery of 
biomarkers predictive of clinical conversion can guide clinical treatment decision-making, 
ultimately leading to risk-stratification for therapeutic interventions that maximize clinical 
benefit while minimizing patient harm.  The identification of biomarkers reflecting MS 
disease biology in RIS not only represents a critical opportunity to better understand 
disease onset and progression, it also permits interrogation of the mechanism of action 
of ocrelizumab in this population.  
Several studies have investigated biomarkers and risk factors associated with the 
development of a first clinical event in RIS patients. The presence of spinal cord lesions 
portends the greatest risk of conversion to clinical MS to date. Age (<40), sex (male) and 
the presence of infratentorial brain lesions have also been identified as putative risk 
factors to predict conversion to MS in RIS patients (Okuda et al. 2011, 2014; Etemadifar 
et al. 2014; Makhani et al 2019; Thouvenot et al. 2019).  Abnormal CSF findings, 
including the presence of OCBs and/or elevated IgG index, have also been suggested 
as additional risk factors (Gastaldi 2017; Nakamura et al. 2014; Matute-Blanch et al. 
2018; Makhani et al. 2019).   
In the context of MS, biomarkers from the CSF are utilized as a surrogate for the CNS 
tissue (Comabella and Montalban 2014) and MRI of the brain and spinal cord is used as 
a non-invasive surrogate marker of disease activity (e.g., contrast-enhancing lesions; 
new and enlarging T2-weighted lesions).  In particular, spinal cord MRI provides 
important additional information to brain MRI in understanding MS pathophysiology, 
allowing more accurate and earlier diagnosis of MS, and in identifying MS patients at 
higher risk of developing more severe disability. Advances in MRI techniques have 
enabled assessment of brain and spinal cord area and volumes. Changes in global and 
regional brain and spinal cord area (i.e., white and gray matter, thalamus) can be 
detected early in the disease course and are highly associated with disability 
progression and severity in MS as well as quality of life measures, including cognition 
and fatigue.  


 
 
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Studies have also focused on the evaluation of fluid biomarkers in RIS reflecting MS 
disease biology and suggest that these may also provide predictive value. In clinically 
definite MS, NfL has emerged as a leading candidate biomarker in blood and CSF. NFL 
correlates with disease activity, including Gd-enhancing MRI lesions and clinical 
relapses (Burman et al. 2014), as well as treatment response in RMS and PPMS 
(Gunnarsson et al. 2011; Axelsson et al. 2014). High levels of NfL in the CSF (Matute-
Blanch et al 2018) and serum (Bjornevik et al 2019), have been identified in individuals 
with RIS and are associated with increased risk for the development of a first clinical 
neurologic event.  Other key biomarkers of disease biology in MS that may be relevant 
to RIS include the presence of OCBs, or antibodies produced in the CSF (Link and 
Huang 2006), as well as the presence of intrathecal memory B cells, plasmablasts 
(Cepok et al. 2005), and the potent B cell chemoattractant CXCL13 (Piccio et al. 2010; 
Bankoti et al. 2014; Palanichamy et al. 2014; Stern et al. 2014). The presence of OCBs 
has been associated with a worse prognosis (Joseph et al. 2009; Winger and Zamvil 
2016) and has been shown to have high predictive value for conversion from CIS to 
clinically definite MS (Tintore et al 2008; Dobson et al 2013), which may also be relevant 
to those with RIS (Matute-Blanch et al. 2018).  Furthermore, it has been observed that 
the peripheral B cells of RIS patients are skewed toward a proinflammatory phenotype 
and are associated with worse prognosis. However, these biomarkers require further 
investigation in RIS as prior studies had relatively small sample size and short follow-up 
periods.  
The research efforts in the present study are aimed toward the identification and 
verification of biomarkers, including neuroimaging, fluid/serologic, and immunologic, as 
well as clinical and paraclinical features that predict the evolution from RIS to a first 
neurologic attack and subsequent MS diagnosis. In addition, to better understand the 
mechanism of action of ocrelizumab in RIS, this study will assess the treatment effect of 
ocrelizumab on biomarkers of MS disease biology in the blood and CSF (i.e., OCBs, 
NfL, B cell subsets, MRI, etc.)  Newly emerging biomarkers reflecting inflammation and 
neurodegeneration, such as cytokines, chemokines, antigen-specific B cells or T cells, 
and GFAP (glial fibrillary associated protein) will be evaluated and may provide insight 
into disease mechanisms and onset of clinical MS (Piccio et al. 2010; Barun and Bar-Or 
2012; Alvermann et al. 2014; Hohmann et al. 2014). Elucidating these factors could 
significantly impact the management of patients with RIS, guide treatment decisions, and 
improve long-term outcomes while also advancing the science underlying MS 
pathogenesis and the emergence of CNS autoimmunity (Alshamrani 2017; Okuda 
2017). 


 
 
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MATERIALS AND METHODS 
PATIENTS 
Approximately 100 patients will be enrolled in the main study. 
Inclusion Criteria 
 
Pre-Screening of First-Degree Family Members 
Family members must meet the following inclusion criteria for pre-screening: 
Signed informed consent form 
First-degree family member of an individual with clinically definite MS 
Age 18-55 years 
No prior exposure to DMT or long-term immunomodulatory medications 
Willingness to participate in full study protocol, if RIS is discovered 
 
 
Screening 
Patients must meet the following inclusion criteria for screening: 
Signed informed consent form 
One of the following: 
First degree family member of an individual with clinically definite MS who was 
identified to have CNS lesions meeting McDonald 2017 criteria for DIS during a pre-
screening MRI. 
Established RIS diagnosis (i.e. CNS lesions consistent with MS, meeting McDonald 
2017 criteria for DIS), either diagnosed within the last 5 years or known to have had 
accumulation of CNS lesions within the last 5 years.  
Age 18-55 years 
No prior exposure to DMT or long-term immunomodulatory medications 
Willingness to participate in full study protocol 
 
Randomization 
Patients must meet the following criteria for study entry and randomization: 
Signed Informed Consent Form 
Aged 18−55 years at time of signing Informed Consent Form 
Ability to provide written informed consent and be compliant with the study protocol 


 
 
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CNS lesions consistent with MS, meeting McDonald 2017 criteria for DIS 
RIS diagnosis established within last 5 years OR with known accumulation of CNS 
lesions within last 5 years  
No alternative diagnosis established during serologic workup for MS mimics 
Women of childbearing potential must agree to remain abstinent (refrain from 
heterosexual intercourse) or use one method of contraception with a failure rate of <1% 
per year or a barrier method supplemented with spermicide.  Contraception must 
continue for the duration of study treatment and for at least 24 weeks after the last dose 
of study treatment. 
      A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months 
of amenorrhea with no identified cause of other than menopause), and has not 
undergone surgical sterilization (removal of the ovaries and/or uterus) 
      Examples of contraceptive methods with a failure rate of <1% per year include 
bilateral tubal ligation, male sterilization, established hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
      The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence and withdrawal are not acceptable methods of 
contraception. 
      Examples of barrier methods supplemented with the use of spermicide include 
male or female condom, cap, diaphragm, or sponge. 
  
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from pre-screening, 
screening and randomization: 
Intolerance to gadolinium-based contrast agent 
Contraindications to MRI 
≥5 years of radiologic stability since first known abnormal MRI, for patients previously 
diagnosed with RIS 
History of remitting clinical symptoms consistent with MS lasting >24 hours prior to CNS 
imaging revealing anomalies suggestive of MS 
CNS MRI anomalies are better accounted for by another disease process, for patients 
previously diagnosed with RIS 
Infection Related 
Known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis) 
History of recurrent aspiration pneumonia requiring antibiotic therapy 


 
 
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History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme 
disease, HTLV-1, herpes zoster myelopathy) 
 
Known active bacterial, viral, fungal, mycobacterial infection, or other infection 
(including tuberculosis or atypical mycobacterial disease, but excluding fungal 
infection of nail beds) or any major episode of infection requiring hospitalization or 
treatment with IV antibiotics within 4 weeks prior to baseline visit or oral antibiotics 
within 2 weeks prior to baseline visit 
Cancer Related 
History of cancer, including solid tumors and hematological malignancies (except 
basal cell, in situ squamous cell carcinomas of the skin, and in situ carcinoma of the 
cervix or the uterus that have been excised and resolved with documented clean 
margins on pathology) 
Pregnant or lactating, or intending to become pregnant during the treatment phase and 6 
months after the last infusion of study drug 
Women of childbearing potential must have a negative serum or urine pregnancy 
test result within 14 days prior to initiation of study drug. 
Other Medical Conditions 
History of or currently active primary or secondary immunodeficiency 
History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies 
History of alcohol or other drug abuse within 24 weeks prior to enrollment 
History or known presence of systemic autoimmune disorders associated with 
systemic symptoms (e.g., lupus, anti-phospholipid antibody syndrome, Sjögren’s 
syndrome, Behçet’s disease) 
Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study 
Significant, uncontrolled disease, as defined by AMA guidelines or similar, such as 
cardiovascular (including congestive heart failure – NYHA grade 3 or 4, cardiac 
arrhythmia), uncontrolled hypertension, pulmonary (including chronic obstructive 
pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes 
mellitus), gastrointestinal, or any other significant disease 
Known presence or history of other neurologic disorders, including but not limited to, 
the following: 
Progressive multifocal leukoencephalopathy, CNS or spinal cord tumor, potential 
metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency) 
History of genetically inherited progressive CNS degenerative disorder (e.g., 
hereditary paraparesis; mitochondrial encephalopathy, lactic acidosis, and stroke-
like episodes [MELAS]) 
Neuromyelitis optica spectrum disorders (NMOSD)  
Ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or 
ischemia of the spinal cord 


 
 
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Severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, 
spinal cord compression) 
Psychosis not yet controlled by a treatment 
Drug Related 
Systemic, high dose corticosteroid therapy within 4 weeks prior to screening 
Contraindications for, or intolerance to, oral or IV corticosteroids, including IV 
methylprednisolone, according to the country label, including hypersensitivity to any 
of the treatment drug constituents 
Prior exposure to immunomodulatory medications and/or DMT 
Prior treatment with any disease modifying therapy for MS including but not 
limited to:  interferon (IFN-β-1a (Avonex, Rebif), IFN-β-1b 
(Betaseron/Betaferon), glatiramer acetate, dimethyl fumarate (DMF; Tecfidera), 
diroximel fumarate (Vumerity) fingolimod (Gilenya) or siponimod (Mayzent), 
ozanimod (Zeposia®) natalizumab (Tysabri), alemtuzimab (Lemtrada), 
cladribine (Mavenclad), rituximab (Rituxan), and other anti-CD20 agents 
Previous treatment with cyclophosphamide, mitoxantrone, azathioprine, 
mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or 
bone marrow transplantation 
Previous or concurrent treatment with any investigational agent or treatment with 
any experimental procedure for MS (e.g., treatment for chronic cerebrospinal 
venous insufficiency) 
Vaccinations:  Receipt of a live or live-attenuated vaccine or an inactivated/non-live 
vaccine within 6 weeks prior to enrollment 
 
Laboratory: Certain laboratory abnormalities or findings at screening, including the 
following: 
Positive serum β-hCG 
Positive for hepatitis B (hepatitis B surface antigen [HBsAg] positive or hepatitis B 
core antibody [total HBcAb] confirmed by positive viral DNA polymerase chain 
reaction [PCR]) 
AST or ALT ≥3.0 ×upper limit of normal 
Total white blood cell count, including differential counts, below lower limit of normal 
Absolute lymphocyte count below lower level of normal  
Absolute neutrophil count below lower limit of normal  
Platelet count below lower limit of normal  
 
  


 
 
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METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Randomization and blinding will be employed to minimize bias in treatment assignment 
and to provide the basis for valid statistical inference.  IxRS will be used to assign study 
identification numbers at the time of signing an informed consent document; this 
includes close family members undergoing pre-screening as well as those with known 
RIS who are being screened for the randomized controlled trial. Eligible patients must be 
randomized through IxRS prior to receiving any study drug.  Patients who discontinue 
treatment for any reason will not be replaced.  Under no circumstances are patients who 
enroll in this study and who have completed treatment as specified, permitted to be 
re-randomized to this study.  
The randomization list will not be available to the study centers, monitors, or to the 
Sponsor project team.  All individuals directly involved in the study will remain blinded to 
the treatment assignment. 
The treatment code will be released to the study team to facilitate analysis of the 
biological samples collected during this study after the unblinding for the primary 
analysis has been completed.  
Study site personnel and patients will be blinded to treatment assignment until after the 
primary analysis.  The Sponsor and its agents will also be blinded to treatment 
assignment, with the exception of individuals who require access to patient treatment 
assignments to fulfill their job roles during a clinical trial.  These roles include the 
unblinded trial statisticians, clinical supply chain managers, sample handling staff, and 
IxRS service provider.  
Treatment Assignment 
This is a randomized, double-blind study.  After initial written informed consent has been 
obtained, an interactive voice or web-based response system (IxRS) will be used to 
assign a study identification number. After completion of screening procedures and 
assessments have been completed, and eligibility has been established for a patient, the 
IxRS system will be used to randomize the patient and receive treatment assignment. 
Patients will be randomly assigned to one of two treatment arms:  ocrelizumab or 
placebo.  Randomization will occur in a 1:1 ratio through use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm.  
Randomization will be stratified according to the following criteria: 
Presence of spinal cord lesions 
Presence of CSF oligoclonal bands 


 
 
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Results of a lumbar puncture/CSF oligoclonal banding analysis performed at baseline 
are required prior to randomization. A subset of study participants may have had lumbar 
puncture/CSF analysis performed previously. Such historic oligoclonal banding results 
may be used for the purpose of stratifying randomization with appropriate source 
documentation. For study participants who have previously had lumbar puncture/CSF 
analysis, all study lumbar punctures are optional. 
For study participants who have never had a lumbar puncture/CSF analysis, this 
procedure is required prior to randomization. Additional lumbar punctures at weeks 104 
and 208 are optional. 
 
Blinding 
This is an assessor blinded study. During the double-blind period, each site will have: a 
principal or Treating Investigator and an Examining Investigator or rater. Both the 
Treating and Examining Investigators will be blinded to treatment assignment.  
The Treating Investigator is the physician responsible for the patient care and should 
be a neurologist experienced in the care of MS patients.  The Treating Investigator will 
make treatment decisions based on the patient’s clinical response and laboratory 
findings.   
The Examining Investigator should be a neurologist or other health care practitioner 
and must be trained in administering the Neurostatus Functional System Scores (FSS) 
and Expanded Disability Status Scale (EDSS) examination prior to study start 
(Appendix 5).   
The Examining Investigator will perform the neurological examination, document the 
FSS scores, and assess EDSS scores.  The Examining Investigator or a qualified 
designee will also be responsible for performing and documenting results from the 
Symbol Digit Modalities Test.  They will only have access to data from the assessments 
listed above.  Every effort will be made to ensure that there is no change in the EDSS 
rater throughout the course of the study for any individual patient.  Whenever possible, 
the same person should perform the examination for the full study duration. 
All efforts should be made to keep the Examining Investigator blinded to the treatment 
assignment during the double-blind period. Patients will be instructed not to discuss any 
symptoms related to the study treatment with the Examining Investigator; the Examining 
Investigator should remind the patient at the start of the examination. 
To prevent potential unblinding of the assigned arm in the double-blind treatment period 
as a result of adverse events or changes to laboratory results, the following, additional 
measures have been implemented: 
Blinding of laboratory parameters: Laboratory parameters that may lead to unblinding to 
treatment assignment, such as fluorescence-activated cell sorting (FACS) cell counts 
including CD19+ cells, lymphocyte count, IgM and IgG levels, will be blinded in all 


 
 
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patients.  In order to ensure patients’ safety in the study and to allow for assessments of 
the re-treatment criteria, a central laboratory will provide study investigators and Medical 
Monitors with reflex messages triggered by critical blinded laboratory results. 
Investigators notified of their patient’s critical laboratory test results will be instructed to 
suspend further treatment with study drug until the patient becomes eligible for re-
treatment.  The reflex messages from a central laboratory, together with non-blinded 
laboratory results, should be carefully reviewed at every visit before continuing with 
study treatment.  The reflex messages will occur during the double-blind, period. During 
the treatment period, patients will be assessed at clinical visits as per Schedule of 
Assessments. 
Prior to the next infusion of study drug, patients will be evaluated for pre-specified 
conditions and laboratory abnormalities to allow for re-treatment. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.5) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment. 
 
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is ocrelizumab. 
Study Treatment Formulation, Packaging, and Handling 
Ocrelizumab and Placebo 
Ocrelizumab will be supplied by Genentech in 15 cc Type I glass vials as a sterile, 
single-use solution for IV infusion and contains no preservatives.  Each vial contains 
300 mg of ocrelizumab, at a nominal fill volume of 10 mL.  The drug product is 
formulated as 30 mg/mL ocrelizumab in 20 mM sodium acetate at pH 5.3, with 106 mM 
trehalose dihydrate and 0.02% polysorbate 20.  Do not use the solution if discolored or if 
the solution contains discrete foreign particulate matter.  The infusion solution must be 
administered using an infusion set with an in-line, sterile, non-pyrogenic, 


 
 
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low-protein-binding filter (pore size of 0.2 micrometer or less).  For information on the 
formulation and handling of ocrelizumab, see the Ocrelizumab Investigator's Brochure, 
local prescribing information, and Drug Preparation Guidelines. 
Placebo for this trial will be supplied by Genentech. It is a preservative-free, sterile, 
colorless to pale yellow solution supplied in 15-cc single-dose glass vials with 20 mm 
stoppers. Vials are filled to enable delivery of 10.0 mL of Ocrelizumab Placebo. 
Ocrelizumab Placebo is composed of the same formulation as the study drug, but does 
not contain the study drug. Density of Ocrelizumab Placebo is 1.01 g/mL. 
Non-Investigational Medicinal Products 
In this study, non-investigational medicinal products will include premedication to the 
study drug infusion.  The following premedication will be used: 
Mandatory methylprednisolone (or an equivalent)  
Mandatory antihistaminic drug (e.g., diphenhydramine)  
Recommended oral analgesic/antipyretic (e.g., acetaminophen) 
 
Refer to Section 0 for further details on premedication administration. 
 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).   
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, along with any associated adverse events, should be 
reported as described in Section 5.4.3.2. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.4. 
Ocrelizumab and Placebo 
The ocrelizumab dose administered will be 600 mg every 24 weeks.  The first dose of 
ocrelizumab will be administered as two 300 mg IV infusions given 14 days apart 
(Weeks 0 and 2).  For the subsequent doses, ocrelizumab will be administered as a 


 
 
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single 600-mg IV infusion every 24 weeks (Weeks 24 and 48).  A minimum interval of 
22 weeks must be maintained between each dose of ocrelizumab. 
Each ocrelizumab dose should be administered according to the guidance provided in 
the most current USPI (https://www.gene.com/download/pdf/ocrevus_prescribing.pdf). 
Ocrelizumab infusions should be initiated and supervised by an experienced 
professional with access to appropriate medical support to manage severe reactions 
such as serious IRRs. 
 
Ocrelizumab must not be administered as an IV push or bolus.  Well-adjusted infusion 
pumps should be used to control the infusion rate, and ocrelizumab should be infused 
through a dedicated line.  It is important not to use evacuated glass containers, which 
require vented administration sets, to prepare the infusion because this causes foaming 
as air bubbles pass through the solution. 
The patient will need to remain at the clinic at every visit for at least 1 hour after the 
completion of the infusion for observation.  After completion of the infusion, the IV 
cannula should remain in situ for at least 1 hour to allow for administration of drugs 
intravenously, if necessary, in the event of a delayed reaction.  If no adverse events 
occur during this period of time, the IV cannula may be removed, and the patient may 
be discharged.  
Premedications 
Methylprednisolone has been shown to decrease the incidence and the severity of 
infusion reactions.  An integrated analysis of patients with MS treated with ocrelizumab 
revealed that the addition of antihistamines pretreatment with methylprednisolone 
decreased the incidence of IRRs by 2-fold. All study patients will receive premedications 
according to the guidelines outlined in the USPI 
(https://www.gene.com/download/pdf/ocrevus_prescribing.pdf).  
Hypotension, as a symptom of IRR, may occur during study drug IV infusions.  
Therefore, withholding antihypertensive treatments should be considered for 12 hours 
prior to and throughout each study drug infusion. 
Re-Treatment Criteria for Ocrelizumab 
Prior to re-treatment with study drug, patients will be evaluated for the following 
conditions and laboratory abnormalities. If any of these are present prior to re-dosing, 


 
 
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further administration of study drug should be suspended until these are resolved or held 
indefinitely: 
Life-threatening (Grade 4) infusion-related event that occurred during a previous study 
drug infusion 
Any significant or uncontrolled medical condition or treatment-emergent, clinically 
significant laboratory abnormality 
Active infection 
Ongoing pregnancy 
 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (ocrelizumab/placebo) will be provided by 
Genentech where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs supplied by Genentech, using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the drug depot with the appropriate 
documentation.  The site’s method of destroying Genentech-supplied IMPs must be 
agreed to by the Sponsor.  The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
Continued Access to Ocrelizumab 
Currently, Genentech, a member of the Roche Group, does not have any plans to 
provide Genentech IMP (ocrelizumab) or any other study treatments to patients beyond 
the second-year extension of the study or the 2 year sub-study.  Genentech may 
evaluate whether to continue providing ocrelizumab in accordance with the Roche 
Global Policy on Continued Access to Investigational Medicinal Product, available at the 
following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 


 
 
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prior to initiation of study drug or ongoing therapy (e.g., physiotherapy) to the study 
completion/discontinuation visit.  All such medications and therapies (including their 
indication) should be reported to the investigator and recorded on the appropriate eCRF. 
Treatment of First Clinical Neurologic Event 
In the case of the development of an acute or progressive clinical neurologic event 
consistent with CNS demyelination during study, the patients should have an 
unscheduled visit and a full assessment, as detailed in the SOA. As described in 
Section 4.5.12 a neurologic event consistent with CNS demyelination for this study is 
defined as the occurrence of new and/or worsening neurological symptoms suggestive 
of MS that persist for >24 hours and should not be attributable to confounding clinical 
factors (e.g., fever, infection, injury, adverse reactions to medications). In the case of an 
acute syndrome, it should be immediately preceded by a stable or improving 
neurological state for least 30 days.  In some rare cases a progressive clinical syndrome 
(e.g., leg weakness, cognitive impairment, EDSS worsening) may develop with a 
temporal profile revealing at least 12-months of neurologic deficit as per the treating 
physician’s judgement. The new or worsening neurological symptoms must be 
adjudicated by a Sponsor-appointed adjudication committee, comprised of three expert 
neuroimmunology clinicians, who will review documentation associated with the event 
and confirm whether a relapse has occurred. Confirmed relapses will contribute to the 
primary endpoint. 
The patient may receive treatment with IV or oral corticosteroids, if judged to be clinically 
appropriate by the investigator.  The following standardized treatment regimen may be 
used as warranted:  1 g/day IV methylprednisolone for a maximum of 5 consecutive 
days.  In addition, at the discretion of the investigator, corticosteroids may be stopped 
abruptly or tapered over a maximum of 10 days.  After a confirmed clinical relapse, 
patients will be discontinued from the study and start commercially available DMT 
approved for MS, including ocrelizumab, at the discretion of the treating physician. 
Whether patients continue or discontinue the treatment based on the occurrence of a 
neurologic event consistent with MS is at the discretion of the treating physician and the 
patient, and whether the patient or investigator feels he or she has met the criteria for 
withdrawal.  
Treatment may be stopped at any time due to lack of clinical benefit, unacceptable 
toxicity, withdrawal of consent, patient or physician decision to discontinue treatment, 
death, or if the sponsor decides to close the trial, whichever occurs first.  
Treatment of Radiologic Event 
In the event of radiologic progression, in which a new contrast-enhancing or T2-weighted 
lesion suggestive of MS develops, the choice to continue or discontinue from the study 


 
 
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in order to initiate treatment with a DMT, including commercial OCREVUS®, is at the 
discretion of the treating physician. If a commercial disease modifying therapy is 
initiated, the participant will be discontinued from all study-related treatments. 
Regardless of whether the participant is started on commercial disease modifying 
therapy, individuals with a radiologic event should complete study assessments until 
they have completed week 208 or until they have had a confirmed clinical relapse, 
whichever occurs first. 
As described above in Section 4.4.1 treatment may be stopped at any time due to lack of 
clinical benefit, unacceptable toxicity, withdrawal of consent, patient or physician 
decision to discontinue treatment, death, or if the sponsor decides to close the trial, 
whichever occurs first. 
Prohibited Therapy 
The following therapies for MS are not permitted during the treatment portion of the 
study (through week 72):  Other B-cell targeted therapies (e.g., rituximab, atacicept, 
belimumab, or ofatumumab, etc.), natalizumab, fingolimod, siponimod, alemtuzumab, 
daclizumab, cladribine, teriflunomide, dimethyl fumarate ,diroximel fumarate  ozanimod, 
interferons, glatiramer acetate, cyclophosphamide, mitoxantrone, azathioprine, 
mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, bone marrow 
transplantation, IV Ig, plasmapheresis, other approved or investigational therapies 
for MS. 
After patients have completed (or discontinued) treatment with study drug, they may 
receive alternative treatment for MS as judged clinically appropriate by the investigator.  
However, as sufficient data are not available regarding risks associated with switching to 
other products, the following recommendations are given:  
Caution is advised if patients remain B-cell depleted.  
Because of the unknown safety risk of administering disease-modifying treatments 
for MS after discontinuation of ocrelizumab, certain treatments for MS, such as 
lymphocyte-depleting agents or lymphocyte-trafficking blockers (alemtuzumab, 
natalizumab, fingolimod, dimethyl fumarate, cyclophosphamide, azathioprine, 
cladribine, daclizumab, etc.) are strongly discouraged for as long as the patient 
remains B cell depleted because of unknown effects on the immune system 
(e.g., increased risk, incidence, or severity of infection). 
 
Immunizations 
Physicians are advised to review the immunization status of patients who are considered 
for treatment with ocrelizumab and follow local/national guidance for adult vaccination 
against infectious disease.  Immunizations should be completed at least 6 weeks prior to 
first administration of ocrelizumab.  


 
 
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Non-live vaccines may be administered while on ocrelizumab if deemed clinically 
necessary. Vaccination study results (VELOCE) show that patients treated with 
ocrelizumab were able to mount an attenuated immune response to non-live vaccines 
and new antigens at week 12 after ocrelizumab infusion compared to placebo. However, 
no data are currently available to show if the same applies also to the SARS-CoV-2 
vaccines. Treatment decisions should be made between a patient and their treating 
neurologist or other medical professional based on a benefit/risk assessment specific to 
the individual patient, and vaccines must be given in accordance with the approved label 
for the vaccine. The best time point for a vaccination in the interval between two 
ocrelizumab dosings is not known and might also be dependent on the individual risk of 
SARS-CoV-2 infection of the patient. In VELOCE, vaccinations started at least 12 weeks 
after the last infusion of ocrelizumab. Like for patients starting on ocrelizumab in a 
clinical study, a time window of at least 6 weeks before the next ocrelizumab infusion 
seems appropriate to allow the B cells generated to the vaccine to get established and 
develop into antibody producing plasmablasts or plasma cells that do not express CD20 
and are therefore preserved once the next dose is given. 
 
Immunization with any live or live-attenuated vaccine (i.e., measles, mumps, rubella, oral 
polio vaccine, Bacille Calmette-Guerin, typhoid, yellow fever, vaccinia, cold-adapted live 
influenza strain vaccine, or any other vaccines not yet licensed but belonging to this 
category) is not recommended during ocrelizumab treatment period and for as long as 
the patient is B cell depleted.  
Data from the ocrelizumab Phase II and III program currently show that over 2 years 
after treatment with ocrelizumab, the proportions of patients with positive antibody titers 
against Streptococcus pneumoniae, influenza, mumps, rubella, varicella, and tetanus 
toxoid were generally similar to the proportions at baseline. 
Of note:  for seasonal influenza vaccines, it is still recommended to vaccinate patients on 
ocrelizumab.  Please refer to the current version of the Ocrelizumab Investigator’s 
Brochure for further guidance and updates on immunization.  
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  Patients will be 
closely monitored for safety and tolerability throughout the study.  Patients should be 
assessed for toxicity prior to each dose; dosing will occur only if the clinical assessment 
and local laboratory test values are acceptable. 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 


 
 
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All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Overview of Clinical Visits 
After the screening, patients who fulfill the entry criteria will be scheduled for baseline 
assessments.  Visits will take place as described in Appendix 1. 
Visits should be scheduled with reference to the date of the baseline visit (Day 1).  
A minimum interval of 22 weeks should be maintained between each infusion. 
At infusion visits, it is anticipated that the patients will have to stay at the hospital or clinic 
for a full day.  Patients treated with ocrelizumab should remain under observation for at 
least 1 hour after the completion of the infusion.  If for logistical reasons the infusion 
cannot be administered on the same study visit day, the infusion should be given within 
the next 24 hours provided that the patient still meets re-treatment criteria. 
Patients who cannot receive their infusion at the scheduled visit or within 24 hours of the 
visit should be rescheduled for a delayed dosing visit (see Section 4.5.3).  Additional 
unscheduled visits for the assessment of disease worsening, new neurological 
symptoms, or safety events may occur at any time.   
Patients who are pregnant or breastfeeding should continue to follow the schedule of 
activities; however, no infusions will occur.  If there is a concern regarding the ability of a 
pregnant or breastfeeding patient to complete all scheduled assessments, or if 
assessments are contraindicated with pregnancy, the investigator must contact the 
Medical Monitor for further discussion. 
Delayed Dosing Visit 
Delayed dosing visits may be scheduled only if the infusion cannot be administered at 
the timepoints defined in the schedules of activities (see Appendix 1).  Thus, a patient 
who had all assessments of a dosing visit performed, but could not receive the infusion, 
should be rescheduled for the infusion on another day.  At the delayed dosing visit, 
additional tests or assessments, such as routine safety laboratory tests, may be 
performed as clinically indicated. 
Unscheduled Visits 
Patients who develop new or worsening neurological symptoms should be seen at the 
investigational site as soon as possible, regardless of the dates of their pre-planned, 
scheduled study visits and regardless of the study period.  The EDSS assessment 


 
 
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should be performed for any suspected neurological worsening.  If an MS relapse is 
diagnosed or suspected, EDSS assessment should be performed within 7 days, in 
addition to completing the appropriate eCRF. 
Other assessments (e.g. MRI) performed at unscheduled (non-dosing) visits will depend 
on the clinical needs of the patient, and would be covered clinically, rather than by the 
research study.  The primary reason for performing an unscheduled visit will be reported 
in the eCRF. 
Medical History, Baseline Conditions, Concomitant Medication, and 
Demographic Data 
Medical history, including, but not limited to, clinically significant diseases, surgeries, 
cancer history (including prior cancer therapies and procedures), general cancer risk 
factors, breast cancer-specific risk factors, reproductive status, smoking history, lumbar 
puncture history, sleep status and smoking status, will be recorded at baseline. 
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to initiation of study treatment and ongoing therapies (e.g., physiotherapy 
including its indication) will be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained, and any changes in 
medications and allergies should be recorded.   
Demographic data will include age, sex, and self-reported race/ethnicity. 
Physical Examinations 
A complete physical examination performed at screening should include an evaluation of 
the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
Height and weight will be measured per the appropriate schedule of activities. 
 
Vital Signs 
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a seated position, pulse rate, and temperature.  


 
 
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On the infusion days, blood pressure, pulse rate, and temperature should be taken 
within 45 minutes prior to the premedication (methylprednisolone) infusion and recorded 
on the appropriate eCRF.  Temperature should be measured and recorded in patient’s 
notes only..  Vitals will be monitored during infusions of study drug according to the 
prescribing information. Clinically significant abnormalities should be recorded on the 
Adverse Event or Infusion-Related Reaction.  In the event of an IRR or if clinically 
indicated, additional vital signs readings (e.g., blood pressure and pulse rate) should be 
taken during and post-infusion at the discretion of the investigator and should be 
recorded on a dedicated Vital Sign eCRF.  
Neurological Examination 
A neurological examination will be performed at every planned visit.  During an 
unscheduled visit, the neurological examination will be performed only if deemed 
necessary. 
In the presence of newly identified or worsening neurological symptoms at any given 
time in the study, a neurological evaluation should be scheduled promptly and performed 
within 7 days of onset of the new or worsening neurological symptom(s). 
Study investigators will screen patients for signs and symptoms of PML through 
evaluation of neurological deficits localized to the cerebral cortex, such as cortical 
symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual 
defects, hemiparesis, and cerebellar symptoms/signs (e.g., gait abnormalities, limb 
incoordination).  A brain MRI scan and CSF analysis may be warranted to assist in the 
diagnosis of PML.  Refer to Appendix 7 for guidance on the diagnosis of PML. 
Patients with suspected PML, defined as a new or worsening neurological symptom that 
necessitates MRI and/or lumbar puncture and CSF analyses to rule out PML, should be 
withheld from study treatment until PML is ruled out by complete serial clinical 
evaluations and appropriate diagnostic testing (see Appendix 7).  The Medical Monitor 
should be immediately contacted by telephone and email. 
A patient with confirmed PML should be withdrawn from treatment.  PML should be 
reported as a serious adverse event (with all available information) with immediate 
notification of the Medical Monitor (see also Section 5.1.1.2). 
Brain and Cervical Spine Magnetic Resonance Imaging 
Pre-screening of family members: 
Pre-screening brain MRIs without contrast will be performed for asymptomatic close 
family members who otherwise qualify for the study and would like to participate. The 
study investigator, or designee, will interpret pre-screening MRI brains to make a 


 
 
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determination about whether they meet McDonald 2017 criteria for dissemination in 
space. Pre-screening MRIs have limited sequences, and as such, are not intended to 
identify non-MS pathologies. Participants will be informed if they meet criteria for RIS. 
Otherwise, any incidental findings would be handled at the discretion of the study 
investigator 
Randomized clinical trial: 
MRI will be used to monitor CNS lesions related to MS pathology and potentially other 
pathology findings.  Brain and cervical spine (C-spine) MRI scans ± Gd will be obtained 
at study visits as shown in the schedule of activities (see Appendix 1).  The evaluation of 
scans for incidental pathology not related to MS, such as migraine, PML, etc., is a local 
responsibility that should be handled according to the local practice.  Any clinically 
significant findings should be reported on the Adverse Event eCRF. 
MRI scans will be read by a centralized reading center for efficacy endpoints.  Prior to 
initiation of treatment on Day 1/Baseline, a quality control (QC) report for the patient’s 
Screening MRI scan must have been received from the centralized reading center 
confirming scan passed QC as well as an MRI Eligibility Report to confirm eligibility for 
the study.  The brain MRI requires approximately 2 business days from scan receipt to 
be quality checked before dosing of ocrelizumab.  Further details on scanning 
acquisition sequences, methods, handling, transmission of the scans, and certification of 
site MRI scanner are described in a separate MRI technical manual.   
In general, focal white matter lesions of vascular origin can be more prevalent in young 
adults and migraineurs compared to demyelinating lesions. These lesions display 
different morphological and topographic characteristics compared to typical 
demyelinating lesions observed in MS.  
Assessment of Disability:  Expanded Disability Status Scale 
Disability in MS is commonly measured by the EDSS (Appendix 5).  EDSS will be 
administered by the Investigator or a qualified designee under the supervision of the 
investigator at the timepoints indicated in the schedule of activities (see Appendix 1).  
Additional EDSS assessments for individual patients may be requested between visits, 
(e.g., at the time of development of new radiologic evidence of MS, clinical neurologic 
event, etc.).  
The EDSS is based on a standard neurological examination, incorporating functional 
systems (pyramidal, cerebellar, brainstem, sensory, bowel, and bladder, visual, and 
cerebral [or mental]) and ambulation rated and scored as FSS.  Note that the following 
item need not be scored:  sexual dysfunction. Each FSS is an ordinal clinical rating scale 
ranging from 0 to 5 or 6.  These ratings are then used in conjunction with observations 


 
 
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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 10.0 (death) (Kurtzke 1983; Kappos 2011).  
Symbol Digit Modalities Test 
The Symbol Digit Modalities Test (SDMT) has demonstrated sensitivity in detecting not 
only the presence of cognitive impairment but also changes in cognitive functioning over 
time (i.e., information processing speed) and in response to treatment. Several studies 
have demonstrated that RIS is associated with cognitive impairment and dysfunction 
similar to that of patients with clinical MS. Further, substantial evidence suggests that 
cognitive problems present in early in MS before any apparent symptoms cross the 
clinical threshold.   
For consistency, it is recommended at each visit the same examiner administer the 
SDMT with the same patient. A four-point decrease in SDMT score is considered 
clinically relevant/meaningful change. 
The oral version of the SDMT should be used for all CELLO-related visits. 
Assessment of Neurologic Event 
Patients will be evaluated for development of a clinical neurologic event consistent with 
CNS demyelination by the Treating Investigator at each visit throughout the study and, if 
necessary, at unscheduled visits to confirm the same occurring between the visits. 
All new or worsening neurological events consistent with MS are to be reported in the 
appropriate eCRF. EDSS should be performed within 7 days from the onset of the 
clinical neurologic event. 
For this study, a neurologic event consistent with CNS demyelination is defined as the 
occurrence of new and/or worsening neurological symptoms suggestive of MS.  
Symptoms must persist for >24 hours and should not be attributable to confounding 
clinical factors (e.g., fever, infection, injury, adverse reactions to medications) and be 
immediately preceded by a stable or improving neurological state for least 30 days.  The 
new or worsening neurological symptoms must be adjudicated by a Sponsor-appointed 
adjudication committee, comprised of three expert neuroimmunology clinicians, who will 
review documentation associated with the event and confirm whether a relapse has 
occurred. Confirmed relapses will contribute to the primary endpoint.   
Investigators will also screen patients for signs and symptoms of worsening neurological 
function localized to the cerebral cortex, such as cortical symptoms/signs, behavioral 
and neuropsychological alteration, retrochiasmal visual defects, hemiparesis, and 
cerebellar symptoms/signs (e.g., gait abnormalities, limb incoordination).  Patients with 


 
 
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suspected PML should be withheld from ocrelizumab treatment until PML is ruled out by 
complete clinical evaluation and appropriate diagnostic testing (see Appendix 7).  A 
patient with confirmed PML should be withdrawn from the study.  PML should be 
reported as a serious adverse event (with all available information) with immediate 
notification of the Medical Monitor. 
If an investigator determines that further testing (e.g. MRI) is necessary to evaluate a 
neurologic event, this would be performed according to standard of medical care. 
Results from any clinically warranted MRIs will be recorded in the eCRF. 
Clinical neurologic events (i.e., regardless of whether they meet criteria for a protocol-
defined neurologic event) will be recorded in the eCRF. 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the laboratory tests will collected on the days indicated in the schedule of 
activities (see Appendix 1). 
Pre-infusion laboratory test results need to be available for review before each infusion, 
unless otherwise specified.   
Samples for the following laboratory tests will be sent to the sites’ local laboratory for 
analysis according to the appropriate SOA unless otherwise indicated (further details will 
be provided in the laboratory manual). 
Hematology:  hemoglobin, hematocrit, RBC, WBC (absolute and differential:  
neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells), and 
quantitative platelet count 
Quantitative Immunoglobulin (local lab evaluation at screening visit only):  Ig levels 
(including Total Ig, IgG, IgM, and IgA isotypes).   
Blood chemistry:  AST, ALT, total bilirubin, urea or BUN, creatinine, potassium, sodium, 
calcium 
Urinalysis:  A urine dipstick will be performed at the site (pH, specific gravity, glucose, 
protein, ketones, blood), and a microscopic examination if abnormal and applicable will 
be performed at the site  
Pregnancy test:  All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
 
All women of childbearing potential must have regular pregnancy tests.  A urine 
pregnancy test (sensitivity of at least 25 mU/mL β-hCG) will be performed locally at the 
timepoints shown in Appendix 1.  On infusion visits, the urine pregnancy test should be 
performed prior to the methylprednisolone infusion.  A positive urine pregnancy test 


 
 
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should be confirmed with a serum test through the central laboratory prior to any further 
dosing with study drug.  If a urine pregnancy test is positive, the patient will not receive 
the scheduled dose, and a confirmatory serum pregnancy test will be performed by the 
central laboratory. 
Viral serology and detection:  All patients must have negative HBsAg test result at 
screening prior to enrollment.  If total HBcAb is positive at screening, hepatitis B virus 
(HBV) DNA measured by PCR must be negative to be eligible. 
Liver function (i.e., ALT/SGPT, AST/SGOT, total bilirubin) should be reviewed 
throughout the study.  Patients who develop evidence of liver dysfunction should be 
assessed for viral hepatitis and, if necessary, referred to a hepatologist or other 
appropriately qualified expert.  Study drug should be withheld until the diagnosis of viral 
hepatitis has been excluded.  Patients who develop hepatitis B should be withdrawn 
from the study treatment. Should treatment for hepatitis be prescribed, this will be 
recorded in the eCRF.  Patients with viral hepatitis due to other agents, such as 
hepatitis A, may resume study treatment after recovery. 
Samples for the following laboratory tests and biomarkers will be sent to the central 
laboratory and/or to the Sponsor or designated processing site, and may be processed 
by the Sponsor’s laboratory or the Sponsor’s qualified designated laboratory (CRO 
and/or academic research laboratories affiliated with the study): 
Quantitative immunoglobulin: Ig levels (including total Ig, IgG, IgM, and IgA isotypes) 
Blood TBNK/B-cell subset panel sample for CD19 and other circulating B-cell subsets, T 
cell subsets, and other innate immune cells, including NK cells, neutrophils, monocytes, 
etc.  
Serum: analysis may include but will not be limited to levels of soluble markers of acute 
injury, disease activity and neurodegeneration (i.e., NfL, GFAP) and/or inflammatory 
markers (i.e., CXCL13, BAFF (B cell activating factor), etc.); other disease associated 
markers (i.e., serum Vit 25 [OH] D); and the relationship between ocrelizumab exposure 
and selected pharmacodynamics 
Blood samples for RNA extraction for exploratory research on non-inherited biomarkers, 
which may include but not be limited to immune gene expression markers 
Peripheral blood mononuclear cells (PBMCs): analysis may include but will not be 
limited to B- and T-cell numbers, other cell types, activation markers, functional 
attributes, activity, and/or molecular status of cells; and levels of soluble inflammatory 
markers, such as TNF, IL-6, IL-10, IL-17, interferon-gamma, soluble CD27 (sCD27), and 
other cytokines and chemokines, etc. 
Exploratory biomarker research may include, but will not be limited to, the assessments 
listed above. Oral samples (gingival swabs) will be stored for future analysis, including 
evaluations of the microbiome in early MS. Given the complexity and exploratory nature 


 
 
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of biomarker analyses, results from the analyses will not be shared with investigators or 
study participants, unless required by law. 
In the case of suspected PML, stored serum or plasma biomarker may be used to 
assess status of JC virus (JCV) antibodies.   
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
CSF:  A CSF specimen will be collected at baseline for all participants who have not 
previously undergone this testing. CSF will be tested for cell count, protein, elevated IgG 
index and one or more IgG oligoclonal bands using the local lab.  The remainder of this 
CSF sample will be retained as a biomarker sample, and analysis may include, but will 
not be limited to NfL and adaptive and innate immune cell subsets.  Levels of soluble 
neurodegeneration markers, and/or inflammatory markers; and the relationship between 
ocrelizumab exposure and selected pharmacodynamics. Fluoroscopy can be used, if 
required, for the LP to draw the CSF. 
Certain analyses may be conducted at study sites as directed by the Sponsor, or the 
sample may be shipped to the central laboratory and/or to the Sponsor or designated 
processing site, and may be processed by the Sponsor’s laboratory or the Sponsor’s 
qualified designated laboratory (CRO and/or academic research laboratories affiliated 
with the study). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions: 
Plasma and/or serum and/or whole blood samples or their derivatives (e.g. peripheral 
blood mononuclear cells, PBMC) collected for biomarker research will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed unless the 
patient has consented for their transfer to the Research Biosample Repository (RBR, 
described in Section 4.5.19 below). 
Any leftover CSF samples that were collected for IgG index/OCB analysis to determine 
eligibility for patients who did not have historical data and the Week 48 CSF sample will 
be destroyed no later than 5 years after the final Clinical Study Report has been 
completed or until exhausted, or earlier depending on local regulations unless the patient 
has consented for their transfer to the RBR.  
Oral samples (gingival swabs) will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed or until exhausted, or earlier depending on 
local regulations unless the patient has consented for their transfer to the RBR. 


 
 
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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.  
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 4.5.19.2 and Section 8.4. 
Hepatitis Screening and Liver Function Monitoring 
Patients with recurrent or chronic hepatitis B or history/presence of hepatitis C infection 
must be excluded from enrollment into the study.  Hepatitis B and C serology will be 
performed at screening. 
A positive result to either HBsAg, total HBcAb associated with positive viral DNA titers as 
measured by PCR, or a positive result for HepCAb should result in the patient's 
exclusion. 
Patients with evidence of past resolved hepatitis B infection (i.e., positive total HBcAb 
associated with a negative viral DNA) can be enrolled and will have the hepatitis B viral 
DNA checked regularly as per the schedule of activities (see Appendix 1). 
Patients in whom the viral DNA becomes positive but in whom the quantity is at the 
lower limit of detection of the assay should have the test repeated as soon as possible.  
Patients found to have a confirmed viral DNA-positive test should be referred to a 
hepatologist for immediate assessment.  These patients will not receive further 
ocrelizumab infusions.  
Liver function (i.e., ALT, AST, alkaline phosphatase, and total bilirubin) should be 
reviewed throughout the study.  Patients developing evidence of liver dysfunction should 
be assessed and, if necessary, referred to a hepatologist or other appropriately qualified 
expert.  Study drug should be withheld until the diagnosis of viral hepatitis has been 
excluded. 
Patients developing hepatitis B or C should be withdrawn from the study.  Should 
treatment be prescribed, this will be recorded on the eCRF.  Patients with viral hepatitis 
due to other agents, such as hepatitis A, may resume treatment after the patient's 
recovery. 


 
 
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Patient-Reported Outcomes 
Patient-reported outcome (PRO) data will be elicited from patients in this study to better 
characterize patient quality of life while on ocrelizumab compared to placebo for patients 
with RIS. The Neuro-QoL, (Quality of Life in Neurological Disorders) will also be used in 
this study to examine patient-reported measures of physical function, emotional and 
cognitive health as well as social abilities. The National Institute of Health’s Neuro-
QoL™ represents a comprehensive system of PRO measures that target neurologic 
disorders, including MS, and encompasses a series of short forms that measure 
physical, social, and mental domains of health-related quality of life.  
The Neuro-QoL™ is required to be administered prior to administration of study drug 
and prior to any other study assessment(s) to ensure the validity of the instruments is 
not compromised.  Also note that the methods for collecting and analyzing PRO data are 
different from those for the ascertainment of observed or volunteered adverse events.  
Due to these differences, PRO data will not be reported as adverse events and no 
attempt will be made to resolve any noticeable discrepancies between PRO data and 
observed or volunteered adverse events. 
PRO instruments will be completed to assess the treatment benefit and more fully 
characterize the safety profile ocrelizumab.  In addition, PRO instruments will enable the 
capture of each patient's direct experience with ocrelizumab. For further information, see 
Appendix 10 for the Neuro-QOL. 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered at the clinic at specified timepoints during the 
study (see schedule of activities in Appendix 1).  At the clinic, instruments will be 
administered before the patient receives any information on disease status, prior to the 
performance of non-PRO assessments, and prior to the administration of study 
treatment, unless otherwise specified. 
PRO instruments, translated into the local language as appropriate, will be provided by 
the Sponsor in pre-printed booklets or digitally to enable the instrument to be 
administered at each specified timepoint.  Any hardcopy booklets will be labeled with the 
timepoint of administration. 
 
During clinic visits PRO instruments should be administered as outlined below: 
Patients' health status should not be discussed prior to administration of the instruments. 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 


 
 
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Sites should allow sufficient time for patients to complete the instruments, estimated to 
be 5−10 minutes 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
Patients should be instructed to answer questions to the best of their ability; there are no 
right or wrong answers. 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
Patients should not obtain advice or help from others (e.g., family members or friends) 
when completing the instruments. 
Site staff should review all completed instruments and should ask the patient to rectify 
any response that is not clearly marked in the appropriate location.  If a response is 
missing, site staff should ask the patient to complete the item or confirm that the item 
was intentionally left blank. 
 
Blood Samples for Whole Genome Sequencing or Whole Exome 
Sequencing (Patients at Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
to identify variants that are predictive of response to study drug, are associated with 
progression RIS to clinical MS, progression to a more severe disease state, are 
associated with susceptibility to developing adverse events, can lead to improved 
adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Research will be aimed at exploring 
inherited characteristics.  The samples may be sent to one or more laboratories for 
analysis. 
Collection and submission of blood samples for WGS is contingent upon the review and 
approval of the exploratory research by each site's Institutional Review Board or Ethics 
Committee (IRB/EC) and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for WGS, this section of the protocol will not be applicable at that 
site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but will also 
be explored in aggregate with data from other studies.  The availability of a larger 


 
 
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dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
Refer to Section 0 for details on use of samples after patient withdrawal, confidentiality 
standards for data, and availability of data from biomarker analyses. 
Optional Lumbar Punctures  
Consenting patients will undergo optional lumbar punctures at baseline, week 104, 208, 
and any unscheduled visits. CSF will be processed and stored, or used for 10X single 
cell sequencing and other advanced immunologic analyses (if patient/site is participating 
in the Immune Cell Network Sub-study). Blood will always be processed (for peripheral 
blood mononuclear cells) and either tested (e.g. with 10X single cell sequencing) or 
stored in parallel to any CSF collections. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
The Informed Consent Form will contain a separate section that addresses optional 
lumbar punctures.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional lumbar punctures.  The investigator should document 
whether or not the patient has given consent to participate and (if applicable) the date(s) 
of consent in the appropriate eCRF. 
Samples may be used for exploratory biomarker research as described in 
Section 4.5.19.  For sampling procedures, storage conditions, and shipment instructions, 
see the laboratory manual.  Refer to Section 0 for details on duration of sample storage, 
use of samples after patient withdrawal, confidentiality standards for data, and 
availability of data from biomarker analyses. 
Optional Samples for Immune Cell Network Sub-study 
Consenting patients will undergo blood draws in parallel with CSF at baseline. 
Longitudinal samples will be obtained from sub-study participants who consent to one or 
more additional lumbar punctures. For these participants, paired blood and CSF will also 
be collected at week 104 and/or 208 (participants may consent to one or both optional 


 
 
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LPs). Blood will always be processed (for peripheral blood mononuclear cells) and either 
tested (e.g. with 10X single cell sequencing) or stored in parallel to any CSF collections. 
The Informed Consent Form will contain a separate section that addresses optional 
blood for the Immune Cell Network Sub-study.  A separate, specific signature will be 
required to document a patient's agreement to undergo optional lumbar punctures.  The 
investigator should document whether or not the patient has given consent to participate 
and (if applicable) the date(s) of consent, in the appropriate eCRF. 
Samples may be used for exploratory biomarker research as described in 
Section 4.5.19.  For sampling procedures, storage conditions, and shipment instructions, 
see the laboratory manual.  Refer to Section 4.5.19 for details on duration of sample 
storage, use of samples after patient withdrawal, confidentiality standards for data, and 
availability of data from biomarker analyses. 
See  


 
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Appendix 2 for additional information.  
Optional Samples for Research Biosample Repository 
Use and storage of RBR samples (which may include leftover samples and/or samples 
collected specifically for the RBR) is summarized below: 
Who can use the 
samples? 
The study team/program has use of the samples and can 
decide if and when other researchers can use the samples. 
When are the samples 
available for analysis? 
Samples can be analyzed any time during or after the study, 
until the samples are used up or no longer needed (or as 
outlined in the locally approved version of the RBR ICF). 
What type of research 
is allowed? 
The samples can be used for study-specific research or for 
extended research as outlined in the RBR section of the ICF. 
Who manages the 
samples? 
Samples are managed by Yale University in collaboration with 
Genentech.   
Where are the 
samples stored? 
During the study, samples are usually managed by a central 
laboratory.  No later than the time of study closure, samples 
are transferred to Yale University and/or Genentech for 
ongoing management. 
 
 
Sample Collection 
For all patients consenting to participate in the RBR, any biospecimens not directly 
utilized during this study will be transferred to the RBR no later than at the end of the 
study. 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to ocrelizumab, neurologic 
or immune/inflammatory diseases, or drug safety: 
Blood samples collected at Baseline, Week 24, Week 48, Week 72, Week 104, 
Week 130, Week 156, Week 182, Week 208, Unscheduled, and Discontinuation 
visits. 
Leftover blood, serum, PBMC samples and any derivatives thereof (e.g., DNA, RNA, 
proteins, peptides) 
Gingival swab samples 
Any remaining CSF specimens 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 


 
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researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
Consent to Participate in the Research Biosample Repository 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples remaining unused at the conclusion of the study will be stored in 
the Yale Data Registry & Research Biorepository. These samples could be used to research other 


 
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neurologic, inflammatory or immune conditions in the future. Samples in the Data Registry & 
Biorepository will be provided with a code-link that will allow linking the biological specimens 
with the phenotypic data from each participant, maintaining the blinding of the identity of the 
participant. 
 
When the study is completed, further access to biologic samples will be provided through the 
Yale Data Registry & Biorespository. 
 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
MSResearch@yale.edu  
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 


 
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TREATMENT, PATIENT, AND STUDY DISCONTINUATION 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
Additionally, patients must be withdrawn from treatment under the following 
circumstances: 
Life-threatening (National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] Grade 4) infusion-related event that occurred during a 
previous ocrelizumab infusion 
Demonstrate active hepatitis B infection, either new onset or reactivation  
PML 
Newly diagnosed malignancy 
Patients who become pregnant /or lactating 
Patients who decide to discontinue treatment 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
If a patient meets any of the treatment withdrawal criteria (see above), the patient must 
be withdrawn from treatment.  Patients who prematurely withdraw from study drug 
treatment will need to return to the clinic for an unscheduled treatment discontinuation 
visit (see Appendix 1 for additional details).  After treatment discontinuation, every effort 
should be made to have the patient enter the follow-up phase of the study. 
For patients who have withdrawn from study drug treatment, the investigator should 
decide as to further treatment of the underlying disease (see Section 4.4 for 
recommendations on alternative treatments for MS post-ocrelizumab). 
Patient Discontinuation from the Study 
Patients will return to the clinic for an end of observation or withdrawal from 
follow-up visit.  
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 


 
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Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
Patient withdrawal of consent 
Study termination or site closure 
Adverse event 
Loss to follow-up 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
If patient is lost to follow-up, the investigator should make every effort to contact the 
patient by telephone to establish as completely as possible the reason for the 
withdrawal. 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
Excessively slow recruitment 
Poor protocol adherence 
Inaccurate or incomplete data recording 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
 


 
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ASSESSMENT OF SAFETY 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with ocrelizumab 
in completed and ongoing studies.  The anticipated important safety risks for 
ocrelizumab are outlined below.  Please refer to Ocrelizumab Investigator's Brochure for 
a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for dosage modification and 
treatment interruption or discontinuation, are provided below. 
Risks Associated with Ocrelizumab 
Important, identified, and potential risks associated with ocrelizumab are described in the 
approved risk management plan, and provided below.  Please refer to the most recent 
version of the Ocrelizumab Investigator’s Brochure for updates on risks associated with 
ocrelizumab treatment. 
Identified Risks and Adverse Drug Reactions 
Infusion-Related Reactions 
All CD20-depleting agents administered via the intravenous route, including 
ocrelizumab, have been associated with acute IRRs.  Following the approved 
administration regimen (which includes the use of premedication prior to treatment with 
ocrelizumab to reduce frequency and severity of IRRs), symptoms of IRRs may occur 
during any ocrelizumab infusion, but have been more frequently reported during the first 
infusion.  Physicians should alert patients that IRRs can occur within 24 hours of the 
infusion.  Across the RMS and PPMS trials, symptoms associated with IRRs included, 
but are not limited to the following:  pruritus, rash, urticaria, erythema, bronchospasms, 
throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, 
hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and 
anaphylaxis. 
Patients should be observed for at least 1 hour after the completion of the infusion for 
any symptom of IRR.  Patients will be informed about delayed post-infusion symptoms 
and instructed to contact the study physician if he or she develops such symptoms. 
Hypotension, as a symptom of IRR, may occur during ocrelizumab infusions.  Therefore, 
withholding of antihypertensive treatments should be considered for 12 hours prior to 
and throughout each ocrelizumab infusion.  


 
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For further guidance on how to manage IRRs please refer to the current Ocrelizumab 
Investigator’s Brochure. 
Infections 
Infection is an identified risk associated with ocrelizumab treatment, predominantly 
involving mild to moderate respiratory tract infections.  Non-disseminated herpes 
virus-associated infections, mostly mild to moderate, were also reported more frequently 
with ocrelizumab (approximately 5%−6%, simplex and zoster) than with comparators 
(approximately 3%). 
During the controlled period of the pivotal trials, the proportion of patients with serious 
infections in RMS was lower in the ocrelizumab group (1.3%) than in the 
interferon β-1a group (2.9%); in PPMS, the proportion of patients with serious infections 
was similar in both groups:  6.7% in the placebo group compared with 6.2% in the 
ocrelizumab group. 
Serious, opportunistic and fatal infections have occurred in patients with lupus and 
rheumatoid arthritis treated with ocrelizumab in Phase III clinical trials.  Data from 
completed studies regarding infection risks with ocrelizumab treatment in these patient 
populations are provided in the Ocrelizumab Investigator’s Brochure.  
No opportunistic infections were reported by any patient with MS treated with 
ocrelizumab during the controlled period of the pivotal trials. 
In interventional clinical studies, there were no reports of hepatitis B reactivation in 
patients with MS treated with ocrelizumab, but it had been reported in 1 patient with 
rheumatoid arthritis treated with ocrelizumab.  HBV screening should be performed in all 
patients before initiation of treatment with ocrelizumab as per local guidelines.  Patients 
with active HBV should not be treated with ocrelizumab.  Patients with positive serology 
should consult liver disease experts before start of treatment and should be monitored 
and managed following local medical standards to prevent hepatitis B reactivation. 
Delay ocrelizumab administration in patients with an active infection until the infection 
is resolved. 
For PML see Potential Risks Section 5.1.1.2 below. 
Impaired Response to Vaccination 
After treatment with ocrelizumab for over 2 years in pivotal clinical trials, the proportion 
of patients with positive antibody titers against Streptococcus pneumoniae, mumps, 
rubella, and varicella were generally similar to the proportions at baseline. 
The results of the randomized, open-label Phase IIIb study (BN29739) that assessed if 
ocrelizumab recipients with RMS raised adequate humoral responses to selected 


 
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vaccines indicate that patients treated with ocrelizumab were able to mount humoral 
responses, albeit blunted, to tetanus toxoid; 23-valent pneumococcal polysaccharide; 
keyhole limpet hemocyanin neoantigen; and seasonal influenza vaccines.  The results 
are summarized in the current version of the Ocrelizumab Investigator’s Brochure. 
Investigators should review the immunization status of patients being considered for 
treatment with ocrelizumab.  Patients who require vaccination should complete it at least 
6 weeks prior to initiation of ocrelizumab.  For seasonal influenza vaccines, it is still 
recommended to vaccinate patients who are on ocrelizumab.  Vaccination with live or 
live-attenuated vaccines are not recommended during the treatment with ocrelizumab 
and until B cells have returned to normal levels. 
Due to the potential depletion of B cells in neonates and infants of mothers who have 
been exposed to ocrelizumab during pregnancy, it is recommended that vaccination with 
live or live-attenuated vaccines should be delayed until B cells have recovered; 
therefore, measuring CD19-positive B-cell level in neonates and infants prior to 
vaccination is recommended. 
It is recommended that all vaccinations other than live or live-attenuated should follow 
the local immunization schedule, and measurement of vaccine-induced response titers 
should be considered to check whether individuals can mount a protective immune 
response because the efficacy of the vaccination may be decreased. 
Decrease in Immunoglobulins 
Treatment with ocrelizumab resulted in a decrease in total Ig over the controlled period 
of the studies, mainly driven by reduction in IgM.  The proportion of patients with 
decrease in Igs below LLN increased over time and with successive dosing.  Based on 
additional patient exposure, in cases of continuous decrease over time, a higher risk of 
serious infection cannot be ruled out.  
Serious infections related to decrease in immunoglobulins (particularly in patients 
previously exposed to immunosuppressive/ immunomodulatory drugs or with pre-
existing hypogammaglobulinaemia) 
Based on additional patient exposure an association between decrease in 
immunoglobulins and serious infections with ocrelizumab treatment was observed and 
was most apparent for IgG.  There was no difference in the pattern (type, latency, 
duration, outcome) of the serious infections reported in this subset of patients compared 
to the overall serious infections profile.  In addition, risk factors for a subset of patients at 
higher risk of serious infections could not be identified. 
Delayed Return of Peripheral B Cells 
Treatment with ocrelizumab leads to rapid depletion of CD19+ B cells in blood by 
14 days posttreatment (first timepoint of assessment) as an expected pharmacologic 


 
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effect.  This was sustained throughout the treatment period.  The longest follow-up 
duration after the last ocrelizumab infusion from Phase II Study WA21493 in 51 patients 
indicates that the median time to repletion (returned to baseline/LLN, whichever 
occurred first) of B cells was 72 weeks (range 27−175 weeks).  Patients with prolonged 
B-cell depletion should be monitored until his or her B cells have repleted. 
Potential Risks 
Progressive Multifocal Leukoencephalopathy  
It has been reported in patients receiving ocrelizumab but only in patients where other 
contributory factors were present, such as prior immunosuppressive treatment (for 
example natalizumab or fingolimod). Physicians should be vigilant for early signs and 
symptoms of PML, which can include any new onset, or worsening of neurological signs 
or symptoms as these can be similar to an MS relapse. If PML is suspected, dosing with 
ocrelizumab must be withheld. Evaluation of PML, including MRI, confirmatory CSF 
testing for JC Viral DNA and repeat neurological assessments, should be considered. If 
PML is confirmed, ocrelizumab must be discontinued permanently.  
Refer to Appendix 7 for guidance for diagnosis of PML.  Please see the Ocrelizumab 
Investigator’s Brochure for more details.  
Hypersensitivity Reactions 
Hypersensitivity may be difficult to distinguish from IRRs in terms of symptoms.  
A hypersensitivity reaction may present during any infusion, although typically would not 
present during the first infusion.  For subsequent infusions, more severe symptoms than 
previously experienced, or new severe symptoms, should prompt consideration of a 
potential hypersensitivity reaction.  If a hypersensitivity reaction is suspected during 
infusion, the infusion must be stopped immediately and permanently.  Patients with 
known IgE-mediated hypersensitivity to ocrelizumab must not be treated. 
Malignancies (including Breast Cancer) 
An increased risk of malignancy with OCREVUS may exist.  In controlled trials in MS, 
malignancies, including breast cancer, occurred more frequently in OCREVUS-treated 
patients.  Breast cancer occurred in 6 of 781 females treated with ocrelizumab and none 
of 668 females treated with REBIF or placebo.  Patients should follow standard breast 
cancer screening guidelines. 
Refer to the current Ocrelizumab Investigator’s Brochure for more details. 
Neutropenia 
In the controlled treatment period, decreased neutrophils were observed in 12% and 
15% of MS patients treated with ocrelizumab in PPMS and RMS, respectively.  Most 
were mild to moderate in severity, approximately 1% of the patients had Grade 3 or 4 
neutropenia; and no temporal association with infections was identified.  Based on 


 
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additional patient exposure, an association between neutropenia and serious infections 
with ocrelizumab treatment was not observed.   
Additional information can be found in the current Ocrelizumab Investigator’s Brochure. 
Risks Associated with Corticosteroids 
The adverse reactions of corticosteroids may result from unwanted glucocorticoid 
actions or from inhibition of the hypothalamic-pituitary-adrenal axis.  Please refer to local 
prescribing information. 
Risks Associated with Antihistamines 
The adverse reactions depend on the sedating properties of the antihistamine and 
include, but are not limited to, nausea, drowsiness, headaches, dry mouth, and allergic 
reactions such as rash.  Please refer to local prescribing information. 
Management of Patients Who Experience Adverse Events 
Dose Modifications 
Study drug dose modifications are not foreseen. 
Treatment Interruption 
Study drug treatment may be temporarily suspended in patients who experience relevant 
adverse events considered to be related to study drug and prevent the patient from 
re-treatment with the study drug (see Section 4.3.2.3 for details on re-treatment criteria). 
For female patients who become pregnant during the study, study drug treatment will be 
discontinued upon confirmation of pregnancy. Study drug will not be re-started, but the 
patient should continue with other study-related visits and assessments, unless they are 
contraindicated due to pregnancy.   
Management Guidelines Infusion-Related Reactions 
Slowing of the infusion rate or interruption of the infusion may be necessary in the event 
of an infusion reaction.  In rare cases, ocrelizumab treatment may need to be 
discontinued.  Please also follow ocrelizumab local label for further guidelines.  
Handling of IRRs will depend on the intensity of symptoms (see also Table 2 for grading 
of intensity of IRRs). 
For a mild to moderate (Grade 1 or 2) non-allergic, infusion-related event, the infusion 
rate should be reduced to half the rate being given at the time of onset of the event 
(e.g., from 50 mL/hr to 25 mL/hr or from 100 mL/hr to 50 mL/hr).  Once the event has 
resolved, the investigator should wait for 30 minutes while delivering the infusion at the 
reduced rate.  If tolerated, the infusion rate may then be increased to the next closest 
rate on the patient’s infusion schedule and the rate increments resumed. 


 
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For a severe infusion-related event (Grade 3) or a complex of flushing, fever, and 
throat pain symptoms, the infusion should be interrupted immediately and the patient 
should receive aggressive symptomatic treatment.  The infusion should be restarted only 
after all the symptoms have disappeared.  The initial infusion rate at restart should be 
half of the infusion rate that was in progress at the time of onset of the reaction. 
For a life-threatening infusion-related event (Grade 4) during an infusion, the infusion 
should be immediately stopped, and the patient should receive appropriate treatment 
(including use of resuscitation medications and equipment that must be available and 
used as clinically indicated).  The patient will be withdrawn from treatment and should 
enter the follow-up phase. 
The above examples of dose interruption and slowing (for mild/moderate and severe 
IRRs) will result in a change in the infusion rate and increase the total duration of the 
infusion but not the total dose. 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) per protocol.  This includes all events of death and any 
study-specific issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), 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 multiple sclerosis 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 cardiac catheterizations). 
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). 


 
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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). 
 
Adverse Events of Special Interest 
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. 
Adverse events of special interest for this study include the following: 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin > 2 × ULN 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of the study drug is suspected 
 
There are no Ocrelizumab Events of Special Interest. 
 
 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are 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).  


 
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Adverse Event Reporting Period 
The study period during which AEs and SAEs as described in Section 5.2 where the patient 
has been exposed to Genentech product must be reported. Reporting period begins after 
informed consent is obtained and initiation of study treatment and ends 24 weeks 
following the last administration of study treatment 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 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 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 OCRELIZUMAB; and/or the AE abates or 
resolves upon discontinuation of OCRELIZUMAB or dose reduction and, if applicable, 
reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than 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., cancer diagnosed 2 days after first dose of OCRELIZUMAB). 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I) or current Investigator Brochure (I.B).  
Unexpected adverse events are those not listed in the P.I. or current 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. 


 
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PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted.  Examples of 
non-directive questions include the following:  
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs.  Avoid colloquialisms and abbreviations. 
Diagnosis versus 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 acceptable to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.3.1), regardless of attribution, will be reported to the appropriate parties.  When 
recording a death, the event or condition that caused or 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”. 
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”). 
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. 


 
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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 
 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.  
Table 2 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0) ,which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b 
Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 
c 
If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section Procedures for Eliciting, Recording, and Reporting Adverse 
Events5.4 for reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
d 
Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
Assessment of Causality of Adverse Events 
Pregnancies 
If a female subject becomes pregnant while receiving the study drug or within 24 weeks 
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 24 weeks a report 


 
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should be completed and expeditiously submitted to Genentech, Inc. Follow-up to obtain 
the outcome of the pregnancy should also occur, and on a voluntary basis we will follow 
the health of children through 1 year (Appendix 9). 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. 
Other Special Situations Reports 
The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech: 
•     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 
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. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient 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 patient who 
participated in the study, this should be reported as an SAE adequately to Genentech 
Drug Safety during the follow-up period.. 
ADVERSE EVENT REPORTING 
The investigational site is responsible for forwarding 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) to the sponsor within 24 hours of awareness.  
 
It is understood and agreed that the Sponsor will be responsible for the collection and 
evaluation of AEs, SAEs, AESIs, Special Situation reports (including pregnancy reports) 
and Product Complaints (with or without an AE) originating from the study. 
Serious Adverse Drug Reactions (SADRs) 


 
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Serious AE reports that are related to the Product or where the causality is assessed as 
unknown or not provided 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. 
Pregnancy Reports 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports 
of pregnancy, 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. 
AESIs 
AESIs requiring expedited reporting (related or possibly related to Genentech product or 
where the causality is assessed as unknown or not provided) shall be forwarded to 
Genentech within fifteen (15) calendar days of the awareness date. Others (non-related 
to Genentech product) shall be sent within thirty (30) calendar days. 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon 
as it becomes available. 
Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following Special Situations 
Reports should be collected and transmitted to Genentech even in the absence of an 
Adverse Event within thirty (30) calendar days: 
Data related to product usage during pregnancy or breastfeeding 
Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous 
administration, medication error (including potentially exposed in case of medication 
errors or intercepted medication errors) or occupational exposure, with or without 
association with an AE/SAE unless otherwise specified in the protocol 
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 
 
Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the patient for whom an adverse event was reported 
Product Complaints 


 
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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. 
Exchange of Single Case Reports with Genentech 
 
Dr. Longbrake will be responsible for collecting all protocol-defined Adverse 
Events (AEs)/Serious Adverse Events (SAEs), pregnancy reports (including 
pregnancy occurring in the partner of a male study subject), other Special 
Situation reports, AESIs and Product Complaints with an AE where the patient 
has been exposed to the Product. Completed MedWatch forms as specified in 
the table below should be sent to the Genentech contact specified below. 
Transmission of these reports (initial and follow-up) will be either electronically 
via email or by fax and within the timelines specified below: 
 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should call via: 
 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
 
Transmission of these reports (initial and follow-up) will be either electronically or 
by fax and within the timelines specified below: 
 
Type of Report  
Timelines  
Serious Adverse Events  (related and 
not related to the Product) 
 
 
30 calendar days from awareness 
date 
 
Special Situation Reports ( With or 
without AE  and pregnancy) 
Product Complaints (With or without 
AE) 
AESI 
 
• The parties will verify that all single case reports have been adequately 
received by Genentech via Dr. Longbrake emailing Genentech a Quarterly 
line-listing documenting single case reports sent by Yale to Genentech in 
the preceding time period.  
 


 
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• 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 Dr. Longbrake 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. 
Reporting Requirements For Adverse Events Originating From Patient Reported 
Outcomes  
Although sites are not expected to review the PRO data, if physician/study personnel 
become aware of a potential adverse event during site review of the PRO questionnaire 
data, he/she will determine whether the criteria for an adverse event have been met and, 
if so, these must be reported using the Adverse Event and Special Situation Reporting 
Form or MedWatch form. 
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) 
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 


 
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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 
Yale University, as the Sponsor 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 filed a clinical trial approval, in compliance with local regulations. 
Yale University, 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.  
 
Yale Center for Clinical Investigation (YCCI)  will be responsible for the expedited 
reporting of safety reports originating from the Study to the Independent Ethics 
Committees/ Institutional Review Boards (IEC/IRB) of the Concerned Member States, 
where applicable. 
Yale University, 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. 
 
YCCI will be responsible for the distribution of safety information to its own investigators, 
where relevant, in accordance with local regulations. 
Additional Reporting Requirements for IND Holders:  
For Investigator-Initiated IND Studies, some additional reporting requirements for the 
FDA apply in accordance with the guidance set forth in 21 CFR § 312.32. 
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 Sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the Sponsor to be possibly related to the use of 
OCRELIZUMAB.  An unexpected adverse event is one that is not already described in 


 
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the OCRELIZUMAB Investigator Brochure.  Such reports are to be telephoned or faxed 
to the FDA and Genentech within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Sponsor 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 Sponsor 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, 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 Sponsor must also be 
faxed to Genentech Patient Safety: 
Fax:  (650) 225-4682 or (650) 225-4630 
Email: usds_aereporting-d@gene.com 
 
YCCI will be responsible for the distribution of safety information to Central IRB. 
 
Biomedical Research Alliance of New York Institutional Review Board 
1981 Marcus Avenue, Suite 210 
Lake Success, NY 11042 
 
 
  
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel:  (888) 835-2555 
Fax:  (650) 225-4682 or (650) 225-4630 
 
AGGREGATE REPORTS 
IND ANNUAL REPORTS 


 
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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  
 
Dr. Erin Longbrake will forward a copy of the Final Study Report to Genentech 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 
Randomization Codes for Blinded Clinical Trials 
 
The blind will be broken for ADR reports that are Serious and Unexpected, unless 
otherwise agreed with applicable regulatory authorities  
QUERIES 
Queries related to the Study will be answered by Yale University. However,  responses 
to all  safety queries from  regulatory authorities, Ethics Committees and Institutional 
Review Board or for publications will be discussed and coordinated between the Parties.  
The Parties agree that Genentech shall have the final say and control over safety 
queries relating to the Product.  Yale University 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. 
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. 
SIGNAL MANAGEMENT AND RISK MANAGEMENT  
 


 
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Genentech is responsible for safety signal management (signal detection and/or 
evaluation) for their own Product. However, it is agreed that Yale, as Sponsor of 
the Study, will be primarily responsible for assessment of the benefit-risk balance 
of the Study. 
 
If Yale issues a safety communication relevant for Genentech (i.e., a safety issue 
that notably impacts the benefit-risk balance of the Study and / or triggers any 
changes to the Study) this will be sent to Roche within five (5) business days of 
its internal approval. 
 
As needed, Genentech will reasonably assist Yale with signal and risk 
management activities related to the Product within the Study. 
 
Genentech will also provide Yale with any new relevant information that may 
modify or supplement known data regarding the Product (e.g., relevant Dear 
Investigator Letter).  
 
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 shall have the final say and control over safety crisis 
management issues relating to the Product. Yale University agrees that it shall not 
answer such queries from media and other sources relating to the Product but shall 
redirect such queries to Genentech. 
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 


 
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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. 
STATISTICAL CONSIDERATIONS 
Unless otherwise specified, all baseline and efficacy analyses will be based on the 
intend-to-treat (ITT) population (defined as all randomized patients). The safety 
evaluable population will include all patients who received any amount of study drug. 
Unless otherwise specified, all baseline and efficacy analyses will use the ITT population 
as assigned by randomization. Safety analyses will be performed by treatment received. 
The primary analysis will occur when the last randomized patient has reached 4 years 
and the specified number of new radiological or clinical evidence of MS has accrued as 
specified in Section 3.1. 
All statistical hypotheses for the primary and secondary endpoints and treatment 
comparisons will tested at the 5% significance level (α =0.05) against two-sided 
alternatives unless otherwise specified. The SAP will contain full details of the statistical 
analyses specified for this protocol. 
 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is estimation and hypothesis testing regarding the effect of 
ocrelizumab on the time from baseline to radiological or clinical evidence of MS relative 
to placebo. P-values, point- and interval estimates of the true underlying hazard ratio will 
be obtained. 
The sample size of this trial is based on testing the null hypothesis of no difference 
between the control and ocrelizumab arms.  This study will enroll approximately 
100  patients with an expected recruitment of over 2 years. The sample size of this study 
is driven by the primary efficacy analysis of radiological or clinical evidence of MS and 
the following assumptions: 
A two-group test of equal times to radiological or clinical evidence of MS 
Two-sided type I error = 0.05 
33% of the patients in the control arm and 20% of patients in the ocrelizumab arm 
having radiological or clinical evidence of MS occurring by 4 years. 


 
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A final analysis is based on approximately 21 radiological or clinical events to have 80% 
power 10% annual  dropout rate. 
 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study and ocrelizumab 
administration will be summarized.  Reasons for premature study discontinuation and 
treatment discontinuation will be listed and summarized.  Major protocol deviations, 
including violations of inclusion/exclusion criteria will also be listed and summarized.  
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics (including age, sex, body mass index), 
medical history, and neurological examination will be summarized using means, 
standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables, as appropriate.  MS disease history (duration since MS first 
symptom, duration since MS diagnosis), MS disease status (MS treatment naïve or 
experienced) will be summarized.  The baseline measures of MRI, EDSS, or other 
important endpoints will also be tabulated.  Summaries will be presented overall and by 
patient cohorts. 
 
EFFICACY ANALYSES 
The primary efficacy analysis population will consist of all randomized patients, with 
patients grouped according to their assigned treatment (i.e., the ITT population). All 
statistical hypotheses for the primary and secondary endpoints and treatment 
comparisons will be tested at the 5% significance level against two-sided alternative 
unless otherwise specified.  
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is to evaluate the efficacy of ocrelizumab 
compared with placebo on delaying the time to development of new radiological or 
clinical evidence of MS, defined as the time from baseline to first new T1 gadolinium-
enhancing lesions and/or new or enlarging T2 lesions consistent with MS OR first clinical 
evidence of MS, i.e., neurological event resulting from CNS demyelination as evidenced 
by acute or progressive clinical syndrome consistent with MS.  
The time to development of radiological or clinical evidence of MS in the ocrelizumab 
arm and placebo arm will be compared and tested using a stratified log-rank test with the 
null and alternative hypotheses as follows: 
H0: There is no difference in the time to onset of radiological or clinical evidence of MS 
between the ocrelizumab and placebo groups. 


 
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H1: There is a difference in the time to onset of radiological or clinical evidence of MS 
between the ocrelizumab and placebo groups. 
The proportion of patients with radiological or clinical evidence of MS over time will be 
estimated using Kaplan-Meier methodology and the overall hazard ratio will be 
estimated using a stratified Cox proportional hazards model. In the presence of a large 
amount of interval censoring, stratified generalized log rank test and stratified 
proportional hazards model with full likelihood function will be used to compare survival 
between groups. 
Estimands for the Primary Analysis 
The primary analysis has a treatment-policy estimand (see ICH E9[R1] 2019) on the 
basis of the following attributes: 
Population:  All randomized patients. 
Variable:  Time from baseline to development of new radiological or clinical evidence of 
MS. 
Intercurrent events:  
Withdrawal from treatment:  Patients will be followed until the primary analysis 
regardless of adherence to study treatment or reason for treatment withdrawal.  Data will 
continue to be collected from such patients and included in the analysis, following a 
treatment-policy strategy. 
Initiation of another MS therapy:  Data will continue to be collected from such patients 
and included in the analysis, following a treatment-policy strategy.  
Patients still ongoing and without an initial evidence of MS event at the time of study 
unblinding will be censored at the date of the last assessment. 
Population-level-summary estimator:  The hazard ratio from a stratified Cox-proportional 
hazards model will be used.  The stratified log-rank p-value will be used to test for 
statistical significance.  Both will be stratified by the factors specified (see Section 4.2.1) 
for randomization. 
Handling of missing data:   
Withdrawal from study:  a patient will be censored at the time of withdrawal from study.  
Missing assessments at scheduled visits prior to last assessment:  Missing data at 
scheduled visits prior to last assessment will not be imputed. 
Secondary Efficacy Endpoints 
The secondary endpoints for this study are to evaluate the efficacy and impact of 
ocrelizumab compared with placebo on the basis of the endpoints as described in 
Section 2.2.1 and biomarkers of disease activity and neuroaxonal damage in peripheral 
blood. 
Each change from baseline for continuous secondary endpoints will be tested and 
analyzed using a stratified mixed-effects model for repeated measures (MMRM) 


 
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assuming missing at random (MAR). Sensitivity analyses will be conducted to assess 
the validity of this assumption, 
For MRI related count endpoints (cumulative number of T2 lesions and T1 gadolinium-
enhancing lesions), generalized linear methods appropriate for count data will be used 
depending on the distribution of the counts, e.g., a stratified negative binomial regression 
model. 
Estimands for the Secondary Analyses 
The estimands for the remaining secondary endpoints will have the same population and 
handling of missing data attributes as for the primary analysis. 
Exploratory Efficacy Endpoints 
Analyses on exploratory efficacy endpoints will be performed as data allows.  
Exploratory efficacy endpoints are listed in Section 2.2.2. Further details will be 
described in the SAP. 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received.  
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs. Study 
treatment exposure (such as treatment duration, total dose received, and number of 
cycles and dose modifications) will be summarized with descriptive statistics.   
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to CTCAE v5.0 grade. All adverse 
events, serious adverse events, adverse events leading to death, adverse events of 
special interest, and adverse events leading to study treatment discontinuation that 
occur on or after the first dose of study treatment (i.e., treatment-emergent adverse 
events) will be summarized by mapped term, appropriate thesaurus level, and severity 
grade.  For events of varying severity, the highest grade will be used in the summaries.  
Deaths and cause of death will be summarized. 
Associated laboratory parameters, such as hepatic function, renal function, and 
hematology values, will be grouped and presented together.  Marked abnormalities will 
also be flagged. 
BIOMARKER ANALYSES 
Biomarkers will be assessed at baseline (screening) and subsequent time points 
following administration of ocrelizumab or placebo. Biomarkers levels at baseline or over 
time may be compared with efficacy or safety measurements to assess prognostic or 


 
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predictive properties. Biomarkers may also be analyzed over time as absolute values 
and/or percent change relative to baseline over time, and may be compared with 
efficacy, other biomarkers, or safety measurements. 
INTERIM ANALYSES 
The iDMC will review interim analyses as specified in the iDMC Charter. Interim 
analyses will be conducted by the unblinded statistician(s) and will focus on 
recruitment/enrollment, study conduct and safety.  
No formal interim analyses for futility or efficacy are planned. However, the aggregate 
rate of the primary outcome will be monitored throughout the study to assure a sufficient 
number of events. The following scenario may trigger an interim look for futility. 
If we are not on target to reach the hypothesized number of events (in the blinded 
dataset) by the end of the follow-up period, we will assess whether an extension to 
follow-up is fiscally feasible. If follow-up is feasible, a non-binding futility analysis using 
an alpha-spending function will be conducted to determine whether it is worth extending 
follow-up. 
 
Similarly, we will monitor the current trend of treatment in this patient population. The 
following scenario may trigger an interim look for efficacy if applicable. 
 
If a new drug is approved, or data supporting the treatment of this patient population is 
released, we will conduct an interim look for superiority, as long as we have 
accumulated at least 50% of the information.  We will use an alpha-spending function to 
maintain the overall type I error rate at 0.05. 
 
 
 
DATA  QUALITY ASSURANCE  
Accurate, consistent, and reliable data will be ensured through the use of 
standard practices and procedures.  
Study site monitoring is necessary to assure adequate protection of the rights of human 
subjects and the safety of all subjects involved in clinical investigations and the quality 
and integrity of the resulting data submitted.  
The Sponsor-Investigator-designated monitor conducts monitoring visits to ensure that 
clinical investigators and study team members are compliant with the protocol, ICH good 
clinical practice, federal, state and local regulations and institutional policies and 
procedures, that data are of high quality and integrity, and that the facilities and staffing 
are adequate for continued study participation. This will be performed by conducting 
monitoring visits including a site initiation visit, regularly scheduled interim monitoring 
visits and/or remote interim monitoring visits while subjects are on study, and a site 
close-out visit at the sites. Following each site visit, a visit report will be generated 


 
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containing information on site activities and a summary of pertinent points and action 
items. The report will be provided with a follow-up letter. Site-specific data status reports 
will be distributed to the site regularly to outline planned, missing or incomplete case 
report forms and any outstanding data queries. 
During monitoring visits, the following may be reviewed: 
Protection of the rights, safety and welfare of subjects through review of informed 
consent process and documentation, adverse events (AEs) and serious adverse events 
(SAEs) and safety procedures 
Subject eligibility 
Source verification 
Protocol compliance 
Deviations and Non-compliance 
Investigator Site File 
GCP compliance 
Investigational Drug/ Device Storage and Accountability (including quantity and disposal 
procedures) 
Laboratory Facilities 
Equipment maintenance and calibration 
Additional study supplies inventory and assessment 
Study progress and/or follow-up on issues with Site Principal Investigator (PI) and 
relevant members of the study team 
The Sponsor-Investigator and YCCI will define the required study monitoring activities in 
a Study Monitoring Plan. 
INVESTIGATOR REQUIREMENTS 
RETENTION OF RECORDS 
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of 
the guideline) require that records and documents pertaining to the conduct of clinical 
trials and the distribution of investigational drug, patient records, consent forms, 
laboratory test results, and medication inventory records, must be retained for 2 years 


 
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after the last marketing application approval in an ICH region or after at least 2 years 
have elapsed since formal discontinuation of clinical development of the investigational 
product.  All state and local laws for retention of records also apply.  
For studies conducted outside the U.S. under a U.S. IND, the Principal Investigator must 
comply with the record retention requirements set forth in the FDA IND regulations and 
the relevant national and local health authorities, whichever is longer. 
STUDY MEDICAL MONITORING REQUIREMENTS 
This clinical research study will be monitored both internally by the PI and externally by 
the central IRB.  In terms of internal review, the PI will continuously monitor and tabulate 
AEs.  Appropriate reporting to the central IRB will be made.  The PI of this study will also 
continuously monitor the conduct, data, and safety of this study to ensure that: 
Interim analyses occur as scheduled, 
Stopping rules for toxicity and/or response are met, 
Risk/benefit ratio is not altered to the detriment of the subjects, 
Appropriate internal monitoring of AEs and outcomes is done, 
Over-accrual does not occur, 
Under-accrual is addressed with appropriate amendments or actions, and 
 Data are being appropriately collected in a reasonably timely manner. 
 
Routine monitoring will be carried out via a periodic team conference among 
investigators during which toxicity data, including all SAEs, will be reviewed and other 
issues relevant to the study such as interim assessment of accrual, outcome, and 
compliance with study guidelines, will be discussed.  Monitoring will be carried out on an 
ongoing basis.  The severity, relatedness, and whether or not the event is expected will 
be reviewed. 
STUDY MEDICATION ACCOUNTABILITY 
Each Site Investigator will ensure maintenance of complete and accurate records of the 
receipt, dispensation, and disposal or return of all study drug at their site in accordance 
with 21 Code of Federal Regulations (CFR), Part 312.57 and 312.62 and Genentech 
requirements. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the drug depot with the appropriate 
documentation.  The site’s method of destroying Genentech-supplied IMPs must be 
agreed to by the Sponsor.  The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. 


 
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DATA COLLECTION 
The study coordinator and investigators are responsible for ensuring that the eligibility 
checklist is completed in a legible and timely manner for every patient enrolled in the 
study, and that data are recorded on the appropriate forms and in a timely manner.  Any 
errors on source data should be lined through, but not obliterated, with the correction 
inserted, initialed, and dated by the study coordinator or PI.  All source documents will 
be available for inspection by the FDA, representatives of the Sponsor, and the Central 
IRB. 
ETHICAL CONSIDERATIONS 
COMPLIANCE WITH LAWS AND REGULATIONS 
Patients who comply with the requirements of the protocol, are tolerating study 
treatment, and may be receiving benefit will be offered dosing beyond close of study at 
the investigator’s discretion after a careful assessment and thorough discussion of the 
potential risks and benefits of continued treatment with the patient.  Such patients may 
have the option to receive ocrelizumab treatment as long as they continue to experience 
clinical benefit in the opinion of the investigator until the earlier of unacceptable toxicity, 
symptomatic deterioration attributed to disease progression, or any of the other reasons 
for treatment discontinuation listed in Section 4.6. 
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. 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
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 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 AEs. 


 
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Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to SAEs that are 
not already identified in the Investigator’s Brochure and that are considered possibly or 
probably related to the ocrelizumab or study drug by the investigator.  Some IRBs may 
have other specific AE requirements to which 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’s Brochure, safety 
amendments and updates, etc.). 
CONFIDENTIALITY 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the ICF (or separate authorization to use and 
disclose personal health information) signed by the patient or 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. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local health 
authorities, Sponsor representatives and collaborators, and the IRB/Ethics Committee 
(EC) for each study site, if appropriate. 


 
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Appendix 1  
Schedule of Activities 
 
Pre-
screening 
(family 
members) 
Screening 
a 
Double-Blind Phase v 
Unscheduled 
Visit b 
Study 
Completion/ 
Early 
Termination, c  
Week 
-6 
-6 
0 
Baseline 
2 
24 
48 
72 
104 
130 
156 
182 
208 
 
 
Visit Windows (days) 
-45-1 
-45-1 
(-28) 
(± 7) (± 7) (± 7) (± 7) (± 7) (± 7) (± 7) (± 7) (± 7) 
 
 
Inclusion/Exclusion Review 
x* 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent d 
x* 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Disease/Disorder 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x* 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and baseline conditions e 
x* 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar Puncture History 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Sleep Status 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Vital signs f 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight and Height g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Complete physical examination h 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
EDSS 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Neurologic examination i 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prescreen MRI 
xw 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI brain p.q 
 
x 
 
 
x 
x 
x 
x 
 
x 
 
x 
xr 
xr 
MRI C-spine p,q 
 
x 
 
 
x 
x 
x 
x 
 
x 
 
x 
xr 
xr 
Symbol Digit Modality test for cognition 
x* 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Neuro QoL 
x* 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Assessment of neurologic event 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology, chemistry, and urinalysis j 
(Local lab) 
 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
Pregnancy test k 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
x 
Hepatitis screening  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B virus DNA test l 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 


 
OCRELIZUMABYale University 
Protocol ML42790, Version 2.0 
94 
 
 
Pre-
screening 
(family 
members) 
Screening 
a 
Double-Blind Phase v 
Unscheduled 
Visit b 
Study 
Completion/ 
Early 
Termination, c  
Week 
-6 
-6 
0 
Baseline 
2 
24 
48 
72 
104 
130 
156 
182 
208 
 
 
Visit Windows (days) 
-45-1 
-45-1 
(-28) 
(± 7) (± 7) (± 7) (± 7) (± 7) (± 7) (± 7) (± 7) (± 7) 
 
 
Quantitative Ig (total Ig, IgG, IgM, and 
IgA) (local lab) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative Ig (total Ig, IgG, IgM, and 
IgA) (central lab) 
 
 
xx 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lumbar puncture/CSF analysis (local lab 
and biomarkers) m,p, s  
 
 
xx 
 
 
 
 
x 
 
 
 
x 
xr 
xr 
Peripheral blood sample for biomarkers 
m,s,t 
x 
 
xx 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Peripheral blood sample, paired with CSF 
 
 
xy 
 
 
 
 
xy 
 
 
 
xy 
Xy 
xy 
Serum samples for biomarkers m,s 
x 
 
xx 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gingival swab for storage 
x* 
 
xx 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events u 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications review  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization IxRS 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Methylprednisolone and antihistamine 
premedication n 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
Ocrelizumab or placebo administration o 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
eCRF = electronic Case Report Form; EDSS = Expanded Disability Status Scale; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; HepCAb = hepatitis C; MRI = magnetic resonance imaging; MS = multiple sclerosis; NfL = neurofilament light; WGS=Whole 
genome sequencing; PBMC=peripheral blood mononuclear cells; CSF= cerebrospinal fluid. 
Note: (x) indicates that an assessment will only be done if needed. 
* If these assessments have been completed during the pre-screening evaluation for an individual who is subsequently found to meet study criteria 
and enrolled in the main study, they do NOT need to be repeated during the Screening and/or Baseline Visits, as long as those visits take place 
within 6 weeks of the pre-screening assessment. 
a 
The screening window is up to 45 days prior to baseline and all screening and baseline assessments must be conducted prior to first dose. 


 
OCRELIZUMABYale University 
Protocol ML42790, Version 2.0 
95 
 
b 
In the case of a neurological event consistent with CNS demyelination during the study, the patient should have an unscheduled visit and all 
assessments completed. An MRI may be optionally performed at this visit if clinically indicated. If the patient comes into the clinic for an 
unscheduled visit for reasons other than relapse, procedures should be performed per standard of care. 
c 
In the case of early termination, the patient will be asked to return for an early termination visit/ study discontinuation visit, at which time all 
assessments must be completed/obtained, except MRI if done within the past 8 weeks, unless clinically indicated. 
d 
Written informed consent will be obtained from all patients during screening in order to be eligible.   
e 
Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 4 weeks prior to the 
screening visit.  In addition, any previous MS medication should be recorded. Demographic data will include age, sex, and self-reported 
race/ethnicity.   
f 
Vital signs will include measurements of heart rate, systolic and diastolic blood pressure, and temperature.  Vital signs should be taken 
approximately 45 minutes prior to premedication.   
g 
After the screening visit, only weight will be measured. 
h 
A full physical examination will be conducted at the screening and early termination visits.  At all other visits, a limited physical examination will 
be conducted.  Any abnormality identified at baseline should be recorded on the eCRF.  Changes from baseline abnormalities should be recorded 
at each subsequent physical examination.  New or worsened clinically significant abnormalities should be recorded as adverse events, if 
appropriate. 
i 
Neurological examinations will be used to distinguish a neurologic event suggestive of MS (i.e., CNS demyelination) from other neurological 
(non-MS) disorders.  Potential neurologic events suggestive of CNS demyelination should be recorded throughout the study period.  Investigators 
will also screen patients for signs and symptoms of worsening neurologic function localized to the cerebral cortex, such as cortical symptoms/signs, 
behavioral and neuropsychological alteration, retrochiasmal visual defects, hemiparesis, cerebellar symptoms/signs (e.g., gait abnormalities, limb 
incoordination).  Patients with suspected PML should be withheld from ocrelizumab treatment until PML is ruled out by complete clinical evaluation 
and appropriate diagnostic testing.  A patient with confirmed PML should be withdrawn from the study.  PML should be reported as a serious 
adverse event (with all available information) with immediate notification of the Medical Monitor. 
j 
Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute and differential, absolute neutrophil count, and quantitative platelet 
count.  Chemistry will include AST, ALT, total bilirubin, urea or BUN, creatinine, potassium, sodium and calcium.  Standard urinalysis will be used to 
assess kidney function. For those patients enrolled with negative HBsAg and positive total HBcAb, HBV DNA (PCR) must be repeated every 24 
weeks during these timepoints. 
k 
Serum or urine β-hCG must be performed at screening in women of childbearing potential within 14 days prior to initiation of study drug.  
Subsequently, urine β-hCG (sensitivity ≥ 25 mIU/mL) must be collected.  On infusion visits, the urine pregnancy test should be performed prior to 
premedication in all women of childbearing potential.  If positive, ocrelizumab should be withheld and pregnancy status confirmed with serum β-
hCG test.   
l 
All patients must have negative HBsAg result and negative HepCAb screening tests prior to study enrollment.  If HBcAb is positive at 
screening, HBV DNA measured by PCR must be negative.  For those patients enrolled with negative HBsAg and positive total HBcAb, HBV DNA 
(PCR) must be repeated every 24 weeks during the treatment period.    
m 
Biomarkers assessed in peripheral blood, CSF, and serum include adaptive and innate immune cell subsets and their soluble factors, RNA, 
DNA, genetic risk factors (e.g. HLA-DRB1*15:0), and other emerging exploratory markers of disease biology as appropriate.  If samples are 


 
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collected on the same day as the ocrelizumab infusion, the blood samples should be collected prior to ocrelizumab administration.  Blood sample 
collection may precede ocrelizumab administration by up to 4 weeks. Leftover biological samples will be stored by the central laboratory for later 
biomarker use. Please refer to the laboratory manual for additional details on laboratory assessments and sample handling. 
n 
To be obtained/performed before administration of ocrelizumab (i.e., pre-dose). Premedication with methylprednisolone and antihistamines 
should be given in accordance to the guidance provided in the USPI. 
o 
The first dose of study drug will be administered as two 300 mg IV infusions given 14 days apart.  For the subsequent doses, study drug will be 
administered as a single 600 mg IV infusion at Weeks 24 and 48.  A minimum interval of 22 weeks must be maintained between each 600 mg dose 
of study drug. 
p 
LP is required at baseline for subjects who have not previously had CSF analysis or who do not have access to source documentation (including 
oligoclonal banding testing) for prior CSF analysis. LP is optional at baseline for subjects who have previously had CSF analysis and have appropriate 
source documentation. LP is always optional at Weeks 104, 208, and unscheduled visits (in case of a clinical neurologic event), at the investigator’s 
discretion. Local lab testing for CSF includes protein, cell count/differential, and oligoclonal banding. CSF oligoclonal banding results must be available 
prior to randomization and study drug administration. Baseline CSF may be collected up to 4 weeks prior to administration of study drug. If MRI and CSF 
are performed on the same day, MRI should precede the collection of the CSF specimen and study drug infusion, and the CSF specimen collection should 
precede the study drug infusion.  Blood biomarker samples should be collected as close as possible in time to the CSF sample, which may be prior to 
study drug administration by up to 4 weeks.   
q 
All MRIs will be read by a central reading center.  Prior to initiation of study drug a QC report for the Screening MRI scan must have been 
received from the centralized reading center confirming scan passed QC.  The brain MRI requires at least 2 business days from scan receipt to be 
quality checked before dosing of study drug. Screening MRIs must also be confirmed by the central MRI reader to meet 2017 McDonald criteria for 
dissemination in space prior to patient randomization. Contrast agent (gadolinium) required only at screening MRI and annually (Weeks 48, 104, 
156, and 208). 
r 
To be obtained/performed optionally, at the Investigators discretion, in case of neurologic event or suspected neurologic event suggestive of 
MS.   
s 
Biological samples may be sent to central laboratory, local laboratory or other academic laboratory and specialized sites for final processing, 
analysis and reporting due to cell viability and biomarker recovery, such as but not limited to B cell, T cell and innate immune cell subset samples in 
CSF. Please refer to laboratory manual for details. 
t 
A PD DNA sample will be collected for patient genotyping (whole genome sequencing; WGS) at the Baseline visit. If the DNA sample is not 
collected at the baseline visit, it may be collected at any subsequent visit. Collection and submission of this sample is contingent upon the review 
and approval of the exploratory research by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for WGS sampling, collection of this sample will not be applicable at that site. 
u 
Adverse events will be reported throughout the study. 
v The primary analysis for this study is event driven, therefore the study duration in the double-blind phase will vary for each patient.  In the event 
that the requisite number of events have accumulated study-wide before the minimum 3-year follow-up, patients will then be unblinded and followed 
for a minimum of 3 years. 


 
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w Pre-screening MRI scans must include FLAIR sequences to establish whether the individual meets 2017 McDonald criteria for DIS. Pre-screening 
MRIs will be interpreted by site PIs to determine whether they meet 2017 McDonald criteria for dissemination in space. Individuals established to 
have RIS in this way must subsequently undergo a full, screening MRI as noted elsewhere. 
x  Baseline blood, gingival swab and CSF samples may be collected up to 4 weeks prior to administration of study drug, but should be performed 
after successful completion of screening activities. Results for CSF oligoclonal banding must be available prior to randomization.  
y Blood collection for biomarkers (either 10X sequencing or storage) should always be paired with any CSF collection. If a subject has declined 
optional LPs, this blood biomarker collection would not take place at those timepoints. 
 
 




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Appendix 2  
Immune Cell Network Sub-study 
RATIONALE 
Single-cell transcriptomic techniques, such as single-cell RNA sequencing (scRNAseq), 
have been utilized in MS to identify cellular heterogeneity across multilineage 
populations to better understand the molecular and cellular processes that contribute to 
the pathogenesis of disease.  Thus, single-cell transcriptomics have the potential utility 
to identify biomarkers that enable the identification of risk factors for MS onset and 
subsequent disease progression.  As such, comprehensive findings derived from 
integrated single cell analysis of blood and CSF in MS patients have revealed 
compartment specific profiles based on cellular composition and transcriptional 
phenotypes.  The immunologic and transcriptional shifts that accompany the evolution 
from RIS to clinical MS are unknown.  Herein, we propose to identify biomarkers that 
characterize the emergence of MS among RIS patients by using single cell 
transcriptomics in blood and CSF.  
PRIMARY OBJECTIVES 
To identify compartment-specific changes in immune cell population frequency and 
phenotype in blood and CSF at single-cell resolution using scRNAseq to better 
understand the (1) immunological shifts accompanying clinical conversion from RIS to 
clinical MS, (2) dynamics and characteristics of B cell reconstitution and (3) clinical 
response to B cell depletion in RIS patients treated with ocrelizumab or placebo, if 
feasible.  
 
SECONDARY OBJECTIVE 
To longitudinally characterize the dynamic changes in B cell and T cell repertoire, as well 
as frequency and phenotype of myelin-reactive T cells in RIS patients treated with 
ocrelizumab or placebo, by comparing those who convert to MS with those who do not. 
 
EXPLORATORY OBJECTIVE 
To longitudinally characterize the dynamic compartment-specific changes in frequency 
and phenotype of myelin-reactive T cells in RIS patients treated with ocrelizumab or 
placebo.  
 
Primary Endpoints 
Change from Baseline to Weeks 104 and 208 in matched peripheral blood and CSF 
immune cell frequency and phenotype as detected by scRNAseq  
Change from Baseline to Weeks 104 and 208 in CSF immune cell frequency and 
phenotype as detected by scRNAseq  
Secondary Endpoints 
Change from Baseline to Weeks 104  and 208 in peripheral blood B cell receptor 
repertoire 
Change from Baseline to Weeks 104, and 208 in CSF B cell receptor repertoire 


 
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Change from Baseline to Weeks 104  and 208 in peripheral blood T cell receptor 
repertoire 
Change from Baseline to Weeks 104 and 208 in CSF T cell receptor repertoire 
Correlation between changes in compartment-specific immune repertoire and 
radiologic/clinical outcomes.  
 
Exploratory Endpoints 
Change from Baseline to Weeks 104 and 208 in frequency and immunophenotype of 
myelin specific CD4+ T cells in peripheral blood as detected by myelin:MHC II tetramers 
Change from Baseline to Weeks 104 and 208 in frequency and immunophenotype of 
myelin specific CD4+ T cells in CSF as detected by myelin:MHC II tetramers 
Change from Baseline to Weeks 104 and 208 in frequency and immunophenotype of 
myelin specific CD8+ T cells in peripheral blood as detected by myelin:MHC I tetramers 
Change from Baseline to Weeks 104 and 208 in frequency and immunophenotype of 
myelin specific CD8+ T cells in CSF as detected by myelin:MHC I tetramers 
Correlation between changes in compartment-specific myelin-reactive T cell composition 
and phenotype with radiologic/clinical outcomes.  
 
SAMPLE SIZE 
Given the exploratory nature of this sub-study, there is insufficient data available in RIS 
patients to reasonably and accurately perform power calculations.  Previous studies in 
MS have detected significant differences in small cohorts ranging from 8−21 patients.  
Therefore, this sub-study will enroll approximately 20 patients to be recruited from 5−10 
study centers. Baseline samples will be collected from all sub-study participants. 
Longitudinal samples will be obtained only from sub-study participants who consent to 
one or more additional lumbar punctures. For these participants, paired blood and CSF 
will be also be collected at weeks 104 and 208 (participants may consent to one or both 
optional LPs) for use in advanced immunologic assays as detailed above.  


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Appendix 3 
Sub-study Schema 
 
 
 
 
 
 




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Appendix 4  
Registry of First Degree Family Members with MS 
RATIONALE 
The pathophysiological processes occurring in MS are believed to occur long before the 
clinical manifestation of MS onset; however, limited information exists that characterizes 
this prodromal phase.  It has been reported that there is increased utilization of health 
care in the years leading up to the clinical recognition of MS.  First degree relatives of 
those living with MS are at increased risk for RIS and MS, with an estimated 3%−10% of 
clinically unaffected siblings having lesions highly suggestive of demyelination.  In 
identical twins this risk is even greater.  If one twin has MS the risk for the other 
developing MS is approximately 25%−30%.  The natural history of these individuals is 
poorly understood.   
This registry will follow first-degree relatives of those patients with MS, that do not meet 
RIS MRI criteria at screening over the course of the approximately a 6 year total study 
duration (i.e., total study length including screening to end of study) in order to better 
understand the natural history of those who are at high-risk of developing MS and to 
gain insight into the earliest pre-clinical and/or prodromal manifestations of disease.  
Annual phone check-ins over the course of the total study duration will assess general 
health (Neuro-QoL™), including clinically significant diseases, neurologic and 
autoimmune diagnosis, symptoms, all medications (i.e., prescription, over-the-counter, 
herbal or homeopathic remedies, supplements), number of emergency department 
visits, hospitalizations, office visits/physician encounters (i.e., specialists), etc.  In the 
event of a MS diagnosis, any MS medication should be recorded.  Demographic data will 
include age, sex, and self-reported race/ethnicity.  Findings derived from this registry 
may ultimately allow for earlier identification of MS by implementing into diagnostic 
procedures.  
Schedule of Assessments for Registry  
 
 
 
To main 
study if 
meets 
criteria 
 
 
If MRI 
does 
not 
qualify 
for main 
study, 
then to 
registry 
Week 
 
Pre-screening 
48 
(phone) 
104 
(phone) 
156 
(phone) 
208 
(phone) 
ICF 
X 
 
 
 
 
Demographic Data 
X 
 
 
 
 
Medical history & baseline 
conditions 
X 
 
 
 
 
MRI brain (only FLAIR 
sequence required) 
X 
 
 
 
 
Symbol Digit Modality Test 
X 
 
 
 
 
Peripheral blood sample 
for DNA and biomarkers 
X 
 
 
 
 
Gingival swab for storage 
X 
 
 
 
 
NeuroQOL 
X 
X 
X 
X 
X 


 
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Updated health/ 
medication history 
 
X 
X 
X 
X 
 
Exploratory Endpoint: 
Change from Baseline to Weeks 48, 104, 156 and 208 in general health (Neuro-QoL™), 
including clinically significant diseases, neurologic and autoimmune diagnosis, 
symptoms, all medications (i.e., prescription, over-the-counter, herbal or homeopathic 
remedies, supplements), number of emergency department visits, hospitalizations, and 
office visits/physician encounters (i.e., specialists), etc., as assessed by phone check-in 


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Appendix 5  
Expanded Disability Status Scale 
 


 
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Source: http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-
Researchers/Clinical-Study-Measures/Functional-Systems-Scores-(FSS)-and-Expanded-Disab


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




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Appendix 7  
Progressive Multifocal Leukoencephalopathy:  Guidance for 
Diagnosis of Progressive Multifocal Leukoencephalopathy 
Action Steps if PML Is Suspected 
If the clinical presentation is suggestive of progressive multifocal leukoencephalopathy 
(PML) (see Table1), further investigations should include brain magnetic resonance 
imaging (MRI) evaluation as soon as possible.  If MRI evaluation reveals lesions 
suspicious for PML (Berger et al. 2013; see Figure 1), a lumbar puncture with evaluation 
of the cerebrospinal fluid (CSF) should be undertaken for the detection of JC virus (JCV) 
DNA by polymerase chain reaction using a validated sensitive assay.  A diagnosis of 
PML can potentially be made by evaluating clinical and MRI findings plus the 
identification of JCV in the CSF.  This sample will be stored for 1 year after the last 
patient, last visit. 
There is no known treatment or cure for PML.  Treatment considerations are discussed 
in the medical literature (Calabrese et al. 2007). 
 
MRI Assessment 
Although there are no pathognomonic findings that differentiate PML from multiple 
sclerosis (MS), a brain MRI scan that includes fluid-attenuated inversion recovery and 
T2-weighted and T1-weighted sequences, with and without gadolinium, should be 
performed to assess patients with neurological changes suggestive of PML 
(see Figure 1). 
Comparison with a baseline scan may assist with interpretation of the findings on the 
newly acquired MRI (see Table 2 in Appendix 7) for differences in lesion characteristics 
that may help differentiate between PML and MS. 
 
CSF Assessment 
The detection of JCV DNA in the CSF of a patient with clinical and MRI features 
suggestive of PML establishes the diagnosis of PML. 
If JCV DNA is not detected in CSF and if clinical suspicion of PML remains high, a 
repeat lumbar puncture should be performed. 
If diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy may 
be considered to establish a definitive diagnosis. 
 


 
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Figure 1 
 
Diagnostic Algorithm Framework for PML (Berger et al. 
2013) 
 
 


 
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Table 1 
Clinical Signs and Symptoms Typical of MS and PML 
 
MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy. 
 
 
Adapted from Kappos et al. 2007. 


 
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Table 2 
MRI Lesion Characteristics Typical of PML and MS 
Feature 
Multiple Sclerosis 
PML 
Location of new 
lesions 
Mostly focal; may affect entire brain 
and spinal cord, in white and possibly 
gray matter; posterior cranial fossa 
lesions are rarely seen 
Diffuse lesions, mainly subcortical and 
rarely periventricular, located almost 
exclusively in white matter, although 
occasional extension to gray matter has 
been seen; posterior fossa frequently 
involved (cerebellum) 
Borders 
Sharp edges; mostly round or 
finger-like in shape (especially 
periventricular lesions), confluent with 
other lesions; U-fibers may be 
involved 
Ill-defined edges; infiltrating; irregular in 
shape; confined to white matter, sparing 
gray matter; pushing against the 
cerebral cortex; U-fibers destroyed 
Mode of extension 
Initially focal, lesions enlarge within 
days or weeks and later decrease in 
size within months 
Lesions are diffuse and asymmetric, 
extending homogeneously; no 
confluence with other lesions; confined 
to white-matter tracks, sparing the 
cortex; continuous progression 
Mass effect 
Acute lesions show some mass 
effect 
No mass effect even in large lesions (but 
lesion slightly abuts cerebral cortex) 
On T2-weighted 
sequence 
Acute lesions:  hyperintense center, 
isointense ring, discrete 
hyperintensity outside the ring 
structure  
Subacute and chronic lesions: 
hyperintense, with no ring structure 
Diffuse hyperintensity, slightly increased 
intensity of newly involved areas 
compared with old areas, little irregular 
signal intensity of lesions 
On T1-weighted 
sequence 
Acute lesions: densely hypointense 
(large lesions) or isointense (small 
lesions); increasing signal intensity 
over time in 80%; decreasing signal 
intensity (axonal loss) in about 20% 
Slightly hypointense at onset, with signal 
intensity decreasing over time and along 
the affected area; no reversion of signal 
intensity 
On FLAIR 
sequence 
Hyperintense, sharply delineated 
Hyperintensity more obvious, true 
extension of abnormality more clearly 
visible than in T2-weighted images 
With enhancement 
Acute lesions:  dense homogeneous 
enhancement, sharp edges  
Subacute lesions:  ring enhancement  
Chronic lesions:  no enhancement 
Usually no enhancement even in large 
lesions; in patients with HIV, some 
peripheral enhancement is possible, 
especially under therapy 
Atrophy 
Focal atrophy possible, due to focal 
white-matter degeneration; no 
progression 
No focal atrophy 
FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging; 
PML = progressive multifocal leukoencephalopathy. 
Adapted from Yousry et al. 2006. 
 
 


 
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REFERENCES 
Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement 
from the AAN Neuroinfectious Disease Section. Neurology 2013;80:1430−8. 
Calabrese LH, Molloy ES, Huang D, et al. Progressive multifocal leukoencephalopathy in 
rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis Rheum 
2007;56:2116−28. 
Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple sclerosis: 
recommendations for patient selection and monitoring. Lancet Neurol 2007;6:431−41. 
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with 
natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 
2006;354:924−33. 
 




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Appendix 8  
2017 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis 
 
Clinical 
Attacks 
Number of lesions with 
objective clinical evidence 
Additional data needed for a 
diagnosis of multiple 
sclerosis 
≥2  
≥2 
None 
≥2  
1 (as well as clear-cut 
historical evidence of a 
previous attack involving a 
lesion in a distinct anatomical 
location) 
None 
≥2  
1 
Dissemination in space 
demonstrated by an additional 
clinical attack implicating a 
different CNS site or by MRI 
1  
≥2 
Dissemination in time 
demonstrated by an additional 
clinical attack or by MRI 
 OR demonstration of CSF-
specific oligoclonal bands 
1  
1 
Dissemination in space 
demonstrated by an additional 
clinical attack implicating a 
different CNS site or by MRI ‡ 
 
AND 
 
Dissemination in time 
demonstrated by an additional 
clinical attack or by MRI 
 
 OR demonstration of CSF-
specific oligoclonal bands 




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Appendix 9  
Pregnancy Outcome and Infant Health Information on First Year 
of Life  
 
Pregnancy Outcome and Infant Health Information on First Year of Life 
 
If twin or  multi-gestational pregnancy, this questionnaire has to be filled out separately for 
each baby born in the multi-gestational pregnancy. 
 
Please check all that apply and provide detailed information on complications in infant on last page. 
 
Table 1: Parent’s (or person with parental responsibility in law) consent to data collection 
 
Has parent’s (or person’s with 
parental responsibility in law) data 
authorization form been signed? 
☐Yes 
☐No 
Date signed 
____________________ 
Other – comment 
___________________ 
Date consent 
withdrawn: 
(if applicable) 
 
 
 
Table 2: Information on birth 
Mode of birth 
☐Vaginal delivery 
Forceps / vacuum: 
- Yes ☐ 
- No ☐ 
☐Cesarean section (CS) 
- scheduled CS ☐ 
- emergency CS ☐ 
Reason for assisted delivery/Cesarean 
section  
 
Gestational age at 
birth 
 
 weeks 
- since conception ☐ 
- since LMP ☐ 
Induced labor 
- Yes ☐ 
- No   ☐ 
 
 


 
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Table 3: Growth alteration, congenital anomalies and functional deficits 
Date of Assessment 
Growth alteration 
- Yes ☐ 
- No  ☐ 
☐Small for gestational age 
(SGA) 
☐Low birth weight 
☐Short birth length 
If Growth alteration 
present: 
Specify weight:  
 
Specify length:   
   
Contributing factors: 
Congenital anomalies 
- Yes ☐ 
- No ☐ 
☐ Major structural 
malformation 
A defect that has either 
cosmetic or functional 
significance to the child 
Specify:   
 
 
 
Contributing factors: 
☐ Minor structural 
malformation 
A defect that occurs 
infrequently but has neither 
cosmetic nor functional 
significance to the child 
Specify:   
 
 
 
☐ Deformation 
A defect attributable to 
deformation of a structure, 
which had previously formed 
normally (usually due to 
mechanical force) 
Specify:   
 
 
 
☐ Disruption 
A defect due to destruction of 
a structure, which has 
previously formed normally 
(may be of vascular, 
infectious, or mechanical 
origin) 
Specify:   
 
 
 
Functional deficit 
(except for infections, 
which should be 
described in separate 
table below) 
- Yes ☐ 
- No  ☐ 
☐Functional deficit 
Specify:   
 
 
 
Contributing factors: 
___________________
_________________ 
 
 
 
 


 
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Status of infant at the time of latest follow-up (at birth, 3 months, 
6 months, 12 months) 
 
Table 4: Status of infant 
Date of Assessment 
Contributing factors/ 
Comments 
Status of infant 
☐Normal 
☐Abnormal, specify abnormality:   
 
☐Neonatal/infant death, specify cause and date of death:  
__________________________________________________ 
______________
______________ 
Nursing status 
☐Exclusive breastfeeding 
☐Mixed feeding (partial breastfeeding along with infant formula 
and/or baby food), specify date since when:   
 
☐Fully weaned, specify date since when:   
 
______________ 
 
Infections in neonate and infant during first year of life 
 
Any infection detected at birth? 
Yes  
No 
Unknown 
 
If infection detected at birth then Tables 5 and 6 should to be filled out and additional 
detailed information may be provided on last page. 
If no infection detected at birth, however an infection developed later during the first year of live, 
please move directly to Table 7. 
If no infection detected at birth, and if also no infection developed during the first 12 months then 
move directly to Table 8. 
 


 
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Table 5: Information on infection in neonate at birth 
 
Specify the event term: 
Event number 
Location of infection present in neonate at birth? 
Site of infection (specify):   
 
Outcome of 
infection? 
Duration of 
infection? 
☐Resolved 
☐Improving 
☐Fatal  
☐Persisting  
☐Unknown 
Duration:  
 
Intensity of infection (Grade 1-5 NCI 
CTCAE)? 
Seriousness of 
infection? 
Treatment with anti- 
infective? 
Pathogen causing 
infection known? 
Severity: ☐Mild (Grade 1) 
☐Moderate (Grade 2) 
☐Severe (Grade 3) 
Serious: 
☐Yes 
☐No 
☐Yes, specify: 
 
☐No 
☐Yes, specify: 
 
☐No 
☐Life-threatening (Grade 4)  
☐Death (Grade 5)  
 
☐Unknown 
☐Unknown 
Relevant laboratory test results (in newborn infant): 
CD19 count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify 
test result: 
If abnormal, date of 
test:   
 
IgG levels 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify test 
result: 
If abnormal, date of 
test:   
 
White blood cell count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify test 
result: 
If abnormal, date of 
test:   
 
Neutrophil count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify test 
result: 
If abnormal, date of 
test:   
 
Lymphocyte count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify test 
result: 
If abnormal, date of 
test:   
 
Other, specify: 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify 
test result: 
If abnormal, date of 
test:   
 
 
 


 
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Table 6:  Maternal risk factors for neonatal infection (during most recent pregnancy, if infant 
developed neonatal infection at birth)  
Maternal risk factors for neonatal infection Date of diagnosis 
If diagnosed, was pregnant mother 
treated with anti-infective prior to 
delivery? 
☐Maternal intrapartum colonization or 
infection with group B streptococcus (GBS) 
☐Maternal listeriosis 
☐Premature rupture of membranes (PROM)  
☐Meconium in amniotic fluid 
(meconium-stained liquid) 
☐Active genital herpes infection 
☐CMV 
☐HPV (papilloma virus) 
Other, specify 
 
 
 
 
________________  
_________________
_________________
______________ 
 
 
 
_____________________________  
_____________________________ 
______________________________
____________________________ 
Relevant laboratory test results in pregnant mother: 
CD19 count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
IgG levels 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
White blood cell count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Neutrophil count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Lymphocyte count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Other, specify: 
(e.g., any specific antibodies and their titers) 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
 
 
 
 


 
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Any infection detected during first year of infant’s life? 
Yes  
No 
Unknown 
 
If infection detected during first year of infant’s life, then Table 7 should to be filled out and 
additional detailed information may be provided on last page. If no infection developed during 
first 12 months of life, then please move directly to Table 8. 
 
Table 7: Information on infection detected during first year of infant’s life 
Specify the event term: 
Event number 
(automatically 
populated by the 
system?) 
Location of infection? 
Infant’s age on 
day of onset of 
infection? 
Outcome of 
infection? 
Duration of 
infection? 
Site of infection (specify):   
 
 
Age: 
 
☐Resolved 
☐Improving  
☐Fatal  
☐Persisting  
☐Unknown 
Duration:  
 
Intensity of infection (Grade 1-5 NCI 
CTCAE)? 
Seriousness of 
infection? 
Treatment with 
anti- infective? 
Pathogen causing 
infection known? 
Severity: ☐Mild (Grade 1) 
☐Moderate (Grade 2)  
☐Severe (Grade 3)  
☐Life-threatening (Grade 4)  
☐Death (Grade 5) 
Serious:  
☐Yes 
☐No 
☐Yes, specify: 
 
☐No 
☐Unknown 
☐Yes (specify): 
 
☐No  
☐Unknown 
Relevant laboratory test results (in infant): 
CD19 count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
IgG levels 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
White blood cell count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Neutrophil count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Lymphocyte count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Other, specify: 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
 


 
OCRELIZUMABYale University 
Protocol ML42790, Version 2.0 
123 
 
Table 8:  Vaccinations administered to infant at birth and during first year of age 
 
Vaccinations administered at 
birth and during first year of 
age 
Date 
administered 
Infant’s age 
on day of 
vaccination 
Comments (abnormal outcome, 
reason for postponing vaccination, 
etc.) 
☐Hepatitis B 
☐Rotavirus 
☐Diphtheria, tetanus, and 
pertussis 
☐Hemophilus influenza type b 
☐Pneumococcal 
☐Poliovirus 
☐Attenuated oral polio 
vaccine 
☐Inactivated polio vaccine 
☐Meningococcal group B 
bacteria 
☐Tuberculosis (Bacille Calmette 
Guérin, BCG) bacteria 
☐Other vaccination, specify: 
 
 
 
Table 9:  Fetal/neonatal abnormalities in previous pregnancies 
Fetal/neonatal abnormalities (in previous 
pregnancies) 
Please, provide specifics including contributing 
factors 
None  ☐ 
Yes  ☐ 
Unknown  ☐ 
Infection; if yes, specify 
Death in utero; if yes, specify reason 
Birth defects; if yes, specify 
Family history of birth defects; if yes, specify 
Small for gestational age at birth (or Intrauterine 
growth retardation) 
Premature delivery (before 37 weeks) 
Other; specify 
 
Detailed information on health-related findings in infant during first year of 
life 
 
Please enter text in the free text box below. 
 




 
OCRELIZUMABYale University 
Protocol ML42790, Version 1.4 
125 
  
Appendix 10 
Neuro-QOL 
 
Anxiety – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
    
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
EDANX53 
I felt uneasy……………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
EDANX46 
I felt nervous……………………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDANX48 
Many situations made me worry………… 
 
1 
 
2 
 
3 
 
4 
 
5 
EDANX41 
My worries overwhelmed me……………. 
 
1 
 
2 
 
3 
 
4 
 
5 
EDANX54 
I felt tense………………………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDANX55 
I had difficulty calming down….………... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDANX18 
I had sudden feelings of panic…………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQANX07 
I felt nervous when my normal routine 
was disturbed……………………….……. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
OCRELIZUMABYale University 
Protocol ML42790, Version 1.4 
126 
  
©2008-2018 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and 
Stroke (NINDS). Used with permission.


 
OCRELIZUMABYale University 
Protocol ML42790, Version 1.4 
127 
  
 
Depression – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
    
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
EDDEP29 
I felt depressed…………………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDEP41 
I felt hopeless……………………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDEP09 
I felt that nothing could cheer me up…….. 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDEP48 
I felt that my life was empty……………... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDEP04 
I felt worthless…………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDEP36 
I felt unhappy……………………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDEP39 
I felt I had no reason for living…………... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDEP45 
I felt that nothing was interesting………... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
©2008-2018 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and 
Stroke (NINDS). Used with permission.


 
 
 
Fatigue – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
   
In the past 7 days… 
  Never 
Rarely 
Sometimes 
Often 
Always 
 
NQFTG13 I felt exhausted…………………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQFTG11 I felt that I had no energy………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQFTG15 I felt fatigued…………………………….. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQFTG06 I was too tired to do my household chores. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQFTG07 I was too tired to leave the house………... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQFTG10 I was frustrated by being too tired to do 
the things I wanted to do………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQFTG14 I felt tired………………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQFTG02 I had to limit my social activity because I 
was tired…………………………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders 
and Stroke (NINDS). Used with permission. 


 
 
 
Cognition Function– Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
 
 
  
In the past 7 days… 
 
 
 
Never 
 
 
Rarely 
(once) 
 
 
Sometimes 
(2-3 times) 
 
Often 
(once a 
day) 
Very often 
(several 
times a day) 
 
NQCOG64r1 I had to read something several times to 
understand it……………………………... 
 
 
5 
4 
 
 
3 
2 
 
1 
 
NQCOG75r1 My thinking was slow…………………… 
 
 
5 
4 
 
 
3 
2 
 
1 
 
NQCOG77r1 I had to work really hard to pay attention 
or I would make a mistake………………. 
 
 
5 
4 
 
 
3 
2 
 
1 
NQCOG80r1 I had trouble concentrating………………. 
 
 
 
 
 
1 
5 
4 
3 
2 
 
 
 
   
How much DIFFICULTY do you currently 
have… 
None 
A little 
Somewhat 
A lot 
Cannot do 
NQCOG22r1 
reading and following complex instructions 
(e.g., directions for a new 
medication)?............................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
NQCOG24r1 
planning for and keeping appointments 
that are not part of your weekly routine, 
(e.g., a therapy or doctor appointment, or a 
social gathering with friends and 
family)?...................................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
NQCOG25r1 managing your time to do most of your 
daily activities?........................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
NQCOG40r1 learning new tasks or instructions?............ 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and Stroke 
(NINDS). Used with permission. 


 
 
 
Emotional and Behavioral Dyscontrol – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
    
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
EDANG42 
I had trouble controlling my temper……... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPER05 
It was hard to control my behavior………. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPER06 
I said or did things without thinking…….. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPER07 
I got impatient with other people………... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPER11 
I was irritable around other people………. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPER12 
I was bothered by little things…………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPER17 
I became easily upset…………………….. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPER19 
I was in conflict with others……………... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
©2008-2018 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and 
Stroke (NINDS). Used with permission. 
 
 


 
 
 
Positive Affect and Well-Being - Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
   
Lately… 
  Never 
Rarely 
Sometimes 
Often 
Always 
 
NQPPF14 
I had a sense of well-being………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPPF12 
I felt hopeful……………………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPPF15 
My life was satisfying…………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPPF20 
My life had purpose……………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPPF17 
My life had meaning…………………….. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPPF22 
I felt cheerful…………………………….. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPPF19 
My life was worth living………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPPF16 
I had a sense of balance in my life………. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPPF07 
Many areas of my life were interesting to 
me………………………………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and Stroke 
(NINDS). Used with permission. 


 
 
 
Ability to Participate in Social Roles and Activities – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
   
In the past 7 days… 
  Never 
Rarely 
Sometimes 
Often 
Always 
NQPRF01 I can keep up with my family 
responsibilities…………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPRF03 I am able to do all of my regular family 
activities…………………………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPRF08 I am able to socialize with my friends…... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPRF09 I am able to do all of my regular activities 
with friends………………………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPRF17 I can keep up with my social 
commitments…………………………….. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPRF26 I am able to participate in leisure 
activities…………………………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPRF32 I am able to perform my daily routines….. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQPRF34 I can keep up with my work 
responsibilities (include work at home)…. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and Stroke 
(NINDS). Used with permission. 


 
 
Satisfaction with Social Roles and Activities – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
   
In the past 7 days… 
   Not at all A little bit 
Somewhat 
Quite a bit 
Very much  
NQSAT 03 I am bothered by my limitations in regular 
family activities .......................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
NQSAT 23 I am disappointed in my ability to 
socialize with my family………………... 
 
5 
 
4 
 
3 
 
2 
 
1 
NQSAT14 
I am bothered by limitations in my regular 
activities with friends.…………………… 
 
5 
 
4 
 
3 
 
2 
 
1 
NQSAT11 
I am disappointed in my ability to meet 
the needs of my friends .............................. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
   
In the past 7 days… 
   Not at all A little bit 
Somewhat 
Quite a bit 
Very much  
NQSAT33 
I am satisfied with my ability to do things 
for fun outside my home……………….... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQSAT32 
I am satisfied with the amount of time I 
spend doing leisure activities……………. 
 
1 
 
2 
 
3 
 
4 
 
5 
NQSAT47 
I am satisfied with how much of my work 
I can do (include work at home).………… 
 
1 
 
2 
 
3 
 
4 
 
5 
NQSAT 46 I am satisfied with my ability to do 
household chores or tasks…………........... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and Stroke 
(NINDS). Used with permission. 
 


 
 
Communication – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
 
How much DIFFICULTY do you currently have… 
None 
A little 
Somewhat 
A lot 
Cannot do 
NQCOG01 writing notes to yourself, such as appointments 
or 'to do' lists?............................ 
 
 
5 
4 
 
 
3 
2 
 
1 
NQCOG04 understanding family and friends on the 
phone?............................................................... 
 
 
5 
4 
 
 
3 
2 
 
1 
NQCOG08 
carrying on a conversation with a small group 
of familiar people (e.g., family or a few 
friends)?............................................................ 
 
 
5 
4 
 
 
3 
2 
 
1 
NQCOG10 organizing what you want to say?.................... 
 
 
5 
4 
 
 
3 
2 
 
1 
NQCOG11 speaking clearly enough to use the 
telephone?......................................................... 
 
 
5 
4 
 
 
3 
2 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and Stroke 
(NINDS). Used with permission. 
 


 
 
 
Upper Extremity Function (Fine Motor, ADL) – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
 
 
 
Without 
any 
difficulty 
With a 
little 
difficulty 
With some 
difficulty 
With 
much 
difficulty 
Unable to 
do 
 
PFA40 
Are you able to turn a key in a lock?.......... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA50 
Are you able to brush your teeth? .............. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
NQUEX44 
Are you able to make a phone call using a 
touch tone key-pad? ................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFB21 
Are you able to pick up coins from a table 
top? ............................................................. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA43 
Are you able to write with a pen or pencil? 
........................................................ 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA35 
Are you able to open and close a zipper?... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA55 
Are you able to wash and dry your body?. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFB26 
Are you able to shampoo your hair? .......... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
 
©2008-2018 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and 
Stroke (NINDS). Used with permission. 
 


 
 
Lower Extremity Function (Mobility) – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
 
 
 
Without 
any 
difficulty 
With a 
little 
difficulty 
With some 
difficulty 
With 
much 
difficulty 
Unable to 
do 
 
PFC45 
Are you able to get on and off the toilet? ... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA30 
Are you able to step up and down curbs?... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA56 
Are you able to get in and out of a car? ..... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA45 
Are you able to get out of bed into a chair? 
.......................................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA12 
Are you able to push open a heavy door? .. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA53 
Are you able to run errands and shop? ....... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA31 
Are you able to get up off the floor from lying 
on your back without help? ............... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
PFA23 
Are you able to go for a walk of at least 15 
minutes? ................................................ 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
 
©2008-2018 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological Disorders and 
Stroke (NINDS). Used with permission. 
 


OCRELIZUMABYale University 
Protocol ML42790, Version 2.0 
137 
 
 
Sleep Disturbance – Short Form 
 
Please respond to each question or statement by marking one box per row. 
 
 
 
In the past 7 days… 
  Never 
Rarely 
Sometimes 
Often 
Always 
NQSLP02 
I had to force myself to get up in the 
morning………………………………….. 
 
1 
 
2 
 
3 
 
4 

5 
NQSLP03 
I had trouble stopping my thoughts at 
bedtime…………………………………... 
 
1 
 
2 
 
3 
 
4 

5 
NQSLP04 
I was sleepy during the daytime…………. 
 
1 
 
2 
 
3 
 
4 

5 
NQSLP05 
I had trouble sleeping because of bad 
dreams…………………………………… 
 
1 
 
2 
 
3 
 
4 

5 
NQSLP07 
I had trouble falling asleep………………. 
 
1 
 
2 
 
3 
 
4 

5 
NQSLP12 
Pain woke me up………………………… 
 
1 
 
2 
 
3 
 
4 

5 
NQSLP13 
I avoided or cancelled activities with my 
friends because I was tired from having a 
bad night's sleep…………………………. 
 
1 
 
2 
 
3 
 
4 

5 
NQSLP18 
I felt physically tense during the middle of 
the night or early morning hours………… 
 
1 
 
2 
 
3 
 
4 

5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for 
Neurological Disorders and Stroke (NINDS). Used with permission. 


  
 
Appendix 11 Safety Reporting Fax Cover Sheet 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: (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 Drug Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
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