A Single-center Prospective Measurement of Upper Extremity Function in Multiple Sclerosis Patients With Advanced Disability Treated With Ocrevus™
Conditions: Multiple Sclerosis, Pathologic Processes, Demyelinating Diseases, Nervous System Diseases, Autoimmune Diseases, Immune System Diseases, Primary Progressive Multiple Sclerosis, Relapsing Remitting Multiple Sclerosis
Sponsor: University of South Florida

CONFIDENTIAL 
 
This is a University of South Florida document that contains confidential 
information.  It is intended solely for the recipient clinical investigator(s) 
and must not be disclosed to any other party.  This material may be used 
only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from the University of South 
Florida. 
 
Protocol:   {University of South Florida} 
Version 4.1 
 
10JAN2020 
 
PROTOCOL 
STUDY TITLE:  
A single-center prospective measurement of 
upper extremity function in multiple sclerosis 
patients with advanced disability treated with 
Ocrevus™   
STUDY DRUG: 
OCREVUS (ocrelizumab) 
 
SUPPORT PROVIDED BY: 
Genentech, Inc. 
 
INVESTIGATOR: 
Principal Investigator: Janice Maldonado, MD 
Office:    
 
813-974-6378 
Fax:   
 
 
813-905-9843 
E-Mail:   
 
janiceyvonne@health.usf.edu 
 
STUDY NUMBER:  
OCRE-UP 
PROTOCOL VERSION/DATE: 
4.1 / 10JAN2020 
 
 

Protocol:  (University of South Florida} 
1/P Version 4.1 
 
10JAN2020 
 
TABLE OF CONTENTS 
Page 
1. 
INTRODUCTION ..........................................................................................  
1 
2. 
OBJECTIVES ...............................................................................................  
 
2.1 
Primary Objectives 
 ..............  
 
2.2 
Secondary Objectives ........................................................................  
 
3. 
STUDY DESIGN ..........................................................................................  
 
3.1 
Description of the Study ....................................................................  
 
3.2 
Rationale for Study Design ................................................................  
 
3.3 
Outcome Measures ...........................................................................  
 
3.3.1 
Primary Outcome Measure .............................................................  
 
3.3.2 
Secondary Outcome Measures ......................................................  
3.4 
Safety Plan ........................................................................................  
 
3.5 
Compliance with Laws and Regulations ............................................  
 
4. 
MATERIALS AND METHODS .....................................................................  
 
4.1 
Subjects .............................................................................................  
 
4.1.1 Subject Selection 
4.1.2 Inclusion Criteria ................................................................................  
 
4.1.3 Exclusion Criteria...............................................................................  
 
4.2 
Method of Treatment Assignment ................................................................  
 
4.3 
Study Treatment ...........................................................................................  
 
4.4     Concomitant and Excluded Therapy .............................................................  
4.5 
Study Assessments ......................................................................................  
 
4.5.1 Overview of Study Visits ....................................................................  
 
 ..................................................................................................  
 
4.6 
Discontinuation of Protocol-Specified Therapy .............................................  
 
4.7 
Subject Discontinuation ................................................................................  
 
4.8 
Study Discontinuation ..................................................................................  
 
4.9 
Statistical Methods .......................................................................................   
4.9.1 
Analysis of the Conduct of the Study ..............................................  
 
4.9.2 
Analysis of Treatment Group Comparability ...................................  
 
4.9.3 
Efficacy Analysis .............................................................................  
 
4.9.4 
Safety Analysis ...............................................................................  
 
4.9.5 
Missing Data ...................................................................................  
 
4.9.6 
Determination of Sample Size ........................................................  
4.10       Data Quality Assurance ............................................................................  
 
5. 
REPORTING OF ADVERSE EVENTS ........................................................  
 
5.1 
Assessment of Safety ..................................................................................  
5.2 
Methods and Timing for Assessing and Recording Safety Variables ...........  
5.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ............  
5.4      MedWatch 3500 Reporting Guidelines ........................................................  
 
5.5 
Additional Reporting Requirements for IND Holders ....................................  
 
6. 
INVESTIGATOR REQUIREMENTS .............................................................  
 
6.1 
Study Initiation ..............................................................................................  
 
6.2 
Study Completion .........................................................................................  
 
6.3 
Informed Consent .........................................................................................  
 
6.4 
Institutional Review Board or Ethics Committee Approval ...........................  
 

Protocol:  (University of South Florida} 
2/P Version 4.1 
 
10JAN2020 
     
 
 
TABLE OF CONTENTS (cont.)                
                                   
6.5 
Study Monitoring Requirements ...................................................................  
 
6.6 
Data Collection .............................................................................................  
 
6.7 
Study Medication Accountability ...................................................................  
 
6.8 
Disclosure and Publication of Data ..............................................................  
 
6.9 
Retention of Records ...................................................................................  
 
7.0      REFERENCES ............................................................................................  
 
 
TABLES AND FIGURES 
 
 
Appendix A: Example Study Flowchart 
Appendix B: Safety Reporting Fax Cover Sheet 
Appendix C:  UEFI 
Appendix D:  SDMT 
Appendix E:  Jamar handheld dynamometer 
Appendix F:  9-Hole Peg Test 
Appendix G: Fatigue Severity Scale (FSS) 
Appendix H: MUSIQoL 
 
 
 

Protocol:  (University of South Florida} 
3/P Version 4.1 
 
10JAN2020 
 
1. 
INTRODUCTION 
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous 
system (CNS) that affects approximately 2.5 million people worldwide. It is a 
chronic condition characterized clinically by focal disorders of the optic nerves, 
brain and spinal cord, which remit to a varying extent and recur over a period of 
many years.  Most patients eventually experience progression and accumulation 
of symptoms which can include profound muscle weakness, impaired gait and 
mobility, bladder and bowel dysfunction, cognitive and visual impairments and 
sexual dysfunction [1]. 
In patients that have disability that involves the upper extremity, this 
can lead to loss of independence in activities of daily living such as dressing, 
feeding and hygiene [2]. Upper extremity(UE) strength is also important for a 
patient being able to independently shift weight in a wheelchair, maneuver an 
electric wheelchair, and change position in bed, thus minimizing risk for 
decubitus ulcers. As opposed to lower extremity function, a very small loss of 
strength and function can translate into significant changes in functional 
independence. The loss of independence then impacts quality of life (QoL) for 
both the patient and the caregiver(s).  
 
2. 
OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVES 
To measure for clinical stabilization (defined as no significant change (≤20%) 
from baseline of UE function in multiple sclerosis patients with upper extremity 
impairment treated with Ocrevus™.   
 
2.2 
SECONDARY OBJECTIVES 
To evaluate the relationship between UE function (objective and subjective) and 
fatigue, cognition and QoL. 
 
3.      STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Ocrevus™ is the first FDA approved disease-modifying treatment for primary 
progressive MS as well as relapsing MS [3]. In the clinical trials considered by 
the FDA (OPERA I/II, ORATORIO), the highest Expanded Disability Status 
Scale (EDSS) included in the participants was 5.5 (OPERA I/II) and 6.5 
(ORATORIO) [4]. The EDSS score is heavily weighted on walking ability and is 
not a useful measurement for UE function [5,6]. The primary endpoint in the 
primary progressive MS trial with Ocrevus™ was EDSS and in the relapsing MS 
studies, EDSS was used as a secondary endpoint. The Multiple Sclerosis 
Functional Composite (MSFC) score (Z score), a composite of quantitative 
measure of walking speed, upper limb coordinated movement (9 Hole Peg 
Test/9HPT) and cognitive function, was obtained as a secondary clinical 

Protocol:  (University of South Florida} 
4/P Version 4.1 
 
10JAN2020 
measure with scores being favorably higher in patients treated with Ocrevus™ 
(OPERA I/II).The z score, however, is not very useful in delineating which of the 
three clinical functions was maintained or showed less progression given that 
three domains are included in the score [7,8,9]. Data presented recently from 
the Oratorio trial analyzed the intention to treat population of PPMS patients and 
the subgroups of patients with upper extremity functional impairment using the 
9HPT; results demonstrated reduction in risk of clinical progression in upper 
extremity disability in patients treated with Ocrevus compared to placebo. There 
was improvement in the change from baseline to week 120 in 9HPT time in 
treated patients. Abnormal baseline 9HPT was defined as >25 seconds and 
upper extremities were defined as “better hand” and “worse hand”, each 
individually tested, with clinical progression determined at 12 and 24 weeks in 3 
sub-categories of progression: lengthened time of 9HPT >15%, >20% and 25%. 
[10] 
In our study we aim to not only replicate the results in the Oratorio trial with 
upper extremity dysfunction, but also widen the spectrum of patients that may 
benefit (given an expanded MS population of patients, not exclusive to PPMS 
and widen the range of potential disability that the patients may have (broader 
EDSS rage 4-8). We anticipate that by using a test that better emulates activities 
of daily life performed with the upper extremity, such as the TEMPA (Test 
d’Evaluation de la performance des membres Superieurs e Personnes Agees) 
we will obtain more real life application of the benefits of receiving treatment with 
Ocrevus, and anticipate that patients can maintain the function they have or 
potentially improve function. 
 
3.2 
RATIONALE FOR STUDY DESIGN 
We anticipate the use of Ocrevus™ in patients with progressive disease which 
includes those with advanced disability, regardless of a dearth of data to guide 
the prescriber regarding its effect in this population.  The rational for this study is 
to gain information which will help the prescribers of Ocrevus™ answer the 
question “Will Ocrevus™ help me if I have hand or arm weakness?” especially if 
posed by a more advanced MS patient (EDSS 4.0-8.0 with UE involvement) 
than those included in the clinical trials. In previous trials (ORATORIO), the 
included patients were only those diagnosed with primary progressive MS and 
their entry EDSS was of a lower disability range (3.0-6.5) than those proposed in 
this study. Therefore, the results cannot be completely extrapolated to the 
population of multiple sclerosis patients with more advanced disability that we 
propose to study. We aim to identify MS patients that have weakness in at least 
one upper limb, knowing that delaying disability affecting the functional use of 
the UE will help patients remain independent for some activities of daily life and 
will contribute to an improved quality of life. 
 
The importance of choosing validated upper limb outcome assessment tools 
cannot be emphasized enough. The Nine-Hole Peg Test (9HPT), an objective 
measure of manual dexterity, which is incorporated into the MSFC, is a widely 
used measure across most clinical trials in multiple sclerosis populations.  
 

Protocol:  (University of South Florida} 
5/P Version 4.1 
 
10JAN2020 
The EDSS is an ordinal scale of neurological disability designed specifically for 
MS patients and will provide specific quantitative measure of upper limb 
strength, sensory impairment and ataxia of the upper limb with each Functional 
System Subscore. This score will aid in deciphering limitations due to tremors or 
ataxias. 
 
The Test d'Evaluation de la performance des Membres Supérieurs des 
Personnes Agées (TEMPA) has been previously studied for validity in clinical 
trials and specifically in multiple sclerosis patient populations and there was a 
strong correlation between the TEMPA and 9HPT. [11, 12] The TEMPA consists 
of 9 tasks that mimic tasks of daily living such as picking up a jar, pouring water 
from a pitcher, handling coins, writing on an envelope and opening a pill 
container, as examples. The tasks are assessed by a rater by measuring speed 
of execution (seconds) and by functional rating of the subject’s independence in 
performing them using an ordinal scale of 0 (completed without difficulty) to -3 
(could not complete the task). The test provides a unilateral and bilateral score 
and evaluates different grasp, grip and pinch functions. Obtaining baseline 
scores and sequential measurements will allow us to graph scores over time for 
each patient and assess the change. This type of testing would give us a clear 
picture of any changes in UE functionality and would highlight meaningful 
clinical data that would be easily translated to patients- stability of function vs 
clinical progression >20% change from baseline. This key data would be a 
helpful reference when discussing starting treatment with Ocrevus™ in this 
population of patients.  
 
The normative values available for the TEMPA were obtained in the elderly 
(ages 60-80, men and women). The speed of execution of the 9 tasks in each 
hand takes about 70 to 80 seconds to complete in this population. [12] 
When one reviews the validity study of the TEMPA in MS patients [average 
EDSS was 7 and age median was 46 years old], this same parameter took them 
between 100 and 400 seconds [1 and 1/2 to 6 minutes] to complete. 
 
Schwid et al in 2002 showed that MS patients did not vary from their baselines 
in performing the 9HPT by >20% day-to day and therefore the if there was 
change measured >20% from their baseline this was stipulated to indicate 
change in function [13]. 
In a pilot study where a technology enhanced training program for improving 
upper limb muscle strength in MS patients the TEMPA was used at baseline and 
8 weeks later, and there was a trend towards statistical significance of 
improvement in function with TEMPA change of 20 to 40 seconds [14].  
Since the 9HPT and TEMPA have been show to correlate and there are 
numerical values measured in both, we plan to emulate the Oratorio study 
and look at   >15%, >20% and >25% [in better hand and in worse hand] change 
from baseline with increases in time implying clinical progression and stability or 
decrease in time implying stability or improvement in function. 
 
 

Protocol:  (University of South Florida} 
6/P Version 4.1 
 
10JAN2020 
The Jamar dynamometer is validated tool often used by occupational therapist 
to measure grip strength [15]. Grip strength is an important part of daily living 
tasks and can give clinicians insight into patient restrictions and clinical 
changes.   
 
The Upper Extremity Functional Index (UEFI)is a self-report questionnaire that 
has been found reliable, valid and sensitive as a patient- reported outcome 
measure tool for quantifying UE function rated on a 5-point Likert scale This 20-
item measure is recommended in research and clinical setting due to its uni-
dimensionality: it measures only UE function [16,17]. Scores range from 0 to 60 
with lower scores indicating more functional difficulty. It has been used in 
several studies in patients with musculoskeletal upper extremity problems, to 
include patients with MS, and UEFI scores correlated with mean 9-HPT scores. 
[18] We anticipate that patients in our study will have perceived stabilization of 
their upper extremity function and plan to use the UEFI to measure this by 
means of its validated 9 points of change from baseline for minimal detectable 
change in function.  
 
The Symbol Digit Modalities Test (SDMT) is a validated measure used to assess 
mental processing speed in MS clinical trials and has an oral response version. 
There is evidence that cognitive measures may correlate with upper extremity 
function. This can possibly be explained by a cerebral relationship between 
motor function and cognition [19]. As a secondary measure we will collect 
SDMTs at each visit to explore correlations with upper extremity function, as well 
as QoL measures. 
 
The natural history of progression of disability in MS is foreseeable in a 2-year 
span period and this is evident when one examines the placebo population in 
the recent Oratorio trial; obtaining these measures over a 2-year period aims to 
observe stability of the upper limb function with Ocrevus™ treatment. 
 
3.3 
OUTCOME MEASURES 
• The UE function will be assessed every 6 months over 24 months to gauge for 
any small changes at certain intervals but to also have a sufficient length of time 
that can be compared in order to assess for any type of change over time. * 
• Incidence of UE functional changes (improved, worsening or stable) with scores 
of time and performance on the TEMPA. 
• In this group of patients (advanced disability) there is less concern with relapse 
rate reduction; relapses happen at a low rate. There is more concern regarding 
any loss of function, and we will focus on UE function. Studies like this would 
provide better data for this type of patient aiding in the process of selecting 
appropriate disease modifying therapy. 
*UE function includes measures on the TEMPA, UEFI and 9HPT. 

Protocol:  (University of South Florida} 
7/P Version 4.1 
 
10JAN2020 
UEFI is subjective and answered by the patient. The Upper Extremity Functional 
Index (UEFI) is a self-administered questionnaire which measures disability in 
patients with upper extremity conditions. The questionnaire lists 20 activities and 
the patient gives a score to each based on the difficulty they have completing 
that activity. The scores given to the 20 questions are added to give a highest 
possible score of 80. The lowest possible score is 0. A lower score indicates that 
the person is reporting increased difficulty with the activities as a result of their 
upper limb condition. The change from baseline per patient and for group means 
will be analyzed. A clinically significant change is determined as a 12% change. 
[20]  
 
The TEMPA scale is composed of nine standardized tasks which represents 
activities of daily living. Four items are unilateral (pick up and move a jar; pick up 
a pitcher and pour water into a glass; handle coins; pick up and move small 
objects) and five bilateral tasks (open a jar and take a spoonful of coffee; unlock 
a lock and open a pill container; write on an envelope and stick on a stamp; 
shuffle and deal playing cards; put a scarf around one ’s neck). The outcome 
parameters used in this study are speed of execution (seconds) and the 
functional rating. The functional rating refers to the participant’s independence in 
each task measured on a four-level scale: (0) successfully completed without 
hesitation or difficulty; (-1) completed, but with some difficulty; (-2) partially 
executed or some steps were performed with significant difficulty; and (-3) not 
completed, even if any degree of assistance was offered. A total score will be 
determined by adding the scores obtained for both the unilateral and bilateral 
tasks. Individual analysis of the unilateral and bilateral scores will be conducted 
to evaluate for functional improvement in the affected UE. Scores typically range 
from 0 to -50, with higher scores representing better performance. [12] The UE 
function will be measured by a consistent rater that is trained and qualified (must 
be a MD or equivalent).  
 
The 9HPT is an objective measure of manual dexterity, which is incorporated 
into the MSFC, is a widely used measure across most clinical trials in multiple 
sclerosis populations. The time to completion is measured twice on both the 
dominant and non-dominant hand. For this study purpose will also record the 
“better” and “worse” limb so that the data can be cautiously compared to prior 
studies completed in multiple sclerosis patients. The task of the 9HPT is for the 
patient to pick up each individual peg, one at a time, and place it in the board 
(that has the same number of peg holes for each peg). Once all the pegs are 
placed in the peg holes the patient then removes each peg, again one at a time, 
placing them back into the peg bowl from which they were originally located. 
Although this measure has been used in several multiple sclerosis trials due to 
its ease of administration, there are many other factors of upper extremity 
function that are not being assessed that can be captured by the TEMPA.  
3.3.1 Primary Outcome Measure 
No significant change in UE function over 24 months after initiation of Ocrevus™ 
measured objectively by measure of time to completion (seconds) and functional 

Protocol:  (University of South Florida} 
8/P Version 4.1 
 
10JAN2020 
scores on TEMPA (0 to -3). The hypothesis is that there is (stabilization) no 
significant change (within 20%) of TEMPA score from baseline to 24 months 
 
3.3.2 Secondary Outcome Measures 
No significant change in UEFI, or 9HPT from baseline to 24 months. 
Exploratory measures: correlations between change in TEMPA/UEFI/9HPT 
scores and FSS, MUSIQOL and SDMT values from baseline through 24months 
after treatment initiation with Ocrevus™.  
3.4 
SAFETY PLAN 
Patients will be evaluated at each study visit for the duration of their participation 
in the study for any new adverse events (AEs), especially for those that may 
interfere with the testing or commercial dosing schedule. 
3.5 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration (FDA) Good Clinical Practices (GCPs), and local ethical and legal 
requirements. 
4.0 
MATERIALS AND METHODS 
This is a 24-month, prospective, observational study which will be conducted at 
the University of South Florida (USF) MS Center. On average 80-100 patients a 
week are seen at the study site. This large patient population offers a suitable 
number of potential candidates in order to meet the enrollment goal. This study 
will be conducted in adult multiple sclerosis patients who have upper extremity 
impairment and must satisfy the approved therapeutic indication for Ocrevus™. 
Decision to treat with Ocrevus™ must precede enrollment. We anticipate 
enrollment will be random and open to any patient that meets the criteria below 
which will aid in the evaluation of our results to the general MS population. The 
targeted population are those patients that more often rely on their upper 
extremity function for activities of daily living due to impairment in other systems 
such as gait.) 
 
Every effort to maintain consistency (by use of the same rater) for the 
administration of the upper extremity assessments will be made. The same 
instructions for the patient questionnaires will be given at each time point.  
 
4.1 
SUBJECTS 
 
4.1.1 Subject Selection 
4.1.2 Inclusion Criteria 
To be eligible for entry into this study, candidates must meet all of the following 
eligibility criteria at the time of study entry: 
 

Protocol:  (University of South Florida} 
9/P Version 4.1 
 
10JAN2020 
• 
Must give written informed consent and any authorizations required by 
local law (e.g., Protected Health Information [PHI]) 
• 
Aged 18-70 at the time of informed consent 
• 
Must have a relapsing or progressive form of MS 
• 
Male subjects and female subjects of child-bearing potential (including 
female subjects who are not post-menopausal for at least 1 year) must be 
willing to practice effective contraception (as defined by the investigator) 
during the study and be willing and able to continue contraception for 6 
months after their last dose of study treatment 
• 
EDSS 4.0-8.0 
• 
UE weakness in at least one limb, defined as grade 4/5 in ≥ 2 muscles per 
limb 
• 
Muscle weakness must be primarily related to MS 
• 
Joint ROM must be within functional limits 
• 
Patient must be able to perform 9HPT and TEMPA tests with at least one 
limb 
 
4.1.3 Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion 
criteria exist at the time of study entry: 
 
• 
Severe weakness in bilateral upper limbs causing complete loss of 
function 
• 
History of severe allergic or anaphylactic reactions or known drug 
hypersensitivity 
• 
 Female subjects considering becoming pregnant while in the study 
• 
 Female subjects who are currently pregnant or breast-feeding 
• 
Unwillingness or inability to comply with the requirements of the protocol 
including the presence of any conditional (physical, mental or social) that 
is likely to affect the subject’s ability to comply with the protocol.  
• 
Active HBV infections 
• 
Prior treatment with Ocrevus™  
• 
Severe tremor/ataxia of the UE as defined by an EDSS with Cerebellar 
Functional System score of 3 or more due to upper extremity score 
(moderate tremor or clumsy movements interfere with function in all 
spheres)  

Protocol:  (University of South Florida} 
10/P Version 4.1 
 
10JAN2020 
• 
Severe spasticity of the UE as defined by EDSS, Pyramidal Functional 
System score- Upper Limb spasticity subscore of 3 or more (severely 
increased muscle tone that is extremely difficult to overcome and full 
range of motion is not possible)   
• 
Cognitive impairment that may interfere with the conduct of the necessary 
testing (determined by the investigator)  
• 
Any other reason that, in opinion of the Investigator and/or the Sponsor, 
the subject is determined to be unsuitable for enrollment in this study 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
There is no randomization in this study. Stratification of results by age and 
baseline UE strength may occur in the analysis. 
 
4.3. 
STUDY TREATMENT  
Ocrelizumab will be provided commercially to patients that participate in this 
study. 
 
4.4 
CONCOMITANT AND EXCLUDED THERAPY 
Physical therapy will be documented and any other ongoing medications.  
4.5 
STUDY ASSESSMENTS 
 
4.5.1 Overview of Study Visits 
Screening/Baseline Visit (Day 0) 
After the ICF is signed, the following information/assessments will be conducted: 
• Review of medical history 
• Review of inclusion/exclusion criteria 
• Documentation on concomitant medications 
• Demographic information 
• Vital signs  
• Measurement of UE function (TEMPA, 9HPT) 
• Questionnaires (UEFI, FSS, SDMT, MUSIQOL) 
• Physical examination/EDSS 
Quarterly Visits* (Months 3, 9, 15, 21) 
• Changes in concomitant medications and AE 
• Questionnaires (UEFI, FSS, SDMT, MUSIQOL) 
• Vital signs 
• Interval history 
 

Protocol:  (University of South Florida} 
11/P Version 4.1 
 
10JAN2020 
*In the case of financial or physical limitations with the patient, the quarterly 
visits will be conducted via phone. In these instances, vital signs will not be 
obtained, as this will not affect the standard of care.  
Semi-annual visits (before Ocrevus™  infusion) (Months 6, 12, 18) 
• Changes in concomitant medications and AEs 
• Review of concomitant medication and AEs 
• Questionnaires (UEFI, FSS, SDMT, MUSIQOL) 
• Physical examination/EDSS  
• Vital signs 
• Interval history 
• Measurement of UE function (TEMPA, 9HPT) 
 
Month 24 End of study (EOS)/Early discontinuation visit  
In the event Ocrevus™ is discontinued prior to the end of the 24-month study, 
the patient will be asked to come in for EOS procedures. Any AEs attributed to 
Ocrevus™ in the opinion of the investigator, will be followed until resolved, and 
documented in the patient study chart.  
• Review of concomitant medication and AEs 
• Patient questionnaires (UEFI, FSS, SDMT, MUSIQOL) 
• Physical examination/EDSS 
• Vital signs 
• Interval history 
• Measurement of UE function (TEMPA, 9HPT) 
 
4.6 
DISCONTINUATION OF COMMERCIAL THERAPY 
In the event Ocrevus™ is discontinued prior to the end of the 24-month study, 
the patient will be asked to come in for EOS procedures. Any AEs attributed to 
Ocrevus™ in the opinion of the investigator, will be followed until resolved, and 
documented in the patient study chart.  
4.7 
SUBJECT DISCONTINUATION 
If a patient discontinues use of Ocrevus, for any reason, they will be asked to 
attend an EOS visit to conduct final assessments (same format as month 24 
visit).  
4.8 
STUDY DISCONTINUATION 
Genentech Study Center, and the Principal Investigator has the right to 
terminate this study at any time.  Reasons for terminating the study may include 
the following: 
• The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to subjects 
• Subject enrollment is unsatisfactory 

Protocol:  (University of South Florida} 
12/P Version 4.1 
 
10JAN2020 
• Data recording are inaccurate or incomplete 
• Study protocol not followed 
 
4.9 
STATISTICAL METHODS 
4.9.1 Analysis of the Conduct of the Study 
All protocol violations will be accounted for and summarized in the results and 
discussion. If there are large amounts of missing data imputation measures may 
be used. 
Demographic information will be collected on all patients in order to present 
descriptive statistics of the population. 
4.9.2 Analysis of Treatment Group Comparability 
There is only one designated treatment group. Descriptive statistics of the 
baseline characteristics of the enrolled population will be presented in the final 
report and manuscript. 
  
4.9.3 Efficacy Analysis  
a. Primary Endpoint   
1. TEMPA scores after 24 months of OcrevusTM treatment. 
Paired sample t-test to compare the 24 month measurements to the baseline 
measurements. 
Mean within-patient changes from baseline through 24 months (TEMPA). One-
way repeated measures ANCOVA for TEMPA scores from baseline, 6 months, 
12 months, 18 months, 24 months which will account for baseline characteristics 
(baseline disability level). A soft stratification will be applied so that recruitment 
will aim to include a spread of types of patients, those below overall EDSS of 6.0 
and those above 6.0. If more than 2/3 of total enrollment is in one of the 
categories, the study team will reestablish efforts to recruit for the other cohort.  
 
If data does not have normal distribution, then other non-parametric analysis will 
be employed (such as sign test for TEMPA functional score). 
 
The threshold to determine a significant clinical change will be >20% from 
baseline value. This clinically significant difference is estimated based on data 
from the Oratorio trials that showed progression among both groups (placebo 
and OcrevusTM) but to a lesser extent in the OcrevusTM arm with an established 
clinically significant threshold of 20%(data will be requested from sponsor for 
use to review 9HPT results for the abnormal function at baseline group of 
patients). Measures will be collected and analyzed as units of time (seconds) 
and as functional scores on an ordinal scale that range from 0 to -3 (0 indicating 

Protocol:  (University of South Florida} 
13/P Version 4.1 
 
10JAN2020 
no signs of dysfunction).Ad hoc analysis may occur that includes evaluation of 
patients with significant clinical changes versus those that did not have 
significant clinical change based on any of the subscales within the TEMPA or 
physical exam. We will review   >15%, >20% and >25% [in better hand and in 
worse hand] change from baseline with increases in time implying clinical 
progression and stability or decrease in time implying stability or improvement in 
function 
 
b. Secondary Endpoints 
Pearson correlation coefficients will be calculated to evaluate correlations 
between UE function (measured by TEMPA and 9HPT) primarily at baseline but 
also at each time point over the 24-month time period to compare patient 
responses on the UEFI, FSS, and MUSIQOL. Correlations with the primary 
endpoint scores and the SDMT will also be analyzed for any indication of new 
cognitive impairment that may interfere with the interpretation of the results.  
 
4.9.4 Safety Analysis 
No safety analysis will occur as these patients will be receiving commercial 
Ocrevus. A summary of adverse events will be constructed using descriptive 
statistics.  
4.9.5 Missing Data 
Study staff will work to ensure missing data is minimized. If there are less than 
two percent of time points missing, then during analysis, last value carry forward 
imputation will be used. If greater than two percent missing, multiple point 
imputation measures will be used. 
4.9.6 Determination of Sample Size 
It is expected that 30 patients will be eligible to enter this study during the 
proposed timeframe. This is a pilot study; the TEMPA is a more comprehensive 
assessment of upper extremity function which we will use in the analysis of this 
group of patients to evaluate what percentage remain stable (within 20% 
variation from baseline) and analyze correlations with other measures of upper 
extremity function (9HPT and patient perception using the UEFI). Therefore, this 
is not a calculated sample size as there is a lack of historical data available for 
this population and the modalities of testing we plan to utilize. We do not have 
historical data to gather estimates for an accurate power calculation. We plan to 
gather data on 30 patients but will screen up to 35 in case of screen failures or 
early withdrawals. Even with the limited calculations we believe that we will be 
able to analyze for a clinically meaningful lack of change (stabilization). 
 
 

Protocol:  (University of South Florida} 
14/P Version 4.1 
 
10JAN2020 
4.10 DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of 
standard practices and procedures. 
5. 
REPORTING OF ADVERSE EVENTS 
 
5.1   ASSESSMENT OF SAFETY 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events 
(AEs) and serious adverse events (SAEs) 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). 
• It is life threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
• It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 

Protocol:  (University of South Florida} 
15/P Version 4.1 
 
10JAN2020 
 
5.2   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).  
Adverse Event Reporting Period 
The study period during which all AEs and SAEs as described in section 5.1 
where the subject has been exposed to a Genentech product must be reported. 
The Reporting period begins after informed consent is obtained and initiation of 
any study procedures and ends 30 days 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., event diagnosed 2 days after first dose of 
ocrelizumab). 
 
Expected AEs are those AEs that are listed or characterized in the Package 
Insert (P.I.)or current Investigator Brochure (IB).  
 

Protocol:  (University of South Florida} 
16/P Version 4.1 
 
10JAN2020 
Unexpected AEs are those not listed in the P.I. or current IB or not identified. 
This includes AEs for which the specificity or severity is not consistent with the 
description in the P.I. or IB. For example, under this definition, hepatic necrosis 
would be unexpected if the P.I. or IB only referred to elevated hepatic enzymes 
or hepatitis. 
 
Unexpected disease progression defined by increase in 1 point on the upper 
extremity strength scores in the Pyramidal FSS of the EDSS above baseline 
subsequently confirmed at repeat assessment 6 months later would imply 
worsening of upper extremity function and require clinical evaluation. 
 
For patients receiving combination therapy, causality will be assessed 
individually for each protocol-mandated therapy. 
 
5.3   PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points 
should be adopted. Examples of non-directive questions include:  
• “How have you felt since your last clinical 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. 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 5.1.2), regardless of attribution, will be reported to the appropriate 
parties. When recording a death, the event or condition that caused or 
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”. 

Protocol:  (University of South Florida} 
17/P Version 4.1 
 
10JAN2020 
c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. 
Such conditions should be reported as medical and surgical history. A 
preexisting medical condition should be re-assessed throughout the trial and 
reported as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE. For 
example, if a subject is hospitalized to undergo coronary bypass surgery, record 
the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study. 
e. 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5 .0 Update 
current versions) will be used for assessing adverse event severity. Below 
Table should be used for assessing severity for adverse events that are not 
specifically listed in the NCI CTCAE. 
 
 
 
 
 
 
 
 
 
 
 

Protocol:  (University of South Florida} 
18/P Version 4.1 
 
10JAN2020 
 
 
 
 
 
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  
d. Grade 4 and 5 events must be reported as serious adverse events  
 
f.         Pregnancy 
If a female subject becomes pregnant while receiving ocrelizumab or within 6 
months after the last dose of ocrelizumab, a report should be completed and 
expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome 
of the pregnancy should also occur. Abortion, whether accidental, therapeutic, 
or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child 
born to a female subject exposed to the ocrelizumab should be reported as an 
SAE. 
 

Protocol:  (University of South Florida} 
19/P Version 4.1 
 
10JAN2020 
Additional information on any ocrelizumab-exposed pregnancy and infant will be 
requested by Genentech Drug Safety at specific time points (i.e. after having 
received the initial report, at the end of the second trimester, 2 weeks after the 
expected date of delivery, and at 3, 6, and 12 months of the infant’s life). 
 
g. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject 
has completed or discontinued study participation if attributed to prior 
ocrelizumab exposure. If the investigator should become aware of the 
development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female subject who participated in the study, this should be 
reported as an SAE adequately to Genentech Drug Safety during the follow-up 
period.  
 
h. 
Case Transmission Verification of Single Case Reports 
The Sponsor agrees to conduct  the Case Transmission verification to ensure 
that all single case reports have been adequately received by Genentech  via 
the Sponsor emailing Genentech a Quarterly line-listing documenting single 
case reports sent by the Sponsor to Genentech in the preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the 
end of the agreed time period. Confirmation of receipt should be received within 
the time period mutually agreed upon. 
If discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall 
handle the matter on a case-by-case basis until satisfactory resolution.  The 
sponsor shall receive reconciliation guidance documents within the ‘Activation 
Package’. 
Following Case Transmission Verification, single case reports which have not 
been received by Genentech shall be forwarded by the Sponsor to Genentech 
within five (5) calendar days from request by Genentech. 
At the end of the study, a final cumulative Case Transmission Verification 
report will be sent to Genentech.  
 
i.  
AEs of Special Interest (AESI) 
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 

Protocol:  (University of South Florida} 
20/P Version 4.1 
 
10JAN2020 
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: 
o 
Treatment-emergent ALT or AST > 3 × ULN in combination with total 
bilirubin > 2 × ULN 
o 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical 
jaundice 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
o 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, 
is considered an infectious agent.  A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings that 
indicate an infection in a patient exposed to a medicinal product.  This term 
applies only when a contamination of the study drug is suspected 
 
  
j. 
Adverse Event Reporting 
The Sponsor will track all protocol-defined AE and pregnancy reports originating 
from the Study for the Product. 
 
Investigators must report all AEs, SAEs, AESIs pregnancy reports and special 
situation reports (if applicable) adequately to Genentech within the timelines 
described below. The completed Medwatch or CIOMS I form or Genentech 
approved reporting forms should be faxed immediately upon completion to 
Genentech at the following contacts: 
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including 
pregnancy reports) and Product Complaints with an AE should be sent to: 
 
Fax: 650-238-6067 
Email:  usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should be sent to: 
Email: kaiseraugst.global_impcomplaint_management@roche.com 
It is understood and agreed that the Sponsor will be responsible for the 
evaluation of AEs/SAEs, AESIs, Special Situation Reports (including pregnancy 
reports) and Product Complaints (with or without an AE) originating from the 
study.  
These single case reports will be exchanged between the parties as outlined 
below so that regulatory obligations are met. 

Protocol:  (University of South Florida} 
21/P Version 4.1 
 
10JAN2020 
 
Relevant follow-up information should be submitted to Genentech Drug Safety 
as soon as it becomes available and/or upon request. 
 
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy 
reports (including pregnancy occurring in the partner of a male study subject), 
other Special Situation Reports and Product Complaints (with or without an AE),  
where the patient has been exposed to the Genentech Product, will be sent on a 
MedWatch form or CIOMS I form or on Genentech approved reporting forms to 
Genentech Drug Safety. Transmission of these reports (initial and follow-up) will 
be either electronically or by fax and within the timelines specified below: 
 
• SADRs 
Serious AE reports that are related to the Product shall be transmitted to 
Genentech/Roche within fifteen (15) calendar days of the awareness 
date. 
 
• Other SAEs 
Serious AEs that are unrelated to the Product shall be reported to 
Genentech/Roche via the AE master log at least annually. 
 
• AESIs  
AESIs shall be forwarded to Genentech/Roche within fifteen (15) 
calendar days of the awareness date.  
 
• Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following 
other Special Situations Reports should be collected even in the 
absence of an Adverse Event and transmitted to Genentech within thirty 
(30) calendar days: 
• Data related to the Product usage during breastfeeding 
• Data related to overdose, abuse, misuse or medication error 
(including potentially exposed or intercepted medication 
errors) 
• In addition, reasonable attempts should be made to obtain 
and submit the age or age group of the patient, in order to 
be able to identify potential safety signals specific to a 
particular population 
 
• Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to 
Genentech within fifteen (15) calendar days of the awareness date. 
 
A Product Complaint is defined as any written or oral information received 
from a complainant that alleges deficiencies related to identity, quality, 
safety, strength, purity, reliability, durability, effectiveness, or performance 

Protocol:  (University of South Florida} 
22/P Version 4.1 
 
10JAN2020 
of a product after it has been released and distributed to the commercial 
market or clinical trial. 
 
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. 
5.4  
 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic 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 description (and number, if assigned) 
• 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 AE to each   
      investigational product and suspect medication 
Follow-up Information 
Additional information may be added to a previously submitted report by any of 
the following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up 
with the original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including 
patient identifiers (i.e. D.O.B. initial, patient number), protocol description and 
number, if assigned, brief AE 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 
 
5.5      Reporting to Regulatory Authorities, Ethics Committees and Investigators 
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. 
 
Genentech will be responsible for the expedited reporting of safety reports originating 
from the Study to the EMA through Eudravigilance Clinical Trial Module (EVCTM). The 

Protocol:  (University of South Florida} 
23/P Version 4.1 
 
10JAN2020 
Sponsor will be responsible for the distribution of safety information to its own 
investigators, where relevant. 
5.6      Additional Reporting Requirements for IND Holders 
For Investigator-Initiated Studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening AE 
that is unexpected and assessed by the Investigator to be possibly related to the 
use of ocrelizumab. An unexpected AE is one that is not already described in 
the ocrelizumab IB. Such reports are to be telephoned or faxed to the FDA and 
Genentech/Roche within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating 
investigators, in a written IND Safety Report, of any serious, unexpected AE that 
is considered reasonably or possibly related to the use of ocrelizumab. An 
unexpected AE is one that is not already described in the ocrelizumab IB. 
 
Written IND Safety reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32. All safety reports previously filed 
by the investigator with the IND concerning similar events should be analyzed 
and the significance of the new report in light of the previous, similar reports 
commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to 
the FDA, Genentech/Roche, and all participating investigators within 15 
calendar days of first learning of the event. The FDA prefers these reports on a 
MedWatch 3500 form, but alternative formats are acceptable (e.g., summary 
letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
All written IND Safety Reports submitted to the FDA by the Investigator must 
also be faxed to Genentech/Roche Drug Safety: 
Fax: (650) 225-4682 or (650) 225-4630 
 
And the sponsor will be responsible for the distribution of safety information to 
Site IRB:  
 

Protocol:  (University of South Florida} 
24/P Version 4.1 
 
10JAN2020 
University of South Florida IRB 
12901 Bruce B. Downs Blvd, MDC35 
Tampa, FL 33612-4799 
rsch-arc@usf.edu 
For questions related to safety reporting, please contact Genentech/Roche Drug 
Safety: 
Tel: (888) 835-2555 
Fax: 650) 225-4682 or (650) 225-4630 
 
AGGREGATE REPORTS 
IND ANNUAL REPORTS 
 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should 
be copied to Genentech: 
 
Copies of such reports should be emailed to Genentech at:   
ocrelizumab-iis-d@gene.com and ctvist_drugsafety@gene.com  
 
Other Reports 
 
The sponsor will forward a copy of the Final Study Report or publication to 
Genentech/Roche upon completion of the Study. 
 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. This includes all IND annual reports and the Clinical Study 
Report (final study report). Additionally, any literature articles that are a result of 
the study should be sent to Genentech. Copies of such reports should be mailed 
to the assigned Clinical Operations contact for the study: 
 
ocrelizumab-iis-d@gene.com, to Genentech Drug Safety CTV oversight mail 
box at: ctvist_drugsafety@gene.com and your Genentech MSL. 
 
QUERIES 
Queries related to the Study will be answered by University of South Florida. 
However, responses to all safety queries from regulatory authorities or for 
publications will be discussed and coordinated between the Parties. The Parties 
agree that Genentech/Roche shall have the final say and control over safety 
queries relating to the Product. University of South Florida 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 

Protocol:  (University of South Florida} 
25/P Version 4.1 
 
10JAN2020 
clearly indicate on the request the reason for urgency and the date by which a 
response is required. 
SAFETY CRISIS MANAGEMENT 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or 
regulatory actions that limit or restrict the way in which the Product is used, or 
where there is media involvement, the Party where the crisis originates will 
contact the other Party as soon as possible. 
The Parties agree that Genentech/Roche shall have the final say and control 
over safety crisis management issues relating to the Product. University of 
South Florida agrees that it shall not answer such queries from media and other 
sources relating to the Product but shall redirect such queries to 
Genentech/Roche. 
 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with 
Genentech or a Genentech representative: 
• Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any sub-investigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations. 
• Current curriculum vitae of the Principal Investigator 
• Written documentation of IRB approval of protocol and informed consent 
document 
• A copy of the IRB-approved informed consent document 
• A signed Clinical Research Agreement 
 
6.2 
STUDY COMPLETION 
The following materials are requested by Genentech when a study is considered 
complete or terminated: 
• Any study report submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. This includes all IND annual reports and the Clinical Study 
Report (final study report). Additionally, any literature articles that are a result of 
the study should be sent to Genentech. Copies of such reports should be mailed 
to the assigned Clinical Operations contact for the study: 

Protocol:  (University of South Florida} 
26/P Version 4.1 
 
10JAN2020 
• Email : ocrelizumab-iis-d@gene.com  
 
6.3 
INFORMED CONSENT 
The informed consent document must be signed by the subject or the subject’s 
legally authorized representative before his or her participation in the study.  The 
case history for each subject shall document that informed consent was 
obtained prior to participation in the study.  A copy of the informed consent 
document must be provided to the subject or the subject's legally authorized 
representative.  If applicable, it will be provided in a certified translation of the 
local language. 
Signed consent forms must remain in each subject’s study file and must be 
available for verification by study monitors at any time. 
 
6.4 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the IRB for review and must be approved 
before the study is initiated.  The study will be conducted in accordance with 
U.S. FDA, applicable national and local health authorities, and IRB 
requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case the IRB must be updated at least once a year.  The 
Principal Investigator must also keep the IRB informed of any significant AEs. 
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 Brochure and that are 
considered possibly or probably related to the molecule or study drug by the 
investigator.  Some IRBs may have other specific AE requirements that 
investigators are expected to adhere.  Investigators must immediately forward to 
their IRB any written safety report or update provided by Genentech (e.g., IND 
safety report, Investigator Brochure, safety amendments and updates, etc.). 
 
6.5 
STUDY MONITORING REQUIREMENTS 
NA 
 

Protocol:  (University of South Florida} 
27/P Version 4.1 
 
10JAN2020 
6.6 
DATA COLLECTION 
 
The information obtained during the conduct of this clinical study is confidential, 
and disclosure to third parties other than those noted below is prohibited. 
Information obtained during the conduct of this study will be collected, 
processed, and transmitted to or for the benefit of the subject to the applicable 
regional or national regulations and principles of confidentiality for each 
participating center.  Information contained therein will be maintained in 
accordance with applicable law protecting patient privacy; including the 
provisions of 45 CFR Part 164 promulgated under the Health Insurance 
Portability and Accountability Act (HIPPA) in addition to applicable regional, 
national, or provincial regulations, and may be inspected by the Investigator, the 
investigators staff.  Processing, evaluation, or use of the information will be 
performed by a health professional for medical purposes and/or by those 
operating under a duty of confidentiality that is equivalent to that of a health 
professional. 
 
The subject will not be identified by name in any study reports, and these 
reports will be used for research purposes only.  Every effort will be made to 
keep the subject’s personal medical data confidential. All data will be entered 
into a computer that is password protected. Data will be stored in a locked office 
of the investigators and maintained for a minimum of three years after 
completion of the study. When any data are published all identifiers will be 
removed. When data or resources are shared with other study investigators or 
collaborators no personal identifiers will be shared. 
 
6.7 
STUDY MEDICATION ACCOUNTABILITY (IF APPLICABLE) 
If study drug will be provided by Genentech, accurate records of all study drug 
dispensed from and returned to the study site should be recorded by using the 
institution’s drug inventory log. 
All expired, partially used or empty containers should be disposed of at the 
study site according to institutional standard operating procedure.   
 
6.8 
DISCLOSURE AND PUBLICATION OF DATA 
 
Subject medical information obtained by this study is confidential, and disclosure 
to third parties other than those noted below is prohibited. 
Upon the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or 
her welfare. 

Protocol:  (University of South Florida} 
28/P Version 4.1 
 
10JAN2020 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, 
Genentech, and the IRB for each study site, if appropriate. 
The results of this study may be published or presented at scientific meetings. 
The Sponsor will comply with the requirements for the publication of study 
results.   
The results of this study will be submitted for poster presentation at an annual 
conference in the year that the data has been analyzed (CMSC or ACTRIMS). 
The manuscript will be submitted for publication after poster presentation to the 
International Journal of Multiple Sclerosis Care. 
Additionally, Section 801 of the Food and Drug Administration Amendments Act 
(FDAAA 801) (PDF) requires Responsible Parties to register and submit 
summary results of clinical trials with ClinicalTrials.gov. The law applies to 
certain clinical trials of drugs (including biological products) and medical 
devices. (refer to FDAAA 801 Requirements to learn about Responsible Party, 
Applicable Clinical Trials, and deadlines for registration and results submission) 
 
6.9 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for 2 years after 
marketing application approval.  If no application is filed, these records must be 
kept 2 years after the investigation is discontinued and the U.S. FDA and the 
applicable national and local health authorities are notified.  Genentech will 
notify the Principal Investigator of these events. 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with U.S. FDA IND regulations and with the record 
retention policies of the relevant national and local health authorities. 

Protocol:  (University of South Florida} 
29/P Version 4.1 
 
10JAN2020 
REFERENCES 
 
1. Ropper AH, Samuels M.A. Principals of Neurology. 9th edition. New York: 
McGraw-Hill, 2009. 
 
2. Lamers, I., Feys, P. Assessing upper limb function in multiple sclerosis. Mult 
Scler J 2014; 20(7)775-784.  
 
3. Genentech. Ocrevus™: Highlights of prescribing information. 2017. 
 
4. Montalban, X., Hauser SL, Kappos L,et al. Ocrelizumab versus placebo in 
Primary Progressive Multiple Sclerosis. N Engl J Med. 2017; 376(3)209-220.  
 
5. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An Expanded 
Disability Status Scale (EDSS). Neurology. 1983; 33:14444-52. 
 
6. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus Interferon Beta 1-a in 
Relapsing Multiple Sclerosis. N Engl J Med. 2017; 376(3)221-234.  
 
7. Goodin DS. Multiple Sclerosis and Related Disorders. Amsterdam, The 
Netherlands: Elsevier, 2014. 
 
8. Ontaneda, D, Fox R, Chatawa J. Clinical trials in progressive multiple sclerosis: 
lessons learned and future perspectives. Lancet. 2015; 14:208-23. 
 
9. Cohen JA, Cutter GR, Fischer JS, et al. Use of the multiple sclerosis functional 
composite as an outcome measure in a phase 3 clinical trial. Arch Neurol. 
2001:58:961-7. 
 
10. Fox, EJ, Markowitz, C, Montalban, X, et al. Effect of Ocrelizumab on Upper 
Extremity Function in Patients With Primary Progressive Multiple Sclerosis in 
the ORATORIO Study. Presented at the 7th Joint European Committee for 
Treatment and Research in Multiple Sclerosis (ECTRIMS) and Americas 
Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 
Meeting; 25–28 October 2017; Paris, France. 
11. Lamer I, Klechtermans S, Baert I, et al. Upper limb assessment in Multiple 
Sclerosis: A Systematic Review of Outcome Measures and their Psychometric 
Properties. Arch Physl Med Rehab. 2014; 95:1184-200.  
 
12. Feys, P, Duportali M, Kos D, Van Asch P, Ketelaer P. Validity of the TEMPA 
for the measurement of upper limb function in multiple sclerosis. 
2002;(16):166-173. 
 
13. Schwid, SR, Goodman, AD, McDermott, MP, Bever, CF, Cook S. functional 
measures in MS : What is a reliable change ? In: American Academy of 
Neurology. Toronto, Ontario, Canada; 1999. 
 

Protocol:  (University of South Florida} 
30/P Version 4.1 
 
10JAN2020 
14.   Gijbels D, Lamers I, Kerkhofs L, Alders G, Knippenberg E, Feys P. The Armeo 
Spring as training tool to improve upper limb functionality in multiple sclerosis : 
a pilot study. J Neuroeng Rehabil. 2011;8(1):5. 
 
15. Hamilton, GF, Mcdonald, C, Chenier T. Measurement of Grip Strength: Validity 
and Reliability of the Sphygmomanometer and Jamar Grip Dynamometer. 
JOSPT. 1992;16(5):215-219. 
 
16. Chesworth BM, Hamilton CB, Walton DM, et al. Reliability and validity of two 
versions of the upper extremity functional index. Physiotherapy Canada. 2014; 
66(3), 243–253.  
 
17. Stratford PW, Binkley, JM, Stratford DM. Development and initial validation of 
the upper extremity functional index. Physiotherapy Canada. 2001; 53(4):259-
267. 
18. Yozbatiran N, Baskurt F, Baskurt Z, et al. Motor assessment of upper extremity 
function and its relation with fatigue, cognitive function and quality of life in 
multiple sclerosis patients. J Neuro Sciences. 2006; 246(1–2), 117–122. 
 
19. Benedict RHB, Holtzer R, Motl RW, et al. Upper and Lower Extremity Motor 
Function and Cognitive Impairment in Multiple Sclerosis. J Int Neuropsychol 
Soc. 2011;(17):643-653.  
 
20. Stratford P, Binkley J, Stratford D. Development and initial validation of the 
upper extremity functional index. Physiotherapy Canada 2001;53(4):259-67. 
 
 
 
 

Protocol:  (University of South Florida} 
31/P Version 4.1 
 
10JAN2020 
   APPENDIX A  Schedule of Assessments 
1. The baseline visit will occur within 4 weeks of the screening visit.  
2. Acceptable windows for all visits are +/- 14 days. In rare cases where the first infusion is greater than 2 months from the baseline visit, the month 3 visit and subsequent visits will be calculated based on the 
initial infusion date. 
3. Semiannual visits will occur prior to the next scheduled Ocrevus™ infusion   
4. Vitals signs will be collected for subjects who conduct the quarterly visit at clinic. Vital signs will not be collected at quarterly visits conducted via phone.  
5. If relapse is suspected, this will be captured as an AE and treated at the discretion of the investigator. Documentation will include any suspicion for PML 
 
 
 
Screening/ 
BL1,2 
M3 
 
M63 
M9 
M123 
 
M15 
 
M183 
 
M21 
M243 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Review of Medical History 
X 
 
 
 
 
 
 
 
 
Review of inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Patient Questionnnaires (UEFI, 
SDMT, FSS, MUSIQOL) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (and EDSS) 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signs 
X 
X4 
X 
X4 
X 
X4 
X 
X4 
X 
Interval History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Measurement of UE function 
(TEMPA, 9HPT, Jamar 
dynamometer) 
X 
 
X 
 
X 
 
X 
 
X 
Relapse Assessment5 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
Protocol:  (University of South Florida} 
32/P Version 4.1 
 
10JAN2020 
APPENDIX B 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: Fax: 650-238-6067 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 

 
Protocol:  (University of South Florida} 
33/P Version 4.1 
 
10JAN2020 
Appendix C   UEFI 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol:  (University of South Florida} 
34/P Version 4.1 
 
10JAN2020 
Appendix D 
SDMT 
 
 
 
 
 
 
 
 
 
 

 
Protocol:  (University of South Florida} 
35/P Version 4.1 
 
10JAN2020 
 
Appendix E 
Jamar handheld dynamometer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol:  (University of South Florida} 
36/P Version 4.1 
 
10JAN2020 
 
Appendix F 
9-hole peg test 
 
 
 

 
Protocol:  (University of South Florida} 
37/P Version 4.1 
 
10JAN2020 
 
Appendix G 
Fatigue Severity Scale (FSS) 
 
 

 
Protocol:  (University of South Florida} 
38/P Version 4.1 
 
10JAN2020 
 
Appendix H    MUSIQoL