Clinical trial NCT02688985
Conditions: Relapsing Multiple Sclerorsis Multiple Sclerosis, Primary Progressive
Sponsor: Genentech, Inc.
Start date: 2016-04-29; Completion date: 2023-04-11
Enrollment: 131 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, multicenter, biomarker study designed to be hypothesis-generating in order to better understand the mechanism of action of ocrelizumab and B-cell biology in RMS or PPMS. The study will be conducted in two cohorts i.e. RMS cohort (4 arm group) and PPMS cohort (one arm group). RMS cohort: Ocrelizumab will be administered as two intravenous (IV) infusions of 300 milligrams (mg) on Days 1 and 15. Subsequent doses will be given as single 600-mg infusions at Weeks 24 and 48. Participants will be randomized in 1:1:1 ratio to receive lumbar puncture (LP) post-treatment at Week 12, 24, or 52 following the first dose of ocrelizumab in three arm groups. A fourth RMS arm with delayed treatment start (Arm 4 \[control group\]) will not be a part of the randomization and will be recruited separately, wherein treatment with ocrelizumab will be delayed for 12 weeks from pre-treatment baseline. PPMS cohort: Ocrelizumab 600 mg will be administered as two 300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks. Participants will receive a LP at the start of the study before dosing with ocrelizumab and second LP at Week 52 following the first dose of ocrelizumab. A long-term extension will be conducted for participants that complete the study and continue to receive ocrelizumab. Treatment with ocrelizumab in the entire study will continue for approximately 4.5 years after the first infusion.

Detailed description:

Arms: arm 1: Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 12. Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72. arm 2: Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 24. Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72. arm 3: Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP before the start of dosing (Week 1, treatment baseline) with ocrelizumab and a second LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72. arm 4: Ocrelizumab treatment will be delayed for 12 weeks from pre-treatment baseline. Participants with RMS will receive ocrelizumab as two 300-mg IV infusion on Days 1 and 15 then as single infusion of 600 mg on Weeks 24 and 48. Participants will receive a LP at Week -12 (pre-treatment baseline) and a second LP before the start of dosing (Week 1, treatment baseline). Participants will be asked to have an additional optional LP at Week 52. Participants that complete the study and continue to receive ocrelizumab will receive single infusions every 24 weeks starting from Week 72. arm 5: For the PPMS cohort, ocrelizumab will be administered as two 300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks during the treatment period and then as a single 600-mg dose every 24 weeks starting week 72 during the Long-Term Extension period.
Interventions: intervention 1: Ocrelizumab intervention 2: Lumbar Puncture intervention 3: Methyloprednisolone intervention 4: Antihistamine
Intervention descriptions: intervention 1: Ocrelizumab will be administered as IV infusion. intervention 2: Participants will receive LP as specified in individual arms. Lumbar puncture is optional at week 52, except for RMS Cohort Arm 3 and PPMS Cohort. In addition, the lumbar punctures in the Long Term Extension phase is every other year. intervention 3: Participants will receive 100 mg of IV methylprenisolone (or an equivalent) prior to ocrelizumab infusion. intervention 4: Participants will receive an antihistamine, such as diphenhydramine, prior to ocrelizumab infusion.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
An Open-label, Multicenter, Biomarker Study to Explore the 
Mechanism of Action of Ocrelizumab and B-Cell Biology in Patients 
with Relapsing Multiple Sclerosis or Primary Progressive Multiple 
Sclerosis 
NCT Number: 
NCT02688985 
Document Date: 
Protocol Version 4: 21-Nov-2016 
 
 


Title
21-Nov-2016 18:25:11
Date and Time (UTC)
Company Signatory
Approver's Name
FINAL PROTOCOL APPROVAL 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
Ocrelizumab—Genentech, Inc. 
Protocol ML29966, Version 4 (Global) 
PROTOCOL 
TITLE: 
AN OPEN-LABEL, MULTICENTER, BIOMARKER 
STUDY TO EXPLORE THE MECHANISM OF 
ACTION OF OCRELIZUMAB AND B-CELL 
BIOLOGY IN PATIENTS WITH RELAPSING 
MULTIPLE SCLEROSIS OR PRIMARY 
PROGRESSIVE MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: ML29966 
VERSION NUMBER: 
4 (Global) 
EUDRACT NUMBER: 
2015-004616-37 
IND NUMBER: 
100,593 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  14 December 2015 
DATES AMENDED: 
Version 2:  22 March 2016 
Version 3 (Germany):  19 October 2016 
Version 4 (Global):  See electronic date stamp below 


Ocrelizumab—Genentech, Inc. 
2/Protocol ML29966, Version 4 (Global) 
PROTOCOL AMENDMENT, VERSION 4 (GLOBAL): 
RATIONALE 
This Version 4 amendment consolidates elements of the previous country-specific 
amendment and revises the study design to add physical examinations at every 
treatment visit.  The rationale for previous amendment (i.e., Version 3 [Germany]) is 
listed for the convenience of sites that did not receive this version of the protocol. 
RATIONALE FOR VERSION 3 (GERMANY) 
Protocol ML29966 was amended to Version 3 to include physical examinations at every 
treatment visit.  The schedule of activities (Appendix 1) was updated to address a 
deficiency letter from the Paul-Erlich-Institut (PEI) dated 13 October 2016.  In this letter, 
the PEI asked that physical examinations be conducted at every treatment visit, prior to 
treatment, to rule out any conditions that may require withholding of study drug (e.g., 
signs of active infection).  Thus, physical examinations were added at Week 3 and 
Week 48. 
RATIONALE FOR VERSION 4 (GLOBAL) 
Protocol ML29966 was amended to Version 4 to include pre-dose physical examinations 
at every treatment visit as in Version 3 (Germany) and to harmonize relevant regional 
feedback into a global amendment. 
Additional changes to the protocol, along with a rationale for each change, are 
summarized below: 
• 
The protocol has been expanded to include a primary progressive multiple sclerosis 
(PPMS) cohort and a relapsing multiple sclerosis (RMS) control arm.  The RMS 
delayed time to start control arm (Arm 4) has been added to the study for RMS 
patients who are willing to delay the first treatment with ocrelizumab for 12 weeks 
after the first lumbar puncture (LP) in cerebrospinal fluid.  Arm 4 will provide a 
control for Arm 1 of the RMS cohort.  Due to the relapsing and remitting nature of 
RMS, some biomarkers may change due to disease course rather than based on 
influence of a drug treatment.  Therefore, some biomarkers may “regress to the 
mean” across the disease course over time, and this change could then inaccurately 
be reported as a change due to drug treatment over time.  Arm 4 will allow for an 
estimate of the natural variability of the disease when analyzing the other treated 
arms.  The PPMS cohort has been added as an exploratory, hypothesis-generating 
part of the trial because less is known about PPMS biomarkers.  Multiple sections 
have been revised to include the PPMS cohort and RMS control arm, including the 
following:    
– 
The Study Rationale and Benefit-Risk Assessment section (Section 1.3) has 
been updated to include information regarding the benefit-risk profile of PPMS, 
according to a pivotal Phase III study of ocrelizumab. 
– 
The study objectives and endpoints (Section 2), as well as the study analyses 
(Section 6.4), have been updated to pertain to the RMS cohort, including 
specific information regarding the RMS control arm, and to the PPMS cohort. 


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– 
The Description of the Study section (Section 3.1) has been updated to include 
information on the PPMS cohort, such as the different dosing regimen and 
timing of LPs; to include information on the RMS control arm, such as the 
delayed dosing regimen and timing of LPs; and to and clarify the overall study 
design. 
– 
The End of Study and Length of Study section (Section 3.2) has been updated 
to account for the extended time period of the RMS control arm (Arm 4). 
– 
The Rationale for Ocrelizumab Dose and Schedule section (Section 3.3.1) and 
the Dosage, Administration, and Compliance section (Section 4.3.2) have been 
updated to include the different dosing regimen for the PPMS cohort.  
– 
The patient population has been updated to reflect the estimated number of 
patients to be included in the study with the addition of the RMS control arm 
and the PPMS cohort (Section 4.1). 
– 
The inclusion and exclusion criteria (Sections 4.1.1 and 4.1.2, respectively) 
have been expanded to include information pertaining to the RMS cohort 
(including the RMS control arm) and the PPMS cohort and have been 
reorganized by general criteria, RMS-specific criteria, and PPMS-specific 
criteria. 
– 
The Method of Randomization section (Section 4.2) has been renamed to 
Method of Determination of the Time of Lumbar Puncture to more accurately 
describe the section, which has been expanded to include details about 
randomization of the RMS cohort and to indicate that the singular PPMS cohort 
will not be randomized. 
– 
The Study Assessments section (Section 4.5) has been revised to indicate that 
assessments apply to the RMS cohort as specified in Appendix 1 for Arms 1−3 
and Appendix 2 for Arm 4, as well as to the PPMS cohort as specified in 
Appendix 3. 
– 
The 25-foot walk test and 9-hole peg test have been added to the neurological 
examinations performed only for the PPMS cohort (Section 4.5.6 and 
Appendix 3). 
– 
Section 5.3.5.8 (Deaths) has been updated to specify reporting requirements 
for deaths due to MS instead of RMS in order to account for the PPMS cohort. 
– 
The Statistical Considerations and Analysis Plan (Section 6) has been updated 
to clarify analyses that pertain to the RMS cohort (including the RMS control 
arm) and to the PPMS cohort. 
– 
Schedules of activities have been added for the RMS control arm (Appendix 2) 
and for the PPMS cohort (Appendix 3). 
• 
The Post-Trial Access to Ocrelizumab section (Section 4.3.6) has been revised to 
allow for possible post-trial access to ocrelizumab under the Roche Global Policy on 
Continued Access to Investigational Medicinal Product. 


Ocrelizumab—Genentech, Inc. 
4/Protocol ML29966, Version 4 (Global) 
• 
The Concomitant Therapy section (Section 4.4) has been updated to reflect that 
concomitant therapy is any medication used from 4 weeks prior to screening until 
study completion instead of 7 days prior to the initiation of study drug until study 
completion and to clarify that medications used after treatment discontinuation 
should be recorded during the Safety Follow-Up Period. 
• 
The Permitted Therapy section (Section 4.4.1) has been revised to include IV or oral 
corticosteroids and to specify that patients who experience a relapse and are 
treated with IV or oral corticosteroids should not discontinue treatment with 
ocrelizumab solely based on the occurrence of a relapse, unless he or she meets 
withdrawal criteria.  
• 
The Medical History and Demographic Data section (Section 4.5.2) has been 
revised to clarify that use of any previous medication for MS should be reported.  
• 
Sections 4.5.4 (Vital Signs) and 4.5.8 (Laboratory, Biomarker, and Other Biological 
Samples) have been revised to align with the current ocrelizumab program.  
Section 4.5.9 (Electrocardiograms) has been deleted for program alignment. 
• 
Section 4.6.1 (Criteria for Re-Treatment with Ocrelizumab) has been added to 
specify that treatment with ocrelizumab should be suspended prior to re-dosing until 
certain conditions are resolved.  
• 
Section 4.6.3 (Study Treatment Discontinuation) has been revised to indicate that, 
although pregnancies will be followed after study treatment discontinuation, infants 
born to patients or their partners will not be followed until 1 year of age, as such 
follow-up is not planned for this study. 
• 
The Risks Associated with Ocrelizumab section (Section 5.1.1) of the protocol has 
been revised to align with the Ocrelizumab Investigator’s Brochure, Version 14. 
• 
The Infusion-Related Reactions and Diagnosis versus Signs and Symptoms 
sections (Sections 5.3.5.1 and 5.3.5.2, respectively) have been updated to align with 
an administrative letter dated 7 April 2016. 
• 
Contact information for the Medical Monitor has been updated (Section 5.4.1). 
• 
Information for men in the study regarding their pregnant partners has been added 
back into the protocol for consistency with current safety recommendations (Section 
5.4.3.2). 
• 
The B-Cell Monitoring Schedule of Activities has been added for monitoring of 
patients with prolonged B-cell depletion after the Safety Follow-up Period 
(Appendix 8). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


Ocrelizumab—Genentech, Inc. 
5/Protocol ML29966, Version 4 (Global) 
PROTOCOL AMENDMENT, VERSION 4 (GLOBAL): 
SUMMARY OF CHANGES 
This Version 4 amendment consolidates elements of the previous country-specific 
amendment and revises the study design to include pre-dose physical examinations at 
every treatment visit.  The Summary of Changes for the previous amendment (i.e., 
Version 3 [Germany]) is listed in this section for the convenience of sites that did not 
receive this version of the protocol.  However, only Version 4 revisions are presented as 
italicized text in the body of the protocol. 
SUMMARY OF CHANGES:  VERSION 3 (GERMANY) 
APPENDIX 1:  Schedule of Assessments 
The schedule of assessments was revised to include pre-dose physical examinations at 
Week 3 and Week 48. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form was revised to reflect the changes to the protocol. 
SUMMARY OF CHANGES:  VERSION 4 (GLOBAL) 
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.3:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
This is an exploratory biomarker study designed to be hypothesis-generating in order to 
better understand the mechanism of action of ocrelizumab and B-cell biology in RMS 
and PPMS.     
Data from the two pivotal Phase III ocrelizumab RMS studies (WA21092 and WA21093) 
confirmed the favorable benefit-risk of ocrelizumab seen in the Phase II study 
(WA21493), and a pivotal Phase III ocrelizumab PPMS study (WA25046) demonstrated 
favorable benefit-risk profile in PPMS (see Section 1.2.1).  Together, these data 
demonstrate that ocrelizumab 600 mg administered every 6 months is effective and well 
tolerated in patients with PPMS or relapsing forms of MS. 
SECTION 2.1:  PRIMARY OBJECTIVES 
The primary objectives for the RMS cohort in this study are:  … 
SECTION 2.2:  EXPLORATORY OBJECTIVES 
The exploratory objectives for the PPMS cohort in this study are: 
• 
To understand the impact of ocrelizumab treatment on NfL as a biomarker of 
neuronal damage in CSF  
• 
To assess the number of CD19+ B cells in CSF (cell number/microliter) before and 
after treatment with ocrelizumab  


Ocrelizumab—Genentech, Inc. 
6/Protocol ML29966, Version 4 (Global) 
• 
To assess the number of CD3+ T cells in CSF (cell number/microliter) before and 
after treatment with ocrelizumab  
 
The exploratory objectives for both cohorts in this study are: 
• 
To understand the impact of ocrelizumab treatment on NfL and other biomarkers of 
neurodegeneration in CSF as a reflection of activity in the CNS and compared with 
peripheral blood 
• 
To measure the impact of ocrelizumab treatment on B cells/B-cell subsets, 
T cells/T-cell subsets, and other cell types (e.g., natural killer [NK] cells, monocytes, 
etc.), functional parameters of B/T/other cell types (activation, cell products), and 
other biomarkers of inflammation in CSF as a reflection of activity in the CNS and 
compared with peripheral blood 
• 
To assess potential correlation between change in blood or CSF biomarkers of 
neurodegeneration or inflammation and change in MRI or efficacy outcome 
measures, such as reduction in Gd-positive lesions or EDSS score 
 
Exploratory objectives for the RMS delayed time to start control arm (Arm 4) will 
include comparisons between Arm 1 of the RMS cohort (second LP at 12 weeks) and 
Arm 4 (second LP at 12 weeks before the first dose of study drug), and may include but 
not be limited to changes in CSF, blood, and MRI biomarkers or efficacy, as outlined 
above. 
SECTION 3.1:  DESCRIPTION OF THE STUDY 
This is an open-label, multicenter, biomarker study conducted at centers in multiple 
countries in which all eligible patients will be enrolled to a single treatment arm of 
ocrelizumab.  The study will include an RMS cohort and a PPMS cohort (see Table 1).  
The RMS cohort is the main cohort and will include the majority of study participants.  
The RMS cohort will be comprised of four arms, three of which will have patients 
randomized into one of three arms (Arms 1−3) depending on the time of their second 
lumbar puncture (LP).  In Arm 4, treatment with ocrelizumab will be delayed for 12 
weeks after the first LP.  The PPMS cohort will comprise a smaller, hypothesis-
generating portion of the trial, as less is known about PPMS biomarkers. 
Arm 4 will provide a control for Arm 1 of the RMS cohort.  Due to the relapsing and 
remitting nature of RMS, some biomarkers may change due to disease course rather 
than based on influence of a drug treatment.  Therefore, some biomarkers may “regress 
to the mean” across the disease course over time, and this change could then 
inaccurately be reported as a change due to drug treatment over time.  Arm 4 will allow 
for an estimate of the natural variability of the disease when analyzing the other treated 
arms.   
Male and female patients age 18−55 years with a diagnosis of RMS or PPMS in 
accordance with the 2010 revised McDonald criteria (Polman et al. 2011; Appendix 6) 
and an EDSS score of 0−5.5 points for RMS patients, or an EDSS score of 3.0−6.5 for 


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7/Protocol ML29966, Version 4 (Global) 
PPMS patients, at screening will be eligible.  Screening will occur over a 4-week period, 
after which eligible patients may begin treatment with ocrelizumab.   
Treatment with ocrelizumab will continue for 1 year after the first infusion, after which 
time patients may be eligible to enter an OLE phase and continue to receive treatment 
with ocrelizumab or to enter safety follow-up.  Alternatively, 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.   
For patients in the RMS cohort (Arms 1−3), Oocrelizumab will be administered at Week 
1, Week 3, Week 24, and Week 48.  The first dose will be administered as two infusions 
of 300 mg given on Day 1 (Week 1) and Day 15 (Week 3).  The subsequent doses will 
be given as single 600-mg infusions.  Patients will be evaluated for safety throughout the 
study.   
For patients in the RMS cohort (Arm 4), after receiving two LPs at Week −12 and Week 
1, the first dose of ocrelizumab will be administered as two 300-mg infusions on Week 1 
(Day 1) and Week 3 (Day 15), with subsequent doses given as single 600-mg infusions 
at Weeks 24 and 48.  The timeline for Arm 4 will continue for an extra 12 weeks to 
accommodate the same one-year dosing regimen.   
For patients in the PPMS cohort, ocrelizumab 600 mg will be administered as two 
300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks (see 
Appendix 3). 
Treatment with ocrelizumab will continue for approximately 1 year after the first 
infusion; however, 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.  Patients may be eligible to continue to receive treatment if ocrelizumab is 
not commercially available in the patient’s country or is not reasonably accessible to the 
patient (see Section 4.3.6), and these patients will continue to be followed.   
Ocrelizumab pPatients who complete the 52-week period of the study (64 weeks for 
patients in Arm 4) and choose not to continue with an OLEon ocrelizumab treatment, or 
ocrelizumab patients who discontinue from treatment early, should enter the Safety 
Follow-up Period and be assessed every 24 weeks for 48 weeks counting from the date 
of the last infusion of the ocrelizumab or until B cells return to baseline level or the lower 
limit of normal, whichever occurs first.  At the end of this periodAfter 48 weeks, if the 
peripheral blood B-cell count remains depleted, monitoring of the patient should continue 
at 24-week intervals until the B-cell count has returned to the baseline value or to the 
lower limit of the normal range, whichever is the lower (see Appendix 8).   


Ocrelizumab—Genentech, Inc. 
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Patients who choose to receive commercially available ocrelizumab will not be followed 
for safety. 
Biomarkers will be monitored in a longitudinal fashion before and after treatment with 
ocrelizumab in order to assess dynamic changes in biomarkers as they relate to drug 
exposure, length of time on drug, response to drug, and MS disease pathogenesis.  
Biomarkers will be assessed via blood draws throughout the study and via LP in CSF 
from LP at baseline before the first dose of ocrelizumab and at one other timepoint.   
Two LPs will be drawn from each patient during the study.  … 
All pPatients in the RMS cohort (Arms 1−3) will receive an LP before the start of dosing 
with ocrelizumab.  Subsequently, these patients will be randomized into one of three 
groups arms for timing of the second LP, either Week 12, 24, or 52 following the first 
dose of ocrelizumab.  Any additional LPs will be optional.   
Patients in Arm 4 will receive two LPs, separated by a 12-week interval, before 
administration of the first dose of ocrelizumab.  Patients in this arm will be asked if 
they are willing to give an optional CSF sample via LP 12 weeks after the ocrelizumab 
dose.     
Patients in the PPMS cohort will receive an LP at the start of the study before dosing 
with ocrelizumab.  Subsequently, they will receive a second LP at Week 52 following 
the first dose of ocrelizumab.   
In the case of MS relapse or worsening (for PPMS patients) during the study, the 
patient should have an unscheduled visit and will be asked to receive an optional LP at 
the time of relapse or worsening (for PPMS patients).  The patient will have another LP 
at the originally scheduled time based on their randomization, or if a relapse occurs after 
they have already given the second LP, the relapse LP will remain optional.   
All pPatients will be evaluated for safety throughout the study.   
… 
A schedule of activitiesstudy schema the RMS cohort Arms 1−3  is provided in Figure 1, 
for the RMS cohort Arm 4 is provided in Figure 2, and for the PPMS cohort is provided 
in Figure 3.  Organization of study cohorts and overall study design is provided in 
Table 1.  
FIGURE 1:  Study Schema:  RMS Cohort Arms 1−3  
Figure 1 has been revised to pertain only to the RMS cohort. 


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FIGURE 2:  Study Schema:  RMS Cohort Arm 4  
Figure 2 has been added to include information about the newly added RMS control arm 
(Arm 4).   
FIGURE 3:  Study Schema:  PPMS Cohort 
Figure 2 has been added to include information about the newly added PPMS cohort.   
TABLE 1:  Study Cohorts and Overall Design 
Table 1 has been added to clarify the study design, which includes the RMS control arm 
(Arm 4) and the PPMS cohort.  Subsequent tables have been renumbered accordingly. 
SECTION 3.2:  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.  LPLV is expected to occur 
approximately 52 weeks after the last patient is enrolled, excluding any follow-up.  
The total length of the study is expected to be approximately 2.53.5 years from the first 
patient enrolled to LPLV, excluding any follow-up.  Patients may be consented for 
participation in an OLE phase if, in the opinion of the investigator, they may benefit from 
treatment with ocrelizumab.  The OLE phase would continue until the Sponsor decides 
to terminate the ocrelizumab program.  
SECTION 3.3.1:  Rationale for Ocrelizumab Dose and Schedule 
The dose level of ocrelizumab administered in this study is 600 mg.  The first dose will 
be administered as two 300-mg IV infusions separated by 14 days in order to lower 
amount of ocrelizumab administered upon first exposure.  For the RMS cohort, tThe 
remaining doses will be administered as single 600-mg doses every 24 weeks.  For the 
PPMS cohort, ocrelizumab will be administered as two 300-mg IV infusions separated 
by 14 days at a scheduled interval of every 24 weeks during the treatment period.  
This dosing regimen is anticipated to be well tolerated and is consistent with the dosing 
regimen used in Study WA21092 and WA21093 in patients with RMS and in Study 
WA25046 in patients with PPMS (see Section 1.2.1). 
SECTION 4.1:  PATIENTS 
Approximately 104 patients will be enrolled in this study; 88 patients with RMS and 
16 patients with PPMS.Approximately 99 patients with RMS will be enrolled in this 
study.  
SECTION 4.1.1:  Inclusion Criteria 
General Inclusion Criteria 
Patients must meet the following criteria for study entry: … 
 
Inclusion Criteria Specific to RMS Patients… 
 


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Inclusion Criteria Specific to RMS Cohort Arm 4 Patients 
• 
Must meet inclusion criteria for the RMS cohort  
• 
Separate signed Informed Consent Form for the RMS Delayed Time to Start 
Control Arm (Arm 4) 
• 
Must be willing to remain on the same dose and regimen of current standard of 
care, or no treatment if treatment-naïve, for 12 weeks after study enrollment 
– 
The treating and/or study physician must agree that the patient is eligible to 
remain on the same dose and regimen of their current standard of care at 
screening, or to receive no treatment if the patient is treatment-naïve, for 
12 weeks after study enrollment. 
 
Inclusion Criteria Specific to PPMS Patients 
• 
Diagnosis of PPMS in accordance with the 2010 revised McDonald criteria 
(Pollman et al. 2011; Appendix 7)  
• 
EDSS score of 3.0 − 6.5 points, inclusive, at screening 
• 
Disease duration from the onset of MS symptoms: 
– 
Less than 10 years in patients with an EDSS at screening ≤ 5.0  
• 
Documented history of at least one of the following laboratory findings in CSF: 
– 
Elevated IgG Index 
– 
One or more IgG OCBs detected by isoelectric focusing 
 
SECTION 4.1.2:  Exclusion Criteria 
General Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Diagnosis of secondary progressive MS (without relapses for at least 1 year) 
• 
Certain laboratory abnormalities or findings at screening, including the following:  
 
Serum IgG 18% below the lower limit of normal (LLN) 
 
Serum IgM 8% below the LLN 
 
Positive rapid plasma reagin (RPR), confirmed by microhemagglutination assay 
(MHA-TP) or fluorescent treponemal antibody absorption (FTA-ABS) test 
 
Serum creatinine > 1.4 mg/dL (> 124 μmol/L) for women or > 1.6 mg/dL 
(> 141 μmol/L) for men 
 
Hemoglobin < 8.5 g/dL (< 5.15 mmol/L) 
– 
Abnormal lymphocyte count (below LLN) 
Re-testing before baseline:  in rare cases in which the screening laboratory 
samples are rejected by the laboratory (e.g., hemolyzed sample) or the results 
are not assessable (e.g., indeterminate) or abnormal, the tests need to be 
repeated within 4 weeks.  Any abnormal screening laboratory value that is 
clinically relevant should be retested in order to rule out any progressive or 
uncontrolled underlying condition.  The last value before randomization must 


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meet study criteria.  In such circumstances, the screening period may need to 
be prolonged but should not exceed 8 weeks. 
 
Exclusion Criteria Specific to RMS Patients 
• 
Diagnosis of PPMS or SPMS without relapses 
 
SECTION 4.2:  METHOD OF RANDOMIZATION FOR LUMBAR 
PUNCTUREMETHOD OF DETERMINATION OF THE TIME 
OF LUMBAR PUNCTURE 
Patients in Arms 1 − 3 of the RMS cohort will be randomized into each of the three 
groups arms at 1:1:1 ratio according to the timing of the second LP at Week 12, 24, or 
52 following the first dose of ocrelizumab (see Table 1).  An independent interactive 
voice/web response system (IxRS) provider will conduct randomization and maintain the 
treatment assignment code.  Enrolled patients will be stratified by the previous 
disease-modifying therapy (DMT) treatment status (DMT-naïve vs. DMT-experienced).  
Therefore, the proportion of DMT-naïve patients will be approximately equal in each of 
three groupsarms.   
A fourth RMS arm with delayed treatment start (Arm 4) will not be a part of the 
randomization and will be recruited separately.   
All patients in the PPMS cohort will receive the second LP at 52 weeks and therefore 
will not be randomized.   
Enrollment of the PPMS cohort and/or the RMS control arm (Arm 4) is open to all 
sites choosing to participate.   
SECTION 4.3.2.1:  Ocrelizumab 
For the RMS cohort, dDose 1 of ocrelizumab will be administered as two 300-mg IV 
infusions (600 mg total) separated by 14 days (i.e., Day 1 [Week 1] and Day 15 [Week 
3]).  Subsequent doses will be administered as one 600 mg IV infusion every 24 weeks 
for a maximum of 3 doses (see Table 2).   
For the PPMS cohort, ocrelizumab 600 mg will be administered as two 300-mg IV 
infusions separated by 14 days at a scheduled interval of every 24 weeks (see Table 3).     
Although ocrelizumab may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator.  Ocrelizumab infusions 
should always be administered in a hospital or clinic environment under close 
supervision of the investigator or a medically qualified staff member.  It is anticipated 
that the patient will need to stay at the hospital or clinic for a full day for the infusion 
visits. 


Ocrelizumab—Genentech, Inc. 
12/Protocol ML29966, Version 4 (Global) 
An overview of the ocrelizumab dosing is presented in Table 2 and Table 3.  The 
ocrelizumab infusions will be administered per the instructions outlined in Table 4 and 
Table 5. 
TABLE 2:  Overview of Ocrelizumab Dosing:  RMS Cohort 
Table 2 has been revised to pertain only to the RMS cohort. 
TABLE 3:  Overview of Ocrelizumab Dosing:  PPMS Cohort 
Table 3 has been added to include information about the PPMS cohort.   
TABLE 4:  Infusion Rates for 300-mg and 600-mg Ocrelizumab Infusions:  
RMS Cohort 
Table 4 has been deleted, as information was outdated. 
TABLE 5:  Infusion Rates for 300-mg Ocrelizumab Infusions:  PPMS Cohort 
Table 5 has been deleted, as information was outdated. 
SECTION 4.3.6:  Post-Trial Access to Ocrelizumab 
 The Sponsor (Genentech, a member of the Roche Group) will offer post-trial access to 
the study drug (ocrelizumab) free of charge to eligible patients in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, as 
outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after completing the study if any of 
the following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for MS 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for MS 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 


Ocrelizumab—Genentech, Inc. 
13/Protocol ML29966, Version 4 (Global) 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide ocrelizumab or any other study treatments or interventions to patients 
who have completed the study in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
SECTION 4.4:  CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days4 weeks prior to initiation of study drugscreening to the study 
completion/discontinuation visit.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF. 
Medications used after treatment discontinuation should be recorded during the Safety 
Follow-up Period. 
SECTION 4.4.1:  Permitted Therapy 
• 
IV or oral corticosteroids 
– 
Patients who experience a relapse may receive treatment with IV or oral 
corticosteroids, if judged to be clinically appropriate by the investigator. Such 
patients should not discontinue treatment solely based on the occurrence of a 
relapse, unless the patient or investigator feels he or she has met the criteria 
for withdrawal (Section 4.6.3). 
 
SECTION 4.5:  STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of activities performed during the studyfor the 
RMS cohort Arms 1−3, Appendix 2 for the schedule of activities for the RMS cohort 
Arm 4, and Appendix 3 for the schedule of activities for the PPMS cohort. 
SECTION 4.5.2:  Medical History and Demographic Data 
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, use of any previous MS medication 
should be recorded.  
SECTION 4.5.4:  Vital Signs 
Vital signs should be performed at all visits.  Vital signs will include the measurements of 
respiratory rate, heart rate, systolic and diastolic blood pressure, and oral or auricular 
temperature while the patient is in a seated position. 


Ocrelizumab—Genentech, Inc. 
14/Protocol ML29966, Version 4 (Global) 
Vital signs should be taken within 45 minutes prior to the premedication 
methylprednisolone infusion.  In addition, vital signs should be obtained prior to the 
ocrelizumab infusion then every 15 minutes (± 5 minutes) for the first hour, followed by 
every 30 minutes (± 10 minutes) until 1 hour after the end of the infusion.  
SECTION 4.5.5:  Assessment of Disability 
Disability in MS will be measured by the EDSS, which will be assessed by a certified 
independent assessor at timepoints according to the appropriate schedule of activities 
at screening; baseline; Weeks 12, 24, 48, 52; in the case of relapse or early termination; 
and during safety follow-up.   
SECTION 4.5.6:  Neurological Examinations 
Neurological examinations will be performed at timepoints according to the appropriate 
schedule of activitiesat screening; baseline; Weeks 12, 24, 48, 52; and in the case of 
relapse or early termination so that the investigator can assess whether the patient is 
experiencing a relapse of MS or another neurological (non-MS) disorder. 
For patients in the PPMS cohort, disease worsening or improvement over the treatment 
period will also be assessed and is defined as a 20% change in timed 25-foot walk test or 
a 20% change in 9-hole peg test time (see Appendix 3). 
SECTION 4.5.7:  Brain Magnetic Resonance Imaging 
MRI scans will be read by a centralized reading center for both efficacy and safety 
endpoints.  Further details on scanning acquisition sequences, methods, handling, 
transmission of the scans, and certification of site MRI radiologist/techniciansscanner are 
described in a separate MRI technical manual. 
SECTION 4.5.8:  Laboratory, Biomarker, and Other Biological Samples 
Pre-infusion laboratory samples should may be drawn up to 14 days before the start of 
infusion so that routine laboratory test results are available for review before the infusion, 
unless otherwise specified.   
• 
Urinalysis Urine dipstick (standard to assess kidney function) 
• 
Viral serology 
 
RPR assessment (must be negative for syphilis) 
 
In the case of suspected PML, serum or plasma biomarker, PK, or ADA samples may be 
used to assess status of JC virus (JCV) antibodies. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Fluoroscopy can be used, if required, for the LP to draw the CSF.  
SECTION 4.5.9:  Electrocardiograms 
Twelve-lead electrocardiogram (ECG) measurements must be obtained at screening 
and when clinically indicated.  ECG recordings must be performed after the patient has 


Ocrelizumab—Genentech, Inc. 
15/Protocol ML29966, Version 4 (Global) 
been resting in a supine position for at least 10 minutes and obtained from the same 
machine whenever possible.  All ECG tracings should be printed and kept with the 
patient’s record.  For safety monitoring purposes, the investigator must review, sign, and 
date all ECG tracings.  
SECTION 4.6.1:  Criteria for Re-Treatment with Ocrelizumab 
Prior to re-treatment with ocrelizumab, patients will be evaluated for the following 
conditions and laboratory abnormalities.  If any of these are present prior to re-dosing, 
further administration of ocrelizumab should be suspended until these are resolved or 
held indefinitely: 
• 
Life-threatening (Grade 4) infusion-related event that occurred during a previous 
ocrelizumab infusion 
• 
Any significant or uncontrolled medical condition or treatment-emergent, 
clinically significant laboratory abnormality 
• 
Active infection 
• 
Ongoing pregnancy 
 
In addition to the criteria above, patients with PPMS will also be evaluated for: 
• 
 ANC < 1.5 × 103/μL 
 
SECTION 4.6.3:  Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Ongoing pregnancy:  Please note that the pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of birth, 
and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and newborn complications.  The health status of any infant born to 
patients or their partners may be followed until the child is 1 year of age. 
 
SECTION 5.1:  SAFETY PLAN 
Safety assessments will include the incidence, nature, and severity of (serious) adverse 
events graded per the NCI CTCAE v4.0.  Safety assessments will be conducted for the 
RMS cohort Arms 1− 3 per the schedule of activities in Appendix 1, for the RMS cohort 
Arm 4 per the schedule of activities in Appendix 2, and for patients in the PPMS cohort 
per the schedule of activities in Appendix 3. 
SECTION 5.1.1:  Risks Associated with Ocrelizumab 
5.1.1.1 Selected Adverse Events 
5.1.1.1.1 
Infusion-Related Reactions 
Studies WA21092 and WA21093 
IRRs were the most common adverse event in patients treated with ocrelizumab 600 mg, 
and the proportion of patients experiencing IRRs was higher in the ocrelizumab 600 mg 
group (34.3%) compared with IFN β 1a treatment group (9.7%).  The rate of IRRs was 


Ocrelizumab—Genentech, Inc. 
16/Protocol ML29966, Version 4 (Global) 
highest during the first infusion of Dose 1 (27.5%) and decreased over time (13.7%, 
9.6%, and 7.8% during Dose 2, 3, and 4, respectively).   
The majority of IRRs in both treatment groups were of Grade 1 or 2.  One patient in the 
IFN β 1a group had an IRR of Grade 3 (associated with first infusion).  There were 
20 patients in the ocrelizumab group who experienced a Grade 3 IRR (14 associated 
with first infusion of the first dose, although Grade 3 events occurred with the second 
and third doses). 
Two serious IRRs were reported.  One patient in the IFN β 1a group had a Grade 3 IRR 
in association with the initial infusion of ocrelizumab placebo.  Symptoms in this patient 
included balance disorder, dizziness, flushing, and hypoaesthesia.  The second serious 
IRR (Grade 4) was reported in association with the initial ocrelizumab infusion.  
Bronchospasm was reported as the IRR symptom.  This event was the only serious IRR 
associated with ocrelizumab infusion reported in studies WA21092 and WA21093. 
During the controlled treatment period, all patients received methylprednisolone (or 
equivalent) as pre treatment prior to all ocrelizumab/placebo infusions.  The majority of 
infusions were also preceded by analgesic/antipyretic and oral antihistamine treatments, 
as recommended.  In patients receiving ocrelizumab, the addition of oral antihistamine to 
methylprednisolone pretreatment for each infusion further decreased the rate of IRRs 
compared to pretreatment with methylprednisolone alone. 
Study WA25046 
IRRs were the most frequently reported adverse events in patients treated with 
ocrelizumab.  The proportion of patients who reported an IRR was higher in the 
ocrelizumab group (39.9%) compared with placebo (25.5%).  The proportion of patients 
who experienced an IRR was highest after the first infusion, with 1 patient withdrawing 
from ocrelizumab treatment at this time.  The proportion of patients experiencing an IRR 
was lower at subsequent infusions.  Overall, 5 patients (1.0%) experienced a serious 
IRR in the ocrelizumab group. 
Study WA21493 
The proportion of patients reporting IRRs was higher in ocrelizumab treated patients 
after the first infusion on Day 1 of the study (9.3% in placebo arm, 34.5% in the 
300 mg × 2 arm, and 43.6% in the 1000 mg × 2 arm).  The percentage of patients 
experiencing IRRs was lower after the second infusion on Day 15 compared with the first 
infusion in the ocrelizumab arms only (11.1% in placebo arm, 3.8% in the 300 mg × 2 
arm, and 9.4% in the 1000 mg × 2 arms).  Most IRRs (> 90%) were of mild to moderate 
intensity (Grades 1 and 2).  


Ocrelizumab—Genentech, Inc. 
17/Protocol ML29966, Version 4 (Global) 
5.1.1.1.2 
Infections 
Studies WA21092 and WA21093 
All Infections 
The percentage of patients experiencing an infection was higher in the pooled 
ocrelizumab treatment group (58.4%) compared with the pooled IFN β 1a treatment 
group (52.4%).  The number of infections reported was also higher in the ocrelizumab 
treatment group (1224 events) than in the IFN β 1a treatment group (948 events).  This 
difference was primarily driven by more patients with upper respiratory tract infections, 
as well as bronchitis, in the ocrelizumab group.  In addition, the rate of herpes 
virus associated infections was also higher in the ocrelizumab treatment group, although 
the overall rate was low.   
The majority of infections were classified by the investigators as Grade 1 or 2 in intensity.  
Thirty one patients in the IFN β 1a group (3.89%) and 24 patients in the ocrelizumab 
group (2.9%) experienced a Grade 3 infection.  Two patients in the ocrelizumab group 
(0.2%) reported an infection of Grade 4 intensity, “biliary sepsis” and “appendicitis.”  No 
fatal infections (Grade 5) were reported during the controlled treatment period. 
No opportunistic infections were reported during the controlled treatment period, despite 
a broad screening that mostly retrieved herpes virus related infections that did not 
present any particular pattern. 
Serious Infections 
The proportion of patients with serious infections was overall low, and was lower in the 
ocrelizumab group (1.3%) than in the IFN β 1a group (2.9%).   
The serious infection profile observed with increased exposure to ocrelizumab was 
similar to that in the treatment controlled period with regard to incidence, type, and 
severity. 
Study WA25046 
The proportion of patients with adverse events or serious adverse events of infection 
was similar in both the placebo and ocrelizumab groups.  The proportion of patients who 
experienced an infection was 69.8% in the ocrelizumab group compared with 67.8% in 
the placebo group.  The most frequently reported adverse events of infection were 
nasopharyngitis and urinary tract infection.  The proportion of patients who experienced 
a serious infection was 6.2% in the ocrelizumab group compared with 5.9% in the 
placebo group.  
Study WA21493 
On review of the double blinded, 24 week safety data in Study WA21493, no imbalance 
in the overall number of infections or serious infections between placebo and active 
ocrelizumab arms was observed.  The rate of infections remained consistent throughout 


Ocrelizumab—Genentech, Inc. 
18/Protocol ML29966, Version 4 (Global) 
the study, including the treatment period (up to Week 96) and the treatment free period 
(up to Week 144).  
5.1.1.1.3 
Malignancies 
In the MS program (studies WA21493, WA21092, WA21093, and WA25046) there were 
20 malignancies in 18 patients receiving ocrelizumab (Table 6). 
Table 6 Summary of Malignancies in the Multiple Sclerosis Studies 
 
Placebo 
IFN 
OCR 
600 mg 
OCR Total Events  
Study WA21493 
 
 
 
 
n 
 
   
 
  
220 
 
Total number of events  
 
  
 
  
1 
1 
Total number of patients 
 
  
 
  
1 a 
 
Studies WA21092 and 
WA21093 b 
 
 
 
 
n 
 
  
826 
825 
 
Total number of events 
 
  
2 
6 
6 
Total number of patients 
 
  
2 
6 
 
Study WA25046 
 
 
 
 
n 
239 
 
  
486 
 
Total number of events 
2 
 
  
13 
13 
Total number of patients 
2 
 
  
11 
 
Overall number of events in 
ocrelizumab patients in studies 
WA21493, WA21092, WA21093, 
and WA25046 
 
 
 
20 
IFN = interferon; OCR = ocrelizumab; OLE = open label extension. 
a Patient received 1000 mg of ocrelizumab. 
b Includes controlled treatment period and OLE up to the clinical cutoff dates.  As of 
31 October 2015, an additional malignancy (malignant melanoma) was reported in an 
ocrelizumab patient in Study WA21092 after the clinical cutoff date for this study. 
 
Studies WA21092 and WA21093 
During the 96 week controlled treatment period, a total of 6 malignancies were reported; 
2 events (1 mantle cell lymphoma and 1 squamous cell carcinoma) occurred in 
2 patients (0.2%) in the IFN β 1a treatment group and 4 events (2 invasive ductal breast 
carcinoma, 1 renal cancer, and 1 malignant melanoma) occurred in 4 patients (0.5%) in 
the ocrelizumab treatment group.   
There were 2 additional malignancies in Study WA21092 during the open label 
extension (1 adenocarcinoma of the colon in a patient initially in the IFN β 1a group and 
1 thyroid cancer in a patient initially in the ocrelizumab group). 


Ocrelizumab—Genentech, Inc. 
19/Protocol ML29966, Version 4 (Global) 
Study WA25046 
A total of 15 malignancies in 13 patients were reported (Table 7):  2 events (basal cell 
carcinoma and adenocarcinoma of the cervix) occurred in 2 patients (0.8%) in the 
placebo group and 13 events (5 basal cell carcinoma, 2 invasive ductal breast 
carcinoma, 1 anaplastic large cell lymphoma, 1 breast cancer, 1 endometrial cancer, 
1 invasive breast carcinoma, 1 malignant fibrous histiocytoma, 1 pancreatic carcinoma 
metastatic) occurred in 11 patients (2.3%) in the ocrelizumab group. 
Table 7 
Malignancies by Body System Class and Preferred Term.  Controlled 
Treatment Period, Safety-Evaluable Population 
MedDRA System Organ Class 
MedDRA Preferred Term 
Placebo 
N = 239 
OCR 600 mg
N = 486 
Total number of patients with at least one adverse event 
2 (0.8%) 
11 (2.3%) 
Overall total number of events 
2 
13 
Neoplasms Benign, Malignant and Unspecified (Incl Cysts 
and Polyps) 
 
 
Total number of patients with at least one adverse event 
2 (0.8%) 
11 (2.3%) 
Overall total number of events 
2 
13 
Basal cell carcinoma 
1  
5  
Invasive ductal breast carcinoma 
0 
2  
Adenocarcinoma of the cervix 
1  
0 
Anaplastic large cell lymphoma 
0 
1  
Breast cancer 
0 
1  
Endometrial cancer 
0 
1  
Invasive breast carcinoma 
0 
1  
Malignant fibrous histiocytoma 
0 
1  
Pancreatic carcinoma metastatic 
0 
1  
MedDRA = Medical Dictionary for Regulatory Activities; OCR = ocrelizumab. 
Note:  Multiple occurrences of the same adverse event in one patient are counted multiple 
times.  Malignancies are identified using adverse events falling into the MedDRA System Organ 
Class “Malignant Tumours (narrow).” 
 
Study WA21493 
There was one malignancy (breast cancer) reported in Study WA21493 in the 
ocrelizumab group.  An additional malignancy of squamous cell carcinoma occurred 
2 days prior to the patient receiving ocrelizumab. 
5.1.1.2 Identified Risks and Adverse Drug Reactions 
This section refers to adverse events considered, after routine/ongoing medical 
evaluation, to be adverse drug reactions (ADRs) to the medical product at the present 
stage of development.  A summary of identified risks in MS is presented in Table 8, and 
serious ADRs to ocrelizumab in MS are presented in Table 9. 


Ocrelizumab—Genentech, Inc. 
20/Protocol ML29966, Version 4 (Global) 
Table 8 Summary of Identified Risks in Multiple Sclerosis 
Risk 
Description of Risk 
Infusion related 
reactions 
In the ocrelizumab group, the most frequently reported AE was 
IRR, and as expected, the percentage of patients experiencing 
IRRs was higher in the ocrelizumab group (RMS:  34.3%; PPMS:  
39.9%) compared with the active control group who received 
placebo infusions (RMS:  9.7%; PPMS:  25.5%).  These IRRs were 
reported more frequently with the first infusion of Dose 1 (approx. 
27.5% in both RMS and PPMS), and were primarily 
mild to moderate in severity (NCI CTCAE Grades 1 and 2).  
Serious IRR occurred in 0.1% and 1.0% of patients, respectively, 
with RMS and PPMS and treated with ocrelizumab.  IRRs are 
manageable through premedication before each infusion (100 mg 
of IV methylprednisolone or equivalent is mandatory, 
anti histaminics are recommended, and analgesics/antipyretics 
considered), as well as by infusion adjustments (slowing or 
interrupting) and symptomatic treatment (e.g., 
acetaminophen/paracetamol, intramuscular or slow IV 
antihistamine administration, bronchodilators). 
Infections 
In the pooled dataset of the pivotal Phase III trials in RMS 
population, the percentage of patients experiencing an infection 
was higher in the pooled ocrelizumab treatment group (58.4%) 
compared with the pooled IFN β 1a treatment group (52.4%).  This 
difference was primarily driven by more patients with upper 
respiratory tract infections in the ocrelizumab group, as well as 
bronchitis and herpes virus associated infections.  The majority of 
infections were classified by the investigators as Grade 1 or 2 in 
intensity.   
The proportion of patients with serious infections was overall low, 
and was lower in the ocrelizumab group (1.3%) than in the IFN β 1a 
group (2.9%).  The serious infection profile observed with increased 
exposure to ocrelizumab was similar to that in the treatment 
controlled period with regard to incidence, type, and severity. 
 
In the PPMS population, the proportion of patients with AEs or 
SAEs of infection was similar in both the placebo and ocrelizumab 
groups.  The proportion of patients who experienced an infection 
was 69.8% in the ocrelizumab group compared with 67.8% in the 
placebo group. The most frequently reported AEs of infection were 
nasopharyngitis and urinary tract infection.  The proportion of 
patients who experienced a serious infection was 6.2% in the 
ocrelizumab group compared with 5.9% in the placebo group.  All 
individual SAEs of infection were reported in fewer than 1% of 
patients in any group, with the exception of pneumonia (placebo 
0.8% vs. OCR 1.2%) and urosepsis (placebo 1.3% vs. OCR 0.4%). 
 


Ocrelizumab—Genentech, Inc. 
21/Protocol ML29966, Version 4 (Global) 
Risk 
Description of Risk 
Decrease in 
immunoglobulins 
Treatment with ocrelizumab resulted in a decrease in total 
immunoglobulins over 2 years, mainly driven by reduction in IgM, 
with no apparent association with serious infections. 
The proportion of patients treated with ocrelizumab in the RMS 
program with immunoglobulins levels below the LLN was 2.4% for 
IgA, 1.5% for IgG, and 16.5% for IgM.  The proportion of patients 
with decrease in immunoglobulins below LLN increased over time 
and successive dosing.  
The proportion of patients treated with ocrelizumab in the PPMS 
study with immunoglobulin levels below the LLN was 0.5% for IgA, 
1.1% for IgG, and 15.5% for IgM. 
Delayed return of 
peripheral B cells 
Treatment with ocrelizumab leads to rapid depletion of 
CD19+  B cells in blood by 14 days post treatment (first timepoint of 
assessment) as an expected pharmacologic effect.  This was 
sustained throughout the treatment period.  The longest follow up 
time 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).   
AE = adverse event; IFN = interferon; IRR = infusion related reaction; IV = intravenous; LLN = lower 
limit of normal; PPMS = primary progressive multiple sclerosis; NCI CTCAE = National Cancer 
Institute Common Terminology Criteria for Adverse Events; RMS = relapsing forms of multiple 
sclerosis; SAE = serious adverse event. 
 
Table 9 Serious Adverse Drug Reactions to Ocrelizumab in Multiple Sclerosis 
Risk 
Notes/Exclusions 
IRRs 
excluding fatal outcome 
Infections a 
excluding fatal outcome 
IRR = infusion related reaction. 
Note:  Any term covered by the medical concepts presented in this list is considered 
“expected” for both non serious and serious reports of suspected unexpected adverse drug 
reactions to health authorities, excluding events with fatal outcome unless detailed otherwise in 
the table. 
a Data not supportive of increased risk compared to placebo/IFN β 1a across all indications.  
Classification for reporting purposes only.  
 
5.1.1.2.1 
Serious Infections 
Serious infections are not considered preliminary ADRs to date since no increase in 
individual serious infections was observed in the ocrelizumab treatment group in the MS 
population.  However, for regulatory purposes only, serious infections will be considered 
as expected ADRs. 
Prolonged peripheral B-cell depletion is the expected outcome of ocrelizumab treatment.  
Infection is a potentially serious complication of B-cell depleting therapy and thus 


Ocrelizumab—Genentech, Inc. 
22/Protocol ML29966, Version 4 (Global) 
requires vigilant attention and prompt investigation and treatment in patients that exhibit 
signs of infection at any time following anti-CD20 antibody therapy.   
Based on the available data from the completed controlled and ongoing open-label 
extension periods of the MS clinical program, the rate of serious infections in patients 
treated with ocrelizumab was low (2.32 per 100 patient years [PY]).  In RMS patients, 
the rate of serious infections in the IFN group was higher (2.43 per 100 PY) than in the 
OCR group (1.24 per 100 PY).  The rate of serious infections in PPMS patients was 
balanced between the placebo (4.24 per 100 PY) and OCR (3.74 per 100 PY) groups 
(see the Ocrelizumab Investigator’s Brochure for further details). 
Serious, opportunistic and fatal infections have occurred in patients with lupus and RA 
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 MS patient treated with ocrelizumab 
(see the Ocrelizumab Investigator’s Brochure for further details). 
There were no reports of hepatitis B reactivation for screening and monitoring of 
hepatitis) in MS patients treated with ocrelizumab, but it was reported in RA (see the 
Ocrelizumab Investigator’s Brochure for further details). 
There were no reports of PML in MS patients treated with ocrelizumab.  Among patients 
treated with rituximab, cases of PML have been observed.  Most, but not all, patients 
who developed PML received rituximab in combination with chemotherapy or following a 
bone marrow transplant in order to treat cancer.  The remaining patients who developed 
PML had other severe autoimmune diseases, such as RA or granulomatosis with 
polyangiitis (GPA/Wegener’s), and all, including the patients who received rituximab for 
MS, had previously received or were receiving other drugs that suppressed their immune 
system at the same time (see the Ocrelizumab Investigator’s Brochure for further details).   
JC virus infection resulting in PML has been observed in patients treated with anti-CD20 
antibodies and other MS therapies and associated with risk factors (e.g., patient 
population, polytherapy with immunosuppressants).  However, a risk of PML cannot be 
ruled out.  Healthcare professionals should be alert to the 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.  Guidance for diagnosis is given in Appendix 5. 
Delay ocrelizumab administration in patients with an active infection until the infection is 
resolved. 


Ocrelizumab—Genentech, Inc. 
23/Protocol ML29966, Version 4 (Global) 
5.1.1.3 Potential Risks 
5.1.1.3.1 
Impaired Response to Vaccination 
The degree of impairment of B-cell dependent humoral response to neo-antigens and 
polysaccharide antigens and its clinical relevance are currently unknown in patients with 
MS. 
5.1.1.3.2 
Malignancies 
Malignancies are considered a potential risk with ocrelizumab due to the potential 
decreased immune surveillance associated with B-cell depletion in the context of 
treatments that are used long-term to treat chronic diseases.   
The overall incidence rate per patient for malignancies in MS (RMS and PPMS 
combined) for ocrelizumab (Table 10) was 0.42 per 100 patient years (100 PY) (95% CI:  
0.26, 0.66) compared with an incidence rate per patient for the control group 
(placebo/IFN) of 0.19 per 100 PY (95% CI:  0.05, 0.50).  Although the incidence rate of 
malignancies in the ocrelizumab treatment groups across the MS program is higher than 
IFN or placebo groups, the overlapping CIs do not allow a firm conclusion regarding a 
higher risk. 
The only cluster identified was for breast cancer (7 patients in the ocrelizumab groups 
across all MS trials compared with none in the comparator groups), and this was 
reflected in an increased incidence rate in female patients treated with ocrelizumab 
when compared with female placebo/interferon controls, albeit with overlapping CIs 
(female placebo/IFN:  0 patients, 0 per 100 PY [95% CI:  0,0.29]; female ocrelizumab:  
7 patients, 0.26 per 100 PY [95% CI:  0.10, 0.54]).   
No firm conclusion can be made to date concerning the risk due to the low number and 
the limited follow-up; hence, the risk remains potential to date.   
5.1.1.3.3 
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.  During clinical trials, no hypersensitivity reactions 
were reported in patients treated with ocrelizumab.  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. 
5.1.1.3.4 
Neutropenia 
In MS patients (12% 15%), treatment with ocrelizumab resulted in a decrease in 
neutrophils of mild to moderate severity, which was not sustained.  It did not necessitate 
treatment with granulocyte-colony stimulating factor and was not temporally associated 
with an infection. 


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A summary of potential risks is presented in Table 10. 
Table 10 
Summary of Potential Risks in Multiple Sclerosis 
Risk 
Description of Risk 
Impaired immunization 
response 
Over 2 years of treatment, the proportion of patients with positive 
antibody titers against S. pneumoniae, mumps, rubella, and 
varicella were generally similar to the proportions at baseline. 
Malignancies 
Across all MS trials, 23 patients reported a malignancy (19 a in the 
ocrelizumab group and 4 in the comparators groups).  This 
imbalance is reflected in the overall incidence rate as described 
above, and the only cluster identified was for breast cancer.  No 
firm conclusion can be made to date concerning the risk due to the 
low number and the limited follow up. 
Neutropenia 
The proportions of patients treated with ocrelizumab and reporting 
any single event of neutropenia defined by an absolute count of 
neutrophils below LLN were:  13.9% in Study WA21093, 15.6% in 
Study WA21092, and 12.1% in Study WA25046 compared with 
9.6% of the patients in the placebo group in Study WA25046.  
Overall, approximately 1% of the patients in the ocrelizumab group 
had Grades 3 or 4 neutropenia (which did not necessitate 
treatment with G CSF) and was not temporally associated with a 
serious infection.  
Hypersensitivity 
No hypersensitivity reactions to ocrelizumab were reported in the 
controlled clinical trials.  Hypersensitivity may be difficult to 
distinguish from IRRs in terms of symptoms (see the Ocrelizumab 
Investigator’s Brochure for further details). 
G CSF = granulocyte colony stimulating factor; IRR = infusion related reaction; LLN = lower limit 
of normal; MS = multiple sclerosis. 
a As of 31 October 2015; includes one malignancy (malignant melanoma) in an ocrelizumab 
patient in Study WA21092 reported after the clinical cutoff date.   
 
SECTION 5.1.1.1:  Identified Risks and Adverse Drug Reactions 
5.1.1.1.1 
Infusion-Related Reactions 
All CD20-depleting agents administered via the intravenous route, including 
ocrelizumab, have been associated with acute 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.  These reactions may present as pruritus, rash, urticaria, erythema, throat 
irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal edema, flushing, 
hypotension, pyrexia, fatigue, headache, dizziness, nausea, and tachycardia.  
Patients should be observed for at least one hour after the completion of the infusion for 
any symptom of IRR.  They will be informed about the possibility of delayed 
post-infusion symptoms and instructed to contact their study physician if they develop 
such symptoms. 


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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.  
5.1.1.1.2  
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% to 6%, simplex and zoster) than with 
comparators (approximately 3%).  
During the controlled period of the pivotal trials, the proportion of patients with 
serious infections was lower in RMS in the ocrelizumab group (1.3%) than in the 
interferon beta-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 (RA) 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 MS patient treated with ocrelizumab.  
There were no reports of hepatitis B reactivation in MS patients treated with 
ocrelizumab, but it had been reported in one RA patient treated with ocrelizumab.  
HBV screening should be performed in all patients before initiation of treatment with 
ocrelizumab as per local guidelines.  Patients with active hepatitis B virus should not 
be treated with ocrelizumab.  Patients with positive serology should consult liver 
disease experts before the start of treatment and should be monitored and managed 
following local medical standards to prevent hepatitis B reactivation.  
There were no reports of PML in patients treated with ocrelizumab.  JC virus (JCV) 
infection resulting in PML has been observed in patients treated with anti-CD20 
antibodies and other MS therapies and associated with risk factors (e.g., patient 
population, polytherapy with immunosuppressants).  However, a risk of PML cannot be 
ruled out.  Healthcare professionals should be alerted to the 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.  Please refer to Appendix 5 for 
guidance for diagnosis of PML.  
Delay ocrelizumab administration in patients with an active infection until the 
infection is resolved.   


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5.1.1.1.3 
Decrease in Immunoglobulins 
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins (Igs) over 
2 years, mainly driven by reduction in IgM, with no observed association with serious 
infections.  The proportion of patients with decrease in Igs below the LLN increased 
over time and with successive dosing.   
5.1.1.1.4 
Delayed Return of Peripheral B Cells 
Treatment with ocrelizumab leads to rapid depletion of CD19+  B cells in blood by 
14 days post-treatment (first timepoint of assessment) as an expected pharmacologic 
effect.  This was sustained throughout the treatment period.  The longest follow-up time 
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 their B cells have repleted. 
SECTION 5.1.1.2:  Potential Risks  
5.1.1.2.1 
Hypersensitivity Reactions  
No hypersensitivity reactions to ocrelizumab were reported in the controlled clinical 
trials.  
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. 
5.1.1.2.2 
Impaired Response to Vaccination 
The degree of impairment of B cell-dependent humoral response to neoantigens and 
polysaccharide antigens and its clinical relevance are currently unknown in patients 
with MS. 
After treatment with ocrelizumab over 2 years, the proportion of patients with positive 
antibody titers against Streptococcus pneumoniae, mumps, rubella, and varicella were 
generally similar to the proportions at baseline. 
No data are available on the effects of vaccination in patients receiving ocrelizumab.  
Physicians 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. 
The safety of immunization with live or live-attenuated viral vaccines following 
ocrelizumab therapy has not been studied, and vaccination with live-attenuated or live 
vaccines is not recommended while B cells are depleted. 


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5.1.1.2.3 
Malignancies including Breast Cancer 
Malignancies are considered a potential risk with ocrelizumab due to the potential 
decreased immune surveillance associated with B-cell depletion in the context of 
treatments that are used long-term to treat chronic diseases.  During the controlled 
treatment period, the incidence rate of malignancies in the ocrelizumab treatment 
groups across the MS program was higher than IFN or placebo groups with overlapping 
confidence intervals.  The incidence rates were within the expected ranges for the MS 
population from epidemiology sources.  The only cluster identified was for breast cancer.  
No firm conclusion can be made to date concerning the risk due to the low number and 
the limited follow-up; hence, the risk remains potential to date.   
5.1.1.2.4 
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, and approximately 1% of the patients had Grade 3 or 
4 neutropenia; and no temporal association with infections was identified.   
Detailed information for all risks can be found in the current Ocrelizumab 
Investigator’s Brochure.  
SECTION 5.3.5.1:  Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
“infusion-related reaction” or “anaphylactic reaction”) on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as “systemic reaction.”  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF.should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction). 
All CD20-depleting agents, including ocrelizumab, have been associated with acute 
infusion-related reactions.  Symptoms of IRRs may occur during any ocrelizumab 
infusion, but have been more frequently reported during the first infusion.  IRRs can 
occur within 24 hours of the infusion.  These reactions may present as pruritus, rash, 
urticaria, erythema, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or 
laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, 
and tachycardia.   
SECTION 5.3.5.2:  Diagnosis versus Signs and Symptoms 
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 


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hepatitis rather than jaundice, asterixis, and elevated transaminases).  For adverse 
events other than infusion-related reactions (see Section 5.3.5.1), a diagnosis (if known) 
should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  … 
SECTION 5.3.5.8:  Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of RMSMS. 
If the death is attributed to progression of RMSMS, "RMS progression" should be 
recorded on the Adverse Event eCRF.   
SECTION 5.4.1:  Emergency Medical Contacts 
Medical Monitor Contact Information  
Genentech Medical Monitor contact information: 
Medical Monitor: 
, M.D. (Primary) 
Telephone No.: 
 
 
SECTION 5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 24 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to study drug.  
The pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy 
Health Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An investigator who 
is contacted by the male patient or his pregnant partner may provide information on the risks of 
the pregnancy and the possible effects on the fetus, to support an informed decision in cooperation 
with the treating physician and/or obstetrician. 
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This study is designed to assess levels of NfL, levels of lymphocyte populations in CSF, 
and to generate hypotheses about biomarkers of ocrelizumab treatment in patients with 
RMS and PPMS.  Levels of NfL in CSF and levels of lymphocyte populations in CSF will 
be compared to baseline levels.  In addition, Arm 1 of the RMS cohort (second LP at 
12 weeks) will be compared to Arm 4 (second LP at 12 weeks before the first dose of 
study drug). 


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In this exploratory biomarker study, the analyses will be mostly descriptive and 
hypothesis-generating.  Inferential statistical methods, if applied, will be employed to 
highlight the data aspect of interest.  Unless otherwise specified, statistical tests will be 
two sided and the statistical significance level will be 5%.  Corresponding 95% 
confidence intervals will be presented as appropriate.  No corrections for multiple testing 
will be applied to the primary endpoint analyses, exploratory endpoint analyses, or 
interim analysis. 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
The main objective of thesample size calculations for this study is to generate 
hypotheses about biomarkers of ocrelizumab treatment.  The NfL parameter, are based 
on the remitting patients, is used for sample size calculation assumed reduction from 
baseline in NfL (Gunnarsson et al. 2011), and other) at Weeks 24 and 52 combined 
(Arms 2 and 3) in the RMS cohort.  Other biomarker measures are not considered for 
power determination.  
Assuming (a) a 30% reduction from baseline pre-treatment NfL (mean [SD] = 860 pg/mL 
[780 pg/mL]) to post-treatment (Week 24 and Week 52 combined; NfL (mean [SD] = 602 
pg/mL [310]) pg/mL]) and a correlation coefficient of r = 0.6, (resulting in an SD of 643 
pg/mL for the change) before and after from pre- to post-treatment, and (b) a desired 
power of 80% with a Ttype 1 error of 5%, thea sample size will be n = of 51 for Groups 2 
and 3 combined (e.g., n = patients is required, with approximately 25 patients in Group 
Arm 2 and n = 26 patients in Group Arm 3).  A total of 25 patients will be included in 
Group 1 to explore the possible reduction in NfL at an earlier timepoint.  Therefore, the 
total sample size for data analysis from three groups will be N = 76. 
This is the first study to explore the impact of ocrelizumab on CSF B-cell count.  In a 
study by Piccio et al. (2010), the rate of undetectable B cells in CSF was 74% (21/26) 
after 24−30 weeks of rituximab treatment as an add-on therapy in addition to 
immunomodulatory therapy.  Based on this information, we would expect that the and a 
sample size of 51 patients (Arm 2 and 3 combined), the expected 95% CI for the CSF 
B-cell undetectable rate will be:  (0.61, 0.85) with the proposed sample size of n = 51 for 
Groups 2 and 3 combined.). 
ToIn the RMS cohort, 15 patients will be included in Arm 1 to explore the possible 
reduction in NfL at Week 12 post-treatment and 15 patients will be assigned to the 
delayed start RMS control arm (Arm 4).  Fifteen patients will be recruited to the PPMS 
cohort.  The above sample sizes are not based on statistical considerations and are 
meant to help explore the changes in biomarkers and generate hypotheses for future 
studies. 
Based on the above, the total sample size for this study will be 96 patients.  The sample 
size will be increased by approximately 10% in order to account for early dropouts 
without providing anypotential missing post-treatment CSF datainformation; therefore, 


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the total number of patients to be enrolled will be increased by 30%.  Therefore, the 
number of patients to be enrolledin the RMS cohort will be N = 99 (33 patients from each 
of three groups).88 (Arm 1:  16 patients, Arm 2:  28 patients, Arm 3:  28 patients, and 
Arm 4:  16 patients), and N = 16 in the PPMS cohort.  Therefore, the total number of 
patients to be enrolled is 104. 
SECTION 6.3:  SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Patients’ demographics, medical history, and neurological examination will be 
summarized.  MS disease history (duration since MS first symptom, duration since MS 
diagnosis), MS disease status (MS treatment naïve or experienced), and MS prior 
treatment (for those being treated) will be summarized.  Also, the baseline measures of 
key CSF biomarkers, MRI, EDSS, or other important endpoints will be summarized.  It 
should be noted that two baseline measures for the RMS control arm (Arm 4) will be 
obtained:  the first at the Week −12 visit, which is 12 weeks before the first infusion of 
ocrelizumab, and the second at the first treatment visit pre-infusion. 
SECTION 6.4:  ANALYSES 
Statistical analyses will be performed on the analysis population, defined as all enrolled 
patients who (a) received at least one infusion of ocrelizumab, even if the infusion was 
incomplete or (b) received at least one LP. 
SECTION 6.4.1:  Primary Endpoints 
Primary endpoints for the RMS cohort (Arms 1−3) include:  
• 
Change in levels of NfL in CSF from treatment baseline to post-treatment with 
ocrelizumab 
• 
Change in number of CD19+  B cells in CSF from treatment baseline to post-
treatment with ocrelizumab  
• 
Change in number of CD3+ T cells in CSF from treatment baseline to post-treatment 
with ocrelizumab 
 
SECTION 6.4.2:  Exploratory Endpoints 
Exploratory endpoints for the PPMS cohort include: 
• 
Change in levels of NfL in CSF from treatment baseline to post-treatment with 
ocrelizumab 
• 
Change in number of CD19+ B cells in CSF from treatment baseline to post-
treatment with ocrelizumab  
• 
Change in number of CD3+ T cells in CSF from treatment baseline to post-
treatment with ocrelizumab 
 
CSF biomarker endpoints for both cohorts may include, but may not be limited to: 
• 
Activation markers, functional attributes, activity, and/or molecular status of cells 
(e.g., proteins, non-heritable RNA levels, etc.) at Weeks 1, 12, 24, and 52 (and 


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optional sample in case of relapse)all collected timepoints before and after 
treatment with ocrelizumab, including optional samples 
• 
Levels of soluble neurodegeneration markers and/or inflammatory markers at 
Weeks 1, 12, 24, and 52 (and optional sample in case of relapse) all collected 
timepoints before and after treatment with ocrelizumab, including optional samples 
 
Blood biomarker endpoints for both cohorts may include, but may not be limited to: 
• 
Change in number of CD19+ B and CD3+ T cells in blood at all collected timepoints 
before and after from baseline to post-treatment with ocrelizumab, including 
optional samples 
• 
Activation markers, functional attributes, activity, and/or molecular status of PBMCs 
or cell products (e.g., proteins, non-heritable RNA levels) at Weeks 1, 3, 12, 24, 36, 
48, and 52 at all collected timepoints before and after treatment with ocrelizumab, 
including at unscheduled visits 
• 
Levels of NfL, levels of soluble neurodegeneration markers, and/or inflammatory 
markers in the peripheral blood serum or plasma at Weeks 1, 3, 12, 24, 36, 48, and 
52  at all collected timepoints before and after treatment with ocrelizumab, 
including at unscheduled visits 
 
MRI biomarker endpoints for both cohorts may include, but may not be limited to: 
• 
Total number of T1 Gd-enhanced lesions at at all collected timepoints before and 
after treatment with ocrelizumabWeeks 12, 24, and 52, including at unscheduled 
visits  
• 
Change in total T2 lesion volume at all collected timepoints before and after 
treatment with ocrelizumabfrom baseline to Weeks 12, 24, and 52, including at 
unscheduled visits  
• 
Total number of new and/or enlarging T2 lesions at all collected timepoints before 
and after treatment with ocrelizumabat Weeks 12, 24, and 52, including at 
unscheduled visits 
• 
Changes in regional or total brain volume at all collected timepoints before and after 
treatment with ocrelizumabfrom baseline or Week 12 to Weeks 24 and 52, 
including at unscheduled visits 
• 
Total number of leptomeningeal-enhancing regions at all collected points before 
and after treatment with ocrelizumab, including at unscheduled visits 
 
Efficacy endpoints for both cohorts may include, but may not be limited to: 
• 
Change in EDSS score from baseline 
 
Other analyses may include evaluation of the possible associations between the 
changes in biomarkers of neurodegeneration or inflammation and change in MRI or 
efficacy outcome measures, such as reduction in Gd-positive lesions or time to 
worsening as measured by the EDSS score (RMS and PPMS cohort), or the 25-foot 
timed walk or the 9-hole peg test (PPMS cohort only). 


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Endpoints for the RMS control arm (Arm 4) will include comparisons between Arm 1 
of the RMS cohort (treatment baseline to second LP at 12 weeks) and Arm 4 
(pre-treatment baseline to treatment baseline, second LP at 12 weeks before the first 
dose of study drug), and may include, but may not be limited to, changes in CSF at all 
collected timepoints including optional samples, blood, and MRI biomarkers or efficacy, 
as outlined above. 
SECTION 6.4.3:  Pharmacokinetic and Immunogenicity Endpoints 
Pharmacokinetics and immunogenicity may be explored in relation to the 
pharmacodynamics of blood and/or CSF biomarkers in both cohorts.  Serum 
concentration of ocrelizumab may be measured at Weeks 12, 24, 48, and 52; in the case 
of early termination; and at safety follow-up.  The level of ocrelizumab may be measured 
in the CSF at Weeks 12, 24, and/or 52 and at Week 52 for the PPMS cohort; and/or in a 
CSF sample taken at an unscheduled visit or from an optional sample.  
SECTION 6.6:  INTERIM ANALYSIS 
An interim analysis may be performed when approximately 50% of patients have had 
their second LP. 
SECTION 7.5:  RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results (including flow cytometry data), and medication inventory 
records, must be retained by the Principal Investigator for at least 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.   
APPENDIX 1:  Schedule of Activities for the RMS Cohort Arms 1-3 
The schedule of activities has been revised to include and clarify assessments for the 
RMS cohort. 
APPENDIX 2:  Schedule of Activities for the RMS Cohort Arm 4 
Appendix 2 has been added to include assessments for the PPMS cohort.  Subsequent 
appendices have been renumbered accordingly. 
APPENDIX 3:  Schedule of Activities for the PPMS Cohort 
Appendix 3 has been added to include assessments for the PPMS cohort.   
APPENDIX 8:  B-Cell Monitoring Schedule of Activities  
Appendix 8 has been added to include assessments for B-cell monitoring.   


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SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol and pertains only to patients in the RMS cohort Arms 1−3.  In addition, separate 
sample Informed Consent Forms have been created for patients in the RMS delayed 
time to start control arm (Arm 4) and for patients in the PPMS cohort. 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 40 
PROTOCOL SYNOPSIS .................................................................................... 41 
1. 
BACKGROUND .......................................................................................... 50 
1.1 
Background on Biomarkers in Multiple Sclerosis................... 50 
1.2 
Background on Ocrelizumab ................................................. 51 
1.2.1 
Summary of Clinical Studies of Ocrelizumab in 
Multiple Sclerosis................................................................... 51 
1.2.1.1 
Clinical Safety........................................................................ 52 
1.2.1.2 
Clinical Activity....................................................................... 54 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 55 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 55 
2.1 
Primary Objectives ................................................................ 55 
2.2 
Exploratory Objectives........................................................... 56 
2.3 
Pharmacokinetic Objective .................................................... 56 
2.4 
Immunogenicity Objective...................................................... 56 
2.5 
Safety Objectives................................................................... 56 
3. 
STUDY DESIGN ......................................................................................... 57 
3.1 
Description of the Study......................................................... 57 
3.2 
End of Study and Length of Study......................................... 62 
3.3 
Rationale for Study Design.................................................... 62 
3.3.1 
Rationale for Ocrelizumab Dose and Schedule..................... 62 
4. 
MATERIALS AND METHODS .................................................................... 63 
4.1 
Patients.................................................................................. 63 
4.1.1 
Inclusion Criteria.................................................................... 63 
4.1.2 
Exclusion Criteria................................................................... 64 
4.2 
Method of Determination of the Time of Lumbar 
Puncture ................................................................................ 67 
4.3 
Study Treatment.................................................................... 67 
4.3.1 
Formulation, Packaging, and Handling.................................. 67 
4.3.1.1 
Ocrelizumab .......................................................................... 67 


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4.3.2 
Dosage, Administration, and Compliance.............................. 68 
4.3.2.1 
Ocrelizumab .......................................................................... 68 
4.3.3 
Methylprednisolone ............................................................... 70 
4.3.4 
Other Prophylactic Treatment................................................ 70 
4.3.5 
Investigational Medicinal Product Accountability ................... 70 
4.3.6 
Post-Trial Access to Ocrelizumab.......................................... 71 
4.4 
Concomitant Therapy ............................................................ 72 
4.4.1 
Permitted Therapy ................................................................. 72 
4.4.2 
Prohibited Therapy ................................................................ 72 
4.5 
Study Assessments ............................................................... 72 
4.5.1 
Informed Consent Forms and Screening Log........................ 72 
4.5.2 
Medical History and Demographic Data ................................ 73 
4.5.3 
Physical Examinations........................................................... 73 
4.5.4 
Vital Signs.............................................................................. 73 
4.5.5 
Assessment of Disability........................................................ 73 
4.5.6 
Neurological Examinations .................................................... 74 
4.5.7 
Brain Magnetic Resonance Imaging...................................... 75 
4.5.8 
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 75 
4.5.9 
Optional Samples for Roche Clinical Repository ................... 77 
4.5.9.1 
Overview of the Roche Clinical Repository............................ 77 
4.5.9.2 
Sample Collection.................................................................. 78 
4.5.9.3 
Confidentiality........................................................................ 78 
4.5.9.4 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 79 
4.5.9.5 
Withdrawal from the Roche Clinical Repository..................... 79 
4.5.9.6 
Monitoring and Oversight....................................................... 79 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 80 
4.6.1 
Criteria for Re-Treatment with Ocrelizumab .......................... 80 
4.6.2 
Patient Discontinuation.......................................................... 80 
4.6.3 
Study Treatment Discontinuation........................................... 81 
4.6.4 
Study and Site Discontinuation.............................................. 81 
5. 
ASSESSMENT OF SAFETY....................................................................... 81 


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5.1 
Safety Plan ............................................................................ 81 
5.1.1 
Risks Associated with Ocrelizumab....................................... 82 
5.1.1.1 
Identified Risks and Adverse Drug Reactions........................ 82 
5.1.1.2 
Potential Risks....................................................................... 84 
5.1.2 
Management of Patients Who Experience 
Specific Adverse Events........................................................ 85 
5.2 
Safety Parameters and Definitions ........................................ 86 
5.2.1 
Adverse Events ..................................................................... 86 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 87 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 87 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 88 
5.3.1 
Adverse Event Reporting Period ........................................... 88 
5.3.2 
Eliciting Adverse Event Information ....................................... 88 
5.3.3 
Assessment of Severity of Adverse Events ........................... 88 
5.3.4 
Assessment of Causality of Adverse Events ......................... 89 
5.3.5 
Procedures for Recording Adverse Events............................ 90 
5.3.5.1 
Infusion-Related Reactions.................................................... 90 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 90 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 91 
5.3.5.4 
Persistent or Recurrent Adverse Events................................ 91 
5.3.5.5 
Abnormal Laboratory Values ................................................. 92 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 92 
5.3.5.7 
Abnormal Liver Function Tests.............................................. 93 
5.3.5.8 
Deaths ................................................................................... 93 
5.3.5.9 
Preexisting Medical Conditions.............................................. 94 
5.3.5.10 
Lack of Efficacy or Worsening of Relapsing 
Multiple Sclerosis................................................................... 94 
5.3.5.11 
Hospitalization or Prolonged Hospitalization.......................... 94 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 95 


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5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 95 
5.4.1 
Emergency Medical Contacts................................................ 96 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 96 
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................... 96 
5.4.2.2 
Events That Occur after Study Drug Initiation........................ 96 
5.4.3 
Reporting Requirements for Pregnancies.............................. 96 
5.4.3.1 
Pregnancies in Female Patients............................................ 96 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 97 
5.4.3.3 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 97 
5.5 
Follow-Up of Patients after Adverse Events .......................... 97 
5.5.1 
Investigator Follow-Up........................................................... 97 
5.5.2 
Sponsor Follow-Up ................................................................ 98 
5.6 
Post-Study Adverse Events................................................... 98 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 98 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 98 
6.1 
Determination of Sample Size ............................................... 99 
6.2 
Summaries of Conduct of Study.......................................... 100 
6.3 
Summaries of Demographic and Baseline 
Characteristics..................................................................... 100 
6.4 
Analyses.............................................................................. 100 
6.4.1 
Primary Endpoints ............................................................... 100 
6.4.2 
Exploratory Endpoints.......................................................... 101 
6.4.3 
Pharmacokinetic and Immunogenicity Endpoints ................ 102 
6.5 
Safety Analyses................................................................... 102 
6.6 
Interim Analysis ................................................................... 103 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 103 
7.1 
Data Quality Assurance....................................................... 103 
7.2 
Electronic Case Report Forms............................................. 103 
7.3 
Source Data Documentation................................................ 104 


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7.4 
Use of Computerized Systems ............................................ 104 
7.5 
Retention of Records........................................................... 105 
8. 
ETHICAL CONSIDERATIONS.................................................................. 105 
8.1 
Compliance with Laws and Regulations .............................. 105 
8.2 
Informed Consent ................................................................ 105 
8.3 
Institutional Review Board or Ethics Committee.................. 106 
8.4 
Confidentiality...................................................................... 107 
8.5 
Financial Disclosure ............................................................ 107 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 107 
9.1 
Study Documentation .......................................................... 107 
9.2 
Protocol Deviations.............................................................. 107 
9.3 
Site Inspections ................................................................... 108 
9.4 
Administrative Structure....................................................... 108 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 108 
9.6 
Protocol Amendments ......................................................... 109 
10. REFERENCES ......................................................................................... 110 
 
 
LIST OF TABLES 
Table 1 
Study Cohorts and Overall Design.............................................. 62 
Table 2 
Overview of Ocrelizumab Dosing:  RMS Cohort ......................... 69 
Table 3 
Overview of Ocrelizumab Dosing:  PPMS Cohort....................... 70 
Table 4 
Guidelines for Management of Specific Adverse Events ............ 85 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 89 
Table 6 
Causal Attribution Guidance ....................................................... 90 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema:  RMS Cohort Arms 1−3...................................... 59 
Figure 2 
Study Schema:  RMS Cohort Arm 4 ........................................... 60 
Figure 3 
Study Schema:  PPMS Cohort.................................................... 61 
 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Activities the RMS Cohort Arms 1−3..................... 112 
Appendix 2 
Schedule of Activities for the RMS Cohort Arm 4...................... 119 
Appendix 3 
Schedule of Activities for the PPMS Cohort.............................. 126 
Appendix 4 
Expanded Disability Status Scale ............................................. 132 
Appendix 5 
New York Heart Association Classification of 
Functional Cardiac Capacity ..................................................... 134 
Appendix 6 
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy............................................................... 135 
Appendix 7 
2010 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis ................................................................................... 139 
Appendix 8 
B-Cell Monitoring Schedule of Activities ................................... 141 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
AN OPEN-LABEL, MULTICENTER, BIOMARKER 
STUDY TO EXPLORE THE MECHANISM OF 
ACTION OF OCRELIZUMAB AND B-CELL 
BIOLOGY IN PATIENTS WITH RELAPSING 
MULTIPLE SCLEROSIS OR PRIMARY 
PROGRESSIVE MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: ML29966 
VERSION NUMBER: 
4 (Global) 
EUDRACT NUMBER: 
2015-004616-37 
IND NUMBER: 
100,593 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by the CRO. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
AN OPEN-LABEL, MULTICENTER, BIOMARKER STUDY TO 
EXPLORE THE MECHANISM OF ACTION OF OCRELIZUMAB 
AND B-CELL BIOLOGY IN PATIENTS WITH RELAPSING 
MULTIPLE SCLEROSIS OR PRIMARY PROGRESSIVE 
MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: 
ML29966 
VERSION NUMBER: 
4 (Global) 
EUDRACT NUMBER: 
2015-004616-37 
IND NUMBER: 
100,593 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
IIIb  
INDICATION: 
Relapsing multiple sclerosis and primary progressive multiple 
sclerosis 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
This is an exploratory biomarker study designed to be hypothesis-generating in order to better 
understand the mechanism of action of ocrelizumab and B-cell biology in relapsing multiple 
sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). 
Primary Objectives 
The primary objectives for the RMS cohort in this study are: 
• 
To understand the impact of ocrelizumab treatment on neurofilament light (NfL) as a 
biomarker of neuronal damage in cerebrospinal fluid (CSF)  
• 
To assess the number of CD19+ B cells in CSF (cell number/microliter) before and after 
treatment with ocrelizumab 
• 
To assess the number of CD3+ T cells in CSF (cell number/microliter) before and after 
treatment with ocrelizumab 
Exploratory Objectives 
The exploratory objectives for the PPMS cohort in this study are: 
• 
To understand the impact of ocrelizumab treatment on NfL as a biomarker of neuronal 
damage in CSF  
• 
To assess the number of CD19+ B cells in CSF (cell number/microliter) before and after 
treatment with ocrelizumab  
• 
To assess the number of CD3+ T cells in CSF (cell number/microliter) before and after 
treatment with ocrelizumab  
The exploratory objectives for both cohorts in this study are: 
• 
To understand the impact of ocrelizumab treatment on NfL and other biomarkers of 
neurodegeneration in CSF as a reflection of activity in the central nervous system (CNS) 
and compared with peripheral blood 


 
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• 
To measure the impact of ocrelizumab treatment on B cells/B-cell subsets, T cells/T-cell 
subsets, and other cell types (e.g., natural killer cells, monocytes, etc.), functional 
parameters of B/T/other cell types (activation, cell products), and other biomarkers of 
inflammation in CSF as a reflection of activity in the CNS and compared with peripheral 
blood 
• 
To assess potential correlation between change in blood or CSF biomarkers of 
neurodegeneration or  inflammation and change in magnetic resonance imaging (MRI) or 
efficacy outcome measures, such as reduction in gadolinium (Gd)-positive lesions or 
Expanded Disability Status Scale (EDSS) score 
 
Exploratory objectives for the RMS delayed time to start control arm (Arm 4) will include 
comparisons between Arm 1 of the RMS cohort (second lumbar puncture [LP] at 12 weeks) 
and Arm 4 (second LP at 12 weeks before the first dose of study drug), and may include but 
not be limited to changes in CSF, blood, and MRI biomarkers or efficacy, as outlined above. 
Pharmacokinetic Objective 
The pharmacokinetic objective for this study is: 
• 
To assess pharmacokinetics of ocrelizumab in CSF compared with serum concentration 
Immunogenicity Objective 
The immunogenicity objective for this study is: 
• 
To assess the incidence of anti-drug antibodies to ocrelizumab 
Safety Objectives 
The safety objective for this study is to evaluate the safety of ocrelizumab on the basis of the 
following endpoints: 
• 
Nature, frequency, severity, and timing of adverse events 
• 
Changes in vital signs, physical findings, and clinical laboratory results during and following 
ocrelizumab administration 
• 
Adverse events related to biomarker sample collection 
Study Design 
Description of Study 
This is an open-label, multicenter, biomarker study conducted at centers in multiple countries in 
which all eligible patients will be enrolled to a single treatment arm of ocrelizumab.  The study 
will include an RMS cohort and a PPMS cohort (see Table 1).  The RMS cohort is the main 
cohort and will include the majority of study participants.  The RMS cohort will be comprised 
of four arms, three of which will have patients randomized into one of three arms (Arms 1−3) 
depending on the time of their second LP.  In Arm 4, treatment with ocrelizumab will be 
delayed for 12 weeks after the first LP.  The PPMS cohort will comprise a smaller, hypothesis-
generating portion of the trial, as less is known about PPMS biomarkers.  
Arm 4 will provide a control for Arm 1 of the RMS cohort.  Due to the relapsing and 
remitting nature of RMS, some biomarkers may change due to disease course rather than 
based on influence of a drug treatment.  Therefore, some biomarkers may “regress to the 
mean” across the disease course over time, and this change could then inaccurately be 
reported as a change due to drug treatment over time.  Arm 4 will allow for an estimate of the 
natural variability of the disease when analyzing the other treated arms.    
Male and female patients age 18−55 years with a diagnosis of RMS or PPMS in accordance 
with the 2010 revised McDonald criteria (Polman et al. 2011; Appendix 7) and an EDSS score 
of 0−5.5 points for RMS patients, or an EDSS score of 3.0−6.5 for PPMS patients, at 
screening will be eligible.  Screening will occur over a 4-week period, after which eligible 
patients may begin treatment with ocrelizumab.   
For patients in the RMS cohort (Arms 1−3), ocrelizumab will be administered at Week 1, 
Week 3, Week 24, and Week 48.  The first dose will be administered as two infusions of 300 mg 
given on Day 1 and Day 15.  The subsequent doses will be given as single 600-mg infusions.   
For patients in the RMS cohort (Arm 4), after receiving two LPs at Week −12 and Week 1, the 
first dose of ocrelizumab will be administered as two 300-mg infusions on Week 1 (Day 1) and 


 
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Week 3 (Day 15), with subsequent doses given as single 600-mg infusions at Weeks 24 and 48.  
The timeline for Arm 4 will continue for an extra 12 weeks to accommodate the same one-year 
dosing regimen.   
For patients in the PPMS cohort, ocrelizumab 600 mg will be administered as two 300-mg IV 
infusions separated by 14 days at a scheduled interval of every 24 weeks (see Appendix 3). 
Treatment with ocrelizumab will continue for approximately 1 year after the first infusion; 
however, 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.  Patients may be eligible to 
continue to receive treatment if ocrelizumab is not commercially available in the patient’s 
country or is not reasonably accessible to the patient (see Section 4.3.6), and these patients 
will continue to be followed.   
Patients who complete the 52-week study (64 weeks for patients in Arm 4) and choose not to 
continue on ocrelizumab treatment, or who discontinue from treatment early, should enter the 
Safety Follow-up Period and be assessed every 24 weeks for 48 weeks counting from the date 
of the last infusion of ocrelizumab.  After 48 weeks, if the peripheral blood B-cell count remains 
depleted, monitoring of the patient should continue at 24-week intervals until the B-cell count 
has returned to the baseline value or to the lower limit of the normal range, whichever is lower 
(see Appendix 8).   
Biomarkers will be monitored in a longitudinal fashion before and after treatment with 
ocrelizumab in order to assess dynamic changes in biomarkers as they relate to drug exposure, 
length of time on drug, response to drug, and MS disease pathogenesis.  Biomarkers will be 
assessed via blood draws throughout the study and via LP in CSF at baseline before the first 
dose of ocrelizumab and at one other timepoint.   
Two LPs will be drawn from each patient during the study.  The two LPs will allow for 
assessment of biomarkers in CSF that are indicative of response to drug, 
pharmacokinetic/pharmacodynamic relationships, and/or disease pathogenesis in the CNS.  
Patients in the RMS cohort (Arms 1−3) will receive an LP before the start of dosing with 
ocrelizumab.  Subsequently, these patients will be randomized into one of three arms for timing 
of the second LP, either Week 12, 24, or 52 following the first dose of ocrelizumab.   
Patients in Arm 4 will receive two LPs, separated by a 12-week interval, before 
administration of the first dose of ocrelizumab.  Patients in this arm will be asked if they are 
willing to give an optional CSF sample via LP 12 weeks after the ocrelizumab dose.  
Patients in the PPMS cohort will receive an LP at the start of the study before dosing with 
ocrelizumab.  Subsequently, they will receive a second LP at Week 52 following the first dose 
of ocrelizumab.   
In the case of MS relapse or worsening (for PPMS patients) during the study, the patient 
should have an unscheduled visit and will be asked to receive an optional LP at the time of 
relapse or worsening (for PPMS patients).  The patient will have another LP at the originally 
scheduled time based on their randomization, or if a relapse occurs after they have already 
given the second LP, the relapse LP will remain optional.   
All patients will be evaluated for safety throughout the study.   
In the case of early termination, the patient will be asked to have an early termination visit. 
Number of Patients 
Approximately 104 patients will be enrolled in this study; 88 patients with RMS and 
16 patients with PPMS.  
Target Population 
Inclusion Criteria 
General Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Ability to comply with the protocol, in the investigator’s judgment 
• 
Age 18−55 years, inclusive 


 
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• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% 
per year during the treatment period and for at least 24 weeks after the last dose of study 
treatment or until their B cells have repleted, whichever is longer 
- 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 other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
- Examples of contraceptive methods with a failure rate of <1% per year include bilateral 
tubal ligation, male sterilization, established, proper use of 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 (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Inclusion Criteria Specific to RMS Patients 
• 
Diagnosis of RMS in accordance with the 2010 revised McDonald criteria (Polman et al. 
2011; Appendix 7)  
• 
EDSS score of 0−5.5 points, inclusive, at screening 
• 
Disease duration from the onset of MS symptoms: 
- Less than 15 years in patients with an EDSS >5.0 at screening 
• 
Either treatment-naïve or receiving treatment with disease-modifying therapies, including 
prior use of interferon (IFN)-β-1a (Avonex®, Rebif®), IFN-β-1b (Betaseron®/Betaferon), or 
glatiramer acetate (Copaxone®) 
• 
At least one clinically documented relapse in the past year and/or at least one T1-weighted 
Gd-enhancing lesion in the past year and/or at least one new T2 lesion in the past year at 
the time of enrollment 
Inclusion Criteria Specific to RMS Cohort Arm 4 
• 
Must meet inclusion criteria for the RMS cohort  
• 
Separate signed Informed Consent Form for the RMS Delayed Time to Start Control Arm (Arm 4) 
• 
Must be willing to remain on the same dose and regimen of current standard of care, or no treatment 
if treatment-naïve, for 12 weeks after study enrollment 
- The treating and/or study physician must agree that the patient is eligible to remain on the same 
dose and regimen of their current standard of care at screening, or to receive no treatment if the 
patient is treatment-naïve, for 12 weeks after study enrollment. 
Inclusion Criteria Specific to PPMS Patients 
• 
Diagnosis of PPMS in accordance with the 2010 revised McDonald criteria (Polman et al. 2011; 
Appendix 7)  
• 
EDSS score of 3.0−6.5 points, inclusive, at screening 
• 
Disease duration from the onset of MS symptoms: 
- Less than 10 years in patients with an EDSS at screening ≤ 5.0  
• 
Documented history of at least one of the following laboratory findings in CSF: 
- Elevated IgG Index 
- One or more IgG oligoclonal bands detected by isoelectric focusing 
Exclusion Criteria  
General Inclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Diagnosis of secondary progressive MS without relapses for at least 1 year 


 
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• 
History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis) 
• 
History of recurrent aspiration pneumonia requiring antibiotic therapy 
• 
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) 
• 
History of or currently active primary or secondary immunodeficiency  
• 
History of coagulation disorders 
• 
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 
• 
Known presence or history of other neurologic disorders, including but not limited to, the 
following: 
- History or known presence of progressive multifocal leukoencephalopathy  
- History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma) 
- History or known presence of potential metabolic causes of myelopathy (e.g., untreated 
vitamin B12 deficiency) 
- History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, 
HTLV-1, herpes zoster myelopathy) 
- History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary 
paraparesis; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [MELAS]) 
- History or known presence of systemic autoimmune disorders, potentially causing progressive 
neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sjögren’s syndrome, 
Behçet’s disease) 
- History or known presence of sarcoidosis 
- Neuromyelitis optica 
- Ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or ischemia of the 
spinal cord 
- Severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord 
compression) 
• 
Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), 
pulmonary (including chronic obstructive pulmonary disease), renal, hepatic, endocrine, 
gastrointestinal, or any other significant disease 
• 
Congestive heart failure (according to New York Heart Association III or IV functional 
severity) 
• 
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  
• 
Any concomitant disease that may require chronic treatment with systemic corticosteroids 
or immunosuppressants during the course of the study 
• 
Contraindications for, or intolerance to, oral or IV corticosteroids, including IV 
methylprednisolone, according to the country label, including: 
- Psychosis not yet controlled by a treatment 
- Hypersensitivity to any of the treatment drug constituents 
• 
Contraindication for LP 
• 
Previous treatment with B cell-targeted therapies (e.g., rituximab, ocrelizumab, atacicept, 
belimumab, or ofatumumab) 


 
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• 
Previous treatment with natalizumab (Tysabri®), alemtuzumab, anti-CD4 agents, cladribine, 
teriflunomide, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, 
cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation 
• 
Treatment with fingolimod (Gilenya®), dimethyl fumarate (Tecfidera®), or similar treatment 
within 6 months prior to enrollment 
• 
Receipt of a live vaccine within 6 weeks prior to enrollment 
- Vaccinations before baseline:  In rare cases where a live vaccine must be administered by the 
patient’s physician, the screening period may need to be prolonged but cannot exceed 12 weeks. 
• 
Systemic corticosteroid therapy within 4 weeks prior to baseline 
- The screening period may be extended (but cannot exceed 8 weeks) for patients who have used 
systemic corticosteroids for their MS before screening.  
• 
Previous or concurrent treatment with any investigational agent or treatment with any 
experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous 
insufficiency) 
• 
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]) or hepatitis C 
(HepCAb)  
- AST or ALT ≥ 2.0 upper limit of normal  
- Platelet count < 100,000/μL (< 100 × 109/L) 
- ANC < 1.5 × 103/μL 
- Abnormal lymphocyte count (below lower level of normal) 
Re-testing before baseline:  in rare cases in which the screening laboratory samples are 
rejected by the laboratory (e.g., hemolyzed sample) or the results are not assessable (e.g., 
indeterminate) or abnormal, the tests need to be repeated.  Any abnormal screening 
laboratory value that is clinically relevant should be retested in order to rule out any 
progressive or uncontrolled underlying condition.  The last value before randomization must 
meet study criteria.  In such circumstances, the screening period may need to be prolonged 
but should not exceed 8 weeks. 
• 
Inability to complete an MRI (contraindications for MRI include but are not restricted to 
weight ≥ 140 kg, pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 
weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of 
the intended MRI, contraindication to gadolinium, etc.)   
• 
Lack of peripheral venous access 
• 
Pregnant or lactating, or intending to become pregnant during the study 
- Women of childbearing potential must have a negative serum pregnancy test result within 7 days 
prior to initiation of study drug. 
Exclusion Criteria Specific to RMS Patients 
• 
Diagnosis of PPMS or secondary progressive multiple sclerosis without relapses 
End 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.   
Length of Study 
The total length of the study is expected to be approximately 3.5 years from the first patient 
enrolled to LPLV. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The investigational medicinal product for this study is ocrelizumab. 


 
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Non-Investigational Medicinal Products 
Premedicate with 100 mg of methylprednisolone (or an equivalent) approximately 30 minutes 
prior to each ocrelizumab infusion to reduce the frequency and severity of infusion-related 
reactions (IRRs). 
Additional premedication with an antihistaminic drug (e.g., diphenhydramine) is recommended 
approximately 30−60 minutes before each infusion of ocrelizumab to further reduce the 
frequency and severity of IRRs.  The addition of an antipyretic (e.g., 
acetaminophen/paracetamol) may also be considered. 
Statistical Methods 
Statistical analyses will be performed on the analysis population, defined as all enrolled patients 
who received at least one infusion of ocrelizumab, even if the infusion was incomplete.   
Primary Endpoints 
Primary endpoints for the RMS cohort include: 
• 
Change in levels of NfL in CSF from treatment baseline to post-treatment with ocrelizumab 
• 
Change in number of CD19+  B cells in CSF from treatment baseline to post-treatment with 
ocrelizumab  
• 
Change in number of CD3+ T cells in CSF from treatment baseline to post-treatment with 
ocrelizumab 
Determination of Sample Size   
The sample size calculations for this study are based on the assumed reduction from baseline in NfL 
(Gunnarsson et al. 2011) at Weeks 24 and 52 combined (Arms 2 and 3) in the RMS cohort.  Other 
biomarker measures are not considered for power determination.  
Assuming (a) a 30% reduction from pre-treatment NfL (mean [SD] = 860 pg/mL [780 pg/mL]) to 
post-treatment NfL (mean [SD] = 602 pg/mL [310 pg/mL]) and a correlation coefficient of 0.6, 
resulting in an SD of 643 pg/mL for the change from pre- to post-treatment, and (b) a desired 
power of 80% with a Type 1 error of 5%, a sample size of 51 patients is required, with 
approximately 25 patients in Arm 2 and 26 patients in Arm 3. 
This is the first study to explore the impact of ocrelizumab on CSF B-cell count.  In a study by 
Piccio et al. (2010), the rate of undetectable B cells in CSF was 74% (21/26) after 24−30 weeks 
of rituximab as an add-on to immunomodulatory therapy.  Based on this information and a 
sample size of 51 patients (Arm 2 and 3 combined), the expected 95% CI for the CSF B-cell 
undetectable rate will be:  (0.61, 0.85). 
In the RMS cohort, 15 patients will be included in Arm 1 to explore the possible reduction in 
NfL at Week 12 post-treatment and 15 patients will be assigned to the delayed start RMS 
control arm (Arm 4).  Fifteen patients will be recruited to the PPMS cohort.  The above 
sample sizes are not based on statistical considerations and are meant to help explore the 
changes in biomarkers and generate hypotheses for future studies. 
Based on the above, the total sample size for this study will be 96 patients.  The sample size 
will be increased by approximately 10% in order to account for potential missing 
post-treatment CSF information; therefore, the number of patients to be enrolled in the RMS 
cohort will be N = 88 (Arm 1:  16 patients, Arm 2:  28 patients, Arm 3:  28 patients, and 
Arm 4:  16 patients), and N = 16 in the PPMS cohort.  Therefore, the total number of patients 
to be enrolled is 104.   
Interim Analyses  
An interim analysis may be performed when approximately 50% of patients have had their 
second LP. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ARR 
annualized relapse rate 
β-hCG 
beta subunit human chorionic gonadotropin 
CI 
confidence interval 
CNS 
central nervous system 
CRO 
CSF 
contract research organization 
cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMT 
disease-modifying therapy 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
EDSS 
electronic data capture 
Expanded Disability Status Scale 
FDA 
Gd 
U.S. Food and Drug Administration 
gadolinium 
FS 
Functional Systems 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HepCAb 
hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council on Harmonisation 
IFN-β 
interferon beta 
Ig 
immunoglobulin 
IMP 
IRR 
investigational medicinal product 
infusion-related reaction 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IV 
intravenous 
IxRS 
interactive voice/web response system 
LLN 
lower limit of normal 
LPLV 
LP 
MRI 
last patient, last visit 
lumbar puncture 
magnetic resonance image  
MS 
multiple sclerosis 
NCI 
NfL 
National Cancer Institute 
neurofilament light (chain) 


 
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OCB 
oligoclonal bands 
NK 
natural killer (cells) 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PPMS 
primary progressive multiple sclerosis 
PY 
patient years 
RA 
rheumatoid arthritis 
RCR 
Roche Clinical Repository 
RMS 
relapsing multiple sclerosis 
RR 
relative reduction 
RRMS 
relapsing-remitting multiple sclerosis 
SPMS 
secondary progressive multiple sclerosis 
ULN 
upper limit of normal 
U.S. 
United States 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON BIOMARKERS IN MULTIPLE SCLEROSIS  
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative 
disease of the central nervous system (CNS) that affects approximately 400,000 people 
in the United States (U.S.) and 2.5 million worldwide (Tullman et al. 2013).  MS primarily 
affects young adults, with 70%−80% of patients having an age of onset (i.e., initial 
clinical presentation to a physician) between 20 and 40 years (Anderson et al. 1992; 
Noonan et al. 2002), and has a strong gender bias, with approximately 64%−70% of 
diagnosed patients being women (Goodin 2014).  MS is subcategorized into three 
phenotypic disease patterns including relapsing-remitting MS (RRMS), primary 
progressive MS (PPMS), and secondary progressive MS (SPMS).  The term “RMS” (i.e., 
relapsing multiple sclerosis) applies to those patients with either RRMS or SPMS who 
continue to suffer relapses.  Patients with RMS, whether or not they suffer from 
neurologic progression in the absence of relapses, have a common inflammatory 
pathophysiology that therefore constitutes a common target for treatment. 
Although the etiology of MS remains largely unknown, it is well accepted that aberrant 
functioning of both the adaptive and innate immune system, including the dysregulation 
of B and T cells, occurs in the majority of patients.  Despite advances in our 
understanding of the pathophysiology of disease and recent regulatory approval of a 
significant number of MS therapies, many patients continue to experience disease 
activity.  Thus, there remains an unmet medical need to develop more effective and 
well-tolerated therapies for the treatment of MS. 
To meet this need, the identification of MS disease biomarkers represents a critical 
opportunity to potentially understand disease pathogenesis, disease progression, and 
the mechanism of action of a therapeutic treatment.  Biomarker identification can 
ultimately guide clinical decision-making, leading to patient stratification for therapeutic 
interventions that maximize clinical benefit while minimizing patient harm.  In the context 
of MS, biomarkers from the cerebrospinal fluid (CSF) are utilized as a surrogate for the 
CNS tissue (Comabella and Montalban 2014) and brain magnetic resonance imaging 
(MRI) is utilized as a non-invasive surrogate marker of disease activity (e.g., 
contrast-enhancing lesions; new and unequivocally enlarging T2-weighted lesions).  
Biomarkers of neuroinflammation in CSF, such as neurofilament light (NfL) chain, an 
acute neuronal injury marker, have been correlated with gadolinium (Gd)-enhancing MRI 
lesions and clinical relapses (Burman et al. 2014) and with response to drug treatment in 
PPMS and RMS (Gunnarsson et al. 2011; Axelsson et al. 2014).  Key sensitive CSF 
biomarkers of disease include the presence of oligoclonal bands (OCBs), or antibodies 
produced in the CSF (Link and Huang 2006), as well as the presence of intrathecal 
memory B-cell plasmablasts (Cepok et al. 2005).  These biomarkers suggest a link 
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To better understand the mechanism of action of ocrelizumab in MS, this study will 
assess known biomarkers (OCBs, NfL, B cells, MRI as a surrogate marker, etc.) and 
explore new potential biomarkers associated with response to ocrelizumab in CSF and 
peripheral blood.  In the context of B cell-depleting therapies, B and T cells trafficking 
between the CNS and periphery, and the chemokine CXCL13, can act as biomarkers of 
inflammation (Piccio et al. 2010; Bankoti et al. 2014; Palanichamy et al. 2014; Stern et al. 
2014).  This study will explore disease mechanism further in a larger patient sample size 
by examining additional biomarkers in CSF, cells, and peripheral blood.  Several 
additional biomarkers, such cytokines, chemokines, and antigen-specific B or T cells, 
may also provide insight into disease mechanisms (Piccio et al. 2010; Barun and Bar-Or 
2012; Alvermann et al. 2014; Hohmann et al. 2014). 
1.2 
BACKGROUND ON OCRELIZUMAB 
Ocrelizumab is a recombinant humanized anti-human monoclonal antibody that 
selectively targets CD20-expressing B cells (Klein et al. 2013).   
CD20 is a cell surface antigen found on pre-B cells, mature B cells, and memory B cells 
but is not expressed on lymphoid stem cells and plasma cells (Stashenko et al. 1980; 
Loken et al. 1987; Tedder and Engel 1994).  While ocrelizumab selectively depletes 
CD20-expressing B cells (Kappos et al. 2011), the capacity of B-cell reconstitution and 
pre-existing humoral immunity are preserved (Martin and Chan 2006; DiLillo et al. 2008).  
In addition, innate immunity and peripheral T-cell numbers are not affected (Clinical 
Study Report for WA21493). 
See the Ocrelizumab Investigator's Brochure for additional details on nonclinical and 
clinical studies. 
1.2.1 
Summary of Clinical Studies of Ocrelizumab in Multiple 
Sclerosis 
Current studies of ocrelizumab include four ongoing controlled clinical trials in patients 
with MS:  three Phase III studies (pivotal studies WA21092 and WA21093 and Study 
WA25046) and one Phase II study (Study WA21493).   
Studies WA21092 and WA21093 are multicenter, randomized, parallel-group, 
double-blind, double-dummy, active-comparator studies of ocrelizumab in patients with 
RMS.  Patients receive 600 mg intravenous (IV) ocrelizumab every 24 weeks or 
interferon beta-1a (IFN-β-1a) 44 μg subcutaneous three times per week.  The primary 
endpoint is the annualized protocol-defined relapse rate by 2 years (96 weeks).   
Study WA25046 is a multicenter, randomized, parallel-group, placebo-controlled study in 
patients with PPMS.  Patients receive 600 mg IV ocrelizumab every 24 weeks as two 
300-mg infusions two weeks apart or placebo.  The primary objective of this study is to 
evaluate the efficacy and safety of ocrelizumab compared with placebo.  The primary 
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measured by a pre-specified increase in Expanded Disability Status Scale (EDSS; see 
Appendix 4) score, sustained for at least 12 weeks.   
The Phase II study (Study WA21493) is a multicenter, randomized, parallel-group, 
double-blind, placebo- and active-comparator (IFN-β-1a), dose-finding study in RRMS.  
Results from the Phase II study showed that, at Week 24, ocrelizumab significantly 
reduced the number of Gd-enhancing lesions on T1-weighted brain MRI and annualized 
relapse rate compared with both placebo and the active comparator.   
See the Ocrelizumab Investigator’s Brochure for additional information.   
1.2.1.1 
Clinical Safety 
Safety in Multiple Sclerosis 
The safety data included are from three Phase III studies in RMS (Studies WA21092 and 
WA21093) and PPMS (Study WA25046) and one Phase II study in RRMS 
(Study WA21493).   
Studies WA21092, WA21093, WA25046, and WA21493 have completed the controlled 
treatment period and are in open-label extension phase. 
In the two RMS Phase III studies (pooled data of Studies WA21092 and WA21093) 
during the 96-week controlled treatment period, ocrelizumab was well tolerated with 
lower rates of treatment discontinuations for adverse events in patients treated with 
ocrelizumab 600 mg (3.5%) than in patients receiving IFN-β-1a (6.2%).  The proportion 
of patients with adverse events (83.3% in both groups) as well as the total number of 
adverse events were similar in the ocrelizumab and the IFN-β-1a treatment groups over 
the 96-week treatment period.  The proportion of patients reporting infections was higher 
in the ocrelizumab group compared with the IFN-β-1a group (58.4% vs. 52.4%, 
respectively).  In addition, there were more events of infection in the ocrelizumab group 
(1224 events) compared with the IFN group (948 events) and these were primarily upper 
respiratory tract infections of Grade 1 or 2 intensity.  The proportion of patients with 
serious adverse events was lower in the ocrelizumab treatment group than in the 
IFN-β-1a treatment group (6.9% in the ocrelizumab treatment group vs. 8.7% in the 
IFN-β-1a treatment group).  Overall, the proportion of patients with serious infections 
was lower in the ocrelizumab group (1.3%) than in the IFN-β-1a group (2.9%).  Two 
serious infusion-related reactions (IRRs) were reported; one in the IFN-β-1a group 
(Grade 3) and one in the ocrelizumab group (Grade 4).  As expected, the proportion of 
patients experiencing IRRs were increased in the ocrelizumab group (34.3%) compared 
with the active control group (9.7%) who received dummy infusions.  During the 96-week 
controlled treatment period, a total of 6 malignancies were reported, 2 events (1 mantle 
cell lymphoma and 1 squamous cell carcinoma) occurred in 2 patients (0.2%) in the 
IFN-β-1a treatment group and 4 events (2 invasive ductal breast carcinoma, 1 renal 
cancer, and 1 malignant melanoma) occurred in 4 patients (0.5%) in the ocrelizumab 
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(suicide and mechanical ileus) in the IFN-β-1 treatment group and 1 patient (suicide) in 
the ocrelizumab treatment group. 
In the PPMS Phase III, double-blind, placebo-controlled Study WA25046, ocrelizumab 
was well tolerated with a similar proportion of patients with adverse events leading to 
discontinuation from treatment (4.1%) compared with the placebo group (3.3%).  The 
proportion of patients who experienced at least one adverse event was 90% in the 
placebo group compared with 95% in the ocrelizumab group.  Taking into account that 
twice as many patients were randomized to ocrelizumab than placebo, the number of 
adverse events experienced by patients with an adverse event was similar (1762 events 
in the placebo group and 3690 events in the ocrelizumab group).  The proportion of 
patients who experienced an infection was 69.8% in the ocrelizumab group compared 
with 67.8% in the placebo group.  The proportion of patients with serious infections was 
similar in both groups:  5.9% in the placebo group compared with 6.2% in the 
ocrelizumab group.  As expected, the proportion of patients who reported an IRR was 
higher in the ocrelizumab group (39.9%) compared with placebo (25.5%).  Overall, 
5 patients (1.0%) experienced a serious IRR in the ocrelizumab group.  A total of 
15 malignancies in 13 patients were reported:  2 events (basal cell carcinoma and 
adenocarcinoma of the cervix) occurred in 2 patients (0.8%) in the placebo group and 
13 events (5 basal cell carcinoma, 2 invasive ductal breast carcinoma, 1 anaplastic 
large-cell lymphoma, 1 breast cancer, 1 endometrial cancer, 1 invasive breast carcinoma, 
1 malignant fibrous histiocytoma, 1 pancreatic carcinoma metastatic) occurred in 
11 patients (2.3%) in the ocrelizumab group.  The proportion of patients with serious 
adverse events (22.2% in the placebo group compared with 20.4% in the ocrelizumab 
group) was similar in both groups.  There were 5 deaths during the controlled treatment 
period, one in the placebo group (road traffic accident) and 4 in the ocrelizumab group 
(pulmonary embolism, pneumonia, pancreatic carcinoma, pneumonia aspiration). 
In the RRMS Phase II study WA21493, treatment with 300 mg × 2 and 1000 mg × 2 
ocrelizumab was generally well tolerated.  The single most common adverse event by 
Preferred Term was IRR, reported by more ocrelizumab-treated patients compared with 
placebo.  The proportion of patients reporting IRRs was higher in ocrelizumab-treated 
patients after the first infusion on Day 1 of the study (9.3% in placebo arm, 34.5% in the 
300-mg × 2 arm, and 43.6% in the 1000-mg × 2 arm).  Rates of infections and serious 
infections were similar in the ocrelizumab arms compared with placebo.  The rate of 
infections remained consistent throughout the study, including the treatment period (up 
to Week 96) and the treatment-free period (up to Week 144).  There was one 
malignancy (breast cancer) reported in Study WA21493 in the ocrelizumab group.  The 
adverse event profile of ocrelizumab during the open-label treatment period up to 
Week 96 and during follow-up and monitoring/observation periods up to Week 144 was 
consistent with observations during the first 24 weeks.   
A total of 3 deaths were reported in RRMS Study WA21493 up to the time of the 
Investigator’s Brochure update in November 2015.  Two fatalities occurred after 


 
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completion of the study treatment and during the Safety Follow-up Period when B cells 
had already repleted. 
See the Ocrelizumab Investigator’s Brochure for additional information regarding safety. 
1.2.1.2 
Clinical Activity 
Study WA25046 met its primary endpoint of confirmed disability progression (CDP) 
sustained for at least 12 weeks, showing that treatment with ocrelizumab significantly 
reduced the progression of clinical disability for 12 weeks compared with placebo (risk 
reduction:  24%; hazard ratio:  0.76; 95% confidence interval [CI]:  0.59 − 0.98; 
p = 0.0321).  The study also met its key secondary endpoints.  Time to CDP sustained for 
24 weeks was significantly (p = 0.0365) reduced with ocrelizumab compared with 
placebo (risk reduction:  25%).  Change in the 25-foot timed walk from baseline to 
Week 120 had a significantly (p = 0.0404) reduction of 29% with ocrelizumab.  Percent 
change in total volume of T2 lesions on MRI from baseline to Week 120 was significantly 
(p < 0.0001) improved with ocrelizumab (decrease of 3.4%) compared with placebo 
(increase of 7.4%).  Finally, percent change in whole brain volume from Week 24 to 
Week 120 was significantly (p < 0.0206) improved with ocrelizumab (17.5% reduction) 
compared with placebo. 
Study WA21493 results at Week 24 demonstrated that both doses of ocrelizumab 
achieved the primary endpoint by significantly reducing the number of Gd-enhancing 
lesions compared with placebo (p < 0.0001).  Both ocrelizumab dose groups showed 
statistically significant reductions in annualized relapse rate (ARR) compared with the 
placebo group (ARR = 0.125 for the ocrelizumab 300 mg × 2 group [p = 0.0005] and 
ARR = 0.169 for the ocrelizumab 1000 mg × 2 group [p = 0.0014]) compared with 
ARR = 0.637 for the placebo group, representing a relative reduction (RR) of 80% and 
73% in ARR versus placebo group for the low- and high-dose ocrelizumab groups, 
respectively.  In exploratory analyses, both ocrelizumab groups were superior to the 
IFN-β-1a group for the primary endpoint (p < 0.0001) and the 300 mg × 2 group for ARR 
(ARR = 0.364 for the IFN-β-1a group, representing an RR of 66% in ARR [p = 0.03] for 
the ocrelizumab 300 mg × 2 group versus the IFN-β-1a group and an RR of 53.6% in 
ARR [p = 0.086] for the ocrelizumab 1000 mg × 2 group versus the IFN-β-1a group) 
(Kappos et al. 2011). 
Patients from both the placebo and IFN-β-1a groups switched to ocrelizumab 300 mg × 2 
after Week 24.  By 48 weeks, the level of benefit of ocrelizumab in reduction of ARR was 
maintained, where the patients in the ocrelizumab 300 mg × 2 group continued to have a 
suppressed ARR of 0.086 from Week 24 to 48, and patients who switched to 
ocrelizumab from either placebo or IFN-β-1a derived a similar degree of efficacy to those 
randomized to ocrelizumab from onset (ARR for placebo to ocrelizumab = 0.161 and for 
IFN-β-1a to ocrelizumab = 0.137 after the switch, representing an RR of 74% and 62.4% 
compared with ARR before the switch, respectively).  From baseline to Week 72, 


 
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patients originally randomized to ocrelizumab 300 mg × 2 maintained clinical efficacy, 
with an ARR of 0.186. 
In studies WA21092 and WA21093, ocrelizumab was superior to IFN-β-1a in reducing 
the three major markers of disease activity over the two-year controlled treatment period.  
The studies met their primary endpoint of significantly reducing ARR, with a 50% 
reduction in the ocrelizumab group compared with the IFN-β-1a group over the two-year 
period.  Additionally, the studies met their secondary endpoints of significantly delaying 
CDP (loss of physical abilities, measured by the EDSS) by approximately 40% sustained 
for both 12 and 24 weeks with ocrelizumab compared with IFN-β-1a in pre-specified, 
pooled analyses of the two studies (p = 0.0006 and p = 0.0025, respectively).  Patients in 
the ocrelizumab group also had significantly reduced acute multiple sclerosis MS-related 
inflammation and brain injury (total number of T1 Gd-enhancing lesions measured by 
MRI) at 24, 48, and 96 weeks by more than 90% and the emergence of more chronic or 
growing areas of MS-related brain injury (T2 hyperintense lesions) at 24, 48, and 96 
weeks by approximately 80% compared with patients in the IFN-β-1a group.  See the 
Ocrelizumab Investigator’s Brochure for additional information regarding efficacy. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
This is an exploratory biomarker study designed to be hypothesis-generating in order to 
better understand the mechanism of action of ocrelizumab and B-cell biology in RMS 
and PPMS.   
Data from the two pivotal Phase III ocrelizumab RMS studies (WA21092 and WA21093) 
confirmed the favorable benefit-risk of ocrelizumab seen in the Phase II study 
(WA21493), and a pivotal Phase III ocrelizumab PPMS study (WA25046) demonstrated 
favorable benefit-risk profile in PPMS (see Section 1.2.1).  Together, these data 
demonstrate that ocrelizumab 600 mg administered every 6 months is effective and well 
tolerated in patients with PPMS or relapsing forms of MS. 
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVES 
The primary objectives for the RMS cohort in this study are: 
• 
To understand the impact of ocrelizumab treatment on NfL as a biomarker of 
neuronal damage in CSF  
• 
To assess the number of CD19+ B cells in CSF (cell number/microliter) before and 
after treatment with ocrelizumab 
• 
To assess the number of CD3+ T cells in CSF (cell number/microliter) before and 
after treatment with ocrelizumab 
 


 
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2.2 
EXPLORATORY OBJECTIVES 
The exploratory objectives for the PPMS cohort in this study are: 
• 
To understand the impact of ocrelizumab treatment on NfL as a biomarker of 
neuronal damage in CSF  
• 
To assess the number of CD19+ B cells in CSF (cell number/microliter) before and 
after treatment with ocrelizumab  
• 
To assess the number of CD3+ T cells in CSF (cell number/microliter) before and 
after treatment with ocrelizumab  
 
The exploratory objectives for both cohorts in this study are: 
• 
To understand the impact of ocrelizumab treatment on NfL and other biomarkers of 
neurodegeneration in CSF as a reflection of activity in the CNS and compared with 
peripheral blood 
• 
To measure the impact of ocrelizumab treatment on B cells/B-cell subsets, 
T cells/T-cell subsets, and other cell types (e.g., natural killer [NK] cells, monocytes, 
etc.), functional parameters of B/T/other cell types (activation, cell products), and 
other biomarkers of inflammation in CSF as a reflection of activity in the CNS and 
compared with peripheral blood 
• 
To assess potential correlation between change in blood or CSF biomarkers of 
neurodegeneration or inflammation and change in MRI or efficacy outcome 
measures, such as reduction in Gd-positive lesions or EDSS score 
  
Exploratory objectives for the RMS delayed time to start control arm (Arm 4) will 
include comparisons between Arm 1 of the RMS cohort (second LP at 12 weeks) and 
Arm 4 (second LP at 12 weeks before the first dose of study drug), and may include but 
not be limited to changes in CSF, blood, and MRI biomarkers or efficacy, as outlined 
above. 
2.3 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for this study is: 
• 
To assess pharmacokinetics of ocrelizumab in CSF compared with serum 
concentration 
 
2.4 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is: 
• 
To assess the incidence of anti-drug antibodies (ADAs) to ocrelizumab 
 
2.5 
SAFETY OBJECTIVES 
The safety objective for this study is to evaluate the safety of ocrelizumab on the basis of 
the following endpoints: 
• 
Nature, frequency, severity, and timing of adverse events 


 
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• 
Changes in vital signs, physical findings, and clinical laboratory results during and 
following ocrelizumab administration 
• 
Adverse events related to biomarker sample collection 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label, multicenter, biomarker study conducted at centers in multiple 
countries in which all eligible patients will be enrolled to a single treatment arm of 
ocrelizumab.  The study will include an RMS cohort and a PPMS cohort (see Table 1).  
The RMS cohort is the main cohort and will include the majority of study participants.  
The RMS cohort will be comprised of four arms, three of which will have patients 
randomized into one of three arms (Arms 1−3) depending on the time of their second 
lumbar puncture (LP).  In Arm 4, treatment with ocrelizumab will be delayed for 
12 weeks after the first LP.  The PPMS cohort will comprise a smaller, hypothesis-
generating portion of the trial, as less is known about PPMS biomarkers.  
Arm 4 will provide a control for Arm 1 of the RMS cohort.  Due to the relapsing and 
remitting nature of RMS, some biomarkers may change due to disease course rather 
than based on influence of a drug treatment.  Therefore, some biomarkers may “regress 
to the mean” across the disease course over time, and this change could then 
inaccurately be reported as a change due to drug treatment over time.  Arm 4 will allow 
for an estimate of the natural variability of the disease when analyzing the other treated 
arms.    
Male and female patients age 18−55 years with a diagnosis of RMS or PPMS in 
accordance with the 2010 revised McDonald criteria (Polman et al. 2011; Appendix 7) 
and an EDSS score of 0−5.5 points for RMS patients, or an EDSS score of 3.0−6.5 for 
PPMS patients, at screening will be eligible.  Screening will occur over a 4-week period, 
after which eligible patients may begin treatment with ocrelizumab.   
For patients in the RMS cohort (Arms 1−3), ocrelizumab will be administered at Week 1, 
Week 3, Week 24, and Week 48.  The first dose will be administered as two infusions of 
300 mg given on Day 1 and Day 15.  The subsequent doses will be given as single 
600-mg infusions.   
For patients in the RMS cohort (Arm 4), after receiving two LPs at Week −12 and 
Week 1, the first dose of ocrelizumab will be administered as two 300-mg infusions on 
Week 1 (Day 1) and Week 3 (Day 15), with subsequent doses given as single 600-mg 
infusions at Weeks 24 and 48.  The timeline for Arm 4 will continue for an extra 
12 weeks to accommodate the same one-year dosing regimen.   


 
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For patients in the PPMS cohort, ocrelizumab 600 mg will be administered as two 
300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks (see 
Appendix 3). 
Treatment with ocrelizumab will continue for approximately 1 year after the first 
infusion; however, 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.  Patients may be eligible to continue to receive treatment if ocrelizumab is 
not commercially available in the patient’s country or is not reasonably accessible to the 
patient (see Section 4.3.6), and these patients will continue to be followed.   
Patients who complete the 52-week study (64 weeks for patients in Arm 4) and choose 
not to continue on ocrelizumab treatment, or who discontinue from treatment early, 
should enter the Safety Follow-up Period and be assessed every 24 weeks for 48 weeks 
counting from the date of the last infusion of ocrelizumab.  After 48 weeks, if the 
peripheral blood B-cell count remains depleted, monitoring of the patient should continue 
at 24-week intervals until the B-cell count has returned to the baseline value or to the 
lower limit of the normal range, whichever is lower (see Appendix 8).   
Biomarkers will be monitored in a longitudinal fashion before and after treatment with 
ocrelizumab in order to assess dynamic changes in biomarkers as they relate to drug 
exposure, length of time on drug, response to drug, and MS disease pathogenesis.  
Biomarkers will be assessed via blood draws throughout the study and via LP in CSF at 
baseline before the first dose of ocrelizumab and at one other timepoint.   
Two LPs will be drawn from each patient during the study. The two LPs will allow for 
assessment of biomarkers in CSF that are indicative of response to drug, 
pharmacokinetic/pharmacodynamic relationships, and/or disease pathogenesis in the 
CNS.  
Patients in the RMS cohort (Arms 1−3) will receive an LP before the start of dosing with 
ocrelizumab.  Subsequently, these patients will be randomized into one of three arms for 
timing of the second LP, either Week 12, 24, or 52 following the first dose of ocrelizumab.   
Patients in Arm 4 will receive two LPs, separated by a 12-week interval, before 
administration of the first dose of ocrelizumab.  Patients in this arm will be asked if 
they are willing to give an optional CSF sample via LP 12 weeks after the ocrelizumab 
dose.  
Patients in the PPMS cohort will receive an LP at the start of the study before dosing 
with ocrelizumab.  Subsequently, they will receive a second LP at Week 52 following 
the first dose of ocrelizumab.   


 
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In the case of MS relapse or worsening (for PPMS patients) during the study, the 
patient should have an unscheduled visit and will be asked to receive an optional LP at 
the time of relapse or worsening (for PPMS patients).  The patient will have another LP 
at the originally scheduled time based on their randomization, or if a relapse occurs after 
they have already given the second LP, the relapse LP will remain optional.   
All patients will be evaluated for safety throughout the study.   
In the case of early termination, the patient will be asked to have an early termination 
visit. 
A study schema for the RMS cohort Arms 1−3 is provided in Figure 1, for the RMS 
cohort Arm 4 is provided in Figure 2, and for the PPMS cohort is provided in Figure 3.  
Organization of study cohorts and overall study design is provided in Table 1.  
Figure 1 Study Schema:  RMS Cohort Arms 1−3  
 
CSF = cerebrospinal fluid; LP = lumbar puncture; RMS = relapsing multiple sclerosis. 
a For the RMS cohort, ocrelizumab will be administered at Weeks 1, 3, 24, and 48.  The first 
dose will be administered as two infusions of 300 mg given on Day 1 and Day 15.  The 
subsequent doses will be given as single 600-mg infusions. 
b The Safety Follow-up Period will begin only if the patient discontinues from treatment early 
or completes the study and does not continue on ocrelizumab treatment (i.e., commercially 
available or from another source).  Patients will be assessed in safety follow-up every 24 
weeks for 48 weeks following the last infusion of ocrelizumab.  After 48 weeks, if the 
peripheral blood B-cell count remains depleted, monitoring of the patient should continue at 
24-week intervals until the B-cell count has returned to the baseline value or to the lower 
limit of the normal range, whichever is lower.     
c Biomarkers will be assessed via blood draws at Week 1 (pre-dose Day 1), Week 3 (pre-dose 
Day 15), and at timepoints noted from Weeks 12 through 52.  Biomarkers will also be 
assessed via LP in CSF before the first dose of ocrelizumab and from a second LP at either 
Week 12, 24, or 52 following the first dose of ocrelizumab.   
 


 
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Figure 2 Study Schema:  RMS Cohort Arm 4 
 
CSF = cerebrospinal fluid; LP = lumbar puncture; RMS = relapsing multiple sclerosis. 
a In the control arm (Arm 4), treatment with ocrelizumab will be delayed for 12 weeks to 
follow the first and second CSF collection, separated by 12 weeks.  Ocrelizumab will then be 
administered at Weeks 1, 3, 24, and 48.  The first dose will be administered as two infusions 
of 300 mg given on Day 1 and Day 15.  The subsequent doses will be given as single 600-mg 
infusions. 
b The Safety Follow-up Period will begin only if the patient discontinues from treatment early 
or completes the study and does not continue on ocrelizumab treatment (i.e., commercially 
available or from another source).  Patients will be assessed in safety follow-up every 24 
weeks for 48 weeks following the last infusion of ocrelizumab.  After 48 weeks, if the 
peripheral blood B-cell count remains depleted, monitoring of the patient should continue at 
24-week intervals until the B-cell count has returned to the baseline value or to the lower 
limit of the normal range, whichever is lower.   
c Biomarkers will be assessed via blood draws at Weeks −12, 1 (pre-dose Day 1), 3 (pre-dose 
Day 15), and at timepoints noted from Weeks 12 through  52.  Biomarkers will also be 
assessed via LP in CSF, in two LPs separated by a 12-week interval, before administration of 
the first dose of ocrelizumab.  Patients in this arm will be asked if they are willing to give an 
optional CSF sample via LP 12 weeks after the ocrelizumab dose.    
 


 
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Figure 3 
Study Schema:  PPMS Cohort 
 
CSF = cerebrospinal fluid; LP = lumbar puncture; PPMS = primary progressive multiple 
sclerosis. 
a For the PPMS cohort, ocrelizumab 600 mg will be administered as two 300-mg IV infusions 
separated by 14 days at a scheduled interval of every 24 weeks. 
b The Safety Follow-up Period will begin only if the patient discontinues from treatment early 
or completes the study and does not continue on ocrelizumab treatment (i.e., commercially 
available or from another source).  Patients will be assessed in safety follow-up every 24 
weeks for 48 weeks following the last infusion of ocrelizumab.  After 48 weeks, if the 
peripheral blood B-cell count remains depleted, monitoring of the patient should continue at 
24-week intervals until the B-cell count has returned to the baseline value or to the lower 
limit of the normal range, whichever is lower.   
c Biomarkers will be assessed via blood draws at Week 1 (pre-dose Day 1), Week 3 (pre-dose 
Day 15), and at timepoints noted from Weeks 12 through 52.  Biomarkers will be assessed via 
LP in CSF before the first dose of ocrelizumab and from a second LP at Week 52 following 
the first dose of ocrelizumab.   
 


 
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Table 1 
Study Cohorts and Overall Design 
 
RMS Cohort 
 
 
First LP 
Second LP 
Arm 1 
Treatment baseline/Week 1 
Week 12 
Arm 2 
Treatment baseline/Week 1 
Week 24 
Arm 3 
Treatment baseline/Week 1 
Week 52 
Arm 4 (control arm) 
Pre-treatment baseline/ 
Week −12 
Treatment baseline/ 
Week 1 
 
PPMS Cohort 
 
 
First LP 
Second LP 
All PPMS patients 
Treatment baseline/Week 1 
Week 52 
LP = lumbar puncture; PPMS = primary progressive multiple sclerosis; RMS = relapsing 
multiple sclerosis.  
Note:  Study Day 1 is the day of the first dose of study drug, and all relative day calculations 
are based on number of days from Study Day 1. 
 
3.2 
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 total length of the study is expected to be approximately 3.5 years from the first 
patient enrolled to LPLV.   
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Ocrelizumab Dose and Schedule 
The dose level of ocrelizumab administered in this study is 600 mg.  The first dose will 
be administered as two 300-mg IV infusions separated by 14 days in order to lower 
amount of ocrelizumab administered upon first exposure.  For the RMS cohort, the 
remaining doses will be administered as single 600-mg doses every 24 weeks.  For the 
PPMS cohort, ocrelizumab will be administered as two 300-mg IV infusions separated 
by 14 days at a scheduled interval of every 24 weeks during the treatment period.  
This dosing regimen is anticipated to be well tolerated and is consistent with the dosing 
regimen used in Study WA21092 and WA21093 in patients with RMS and in 
Study WA25046 in patients with PPMS (see Section 1.2.1).   


 
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 104 patients will be enrolled in this study; 88 patients with RMS and 
16 patients with PPMS.  
4.1.1 
Inclusion Criteria 
General Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Ability to comply with the protocol, in the investigator’s judgment 
• 
Age 18 − 55 years, inclusive 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 24 weeks after the last 
dose of study treatment or until their B cells have repleted, whichever is longer 
– 
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 other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
– 
Examples of contraceptive methods with a failure rate of <1% per year include 
bilateral tubal ligation, male sterilization, 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 (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
Inclusion Criteria Specific to RMS Patients 
• 
Diagnosis of RMS in accordance with the 2010 revised McDonald criteria (Polman 
et al. 2011; Appendix 7)  
• 
EDSS score of 0 − 5.5 points, inclusive, at screening 
• 
Disease duration from the onset of MS symptoms: 
– 
Less than 15 years in patients with an EDSS > 5.0 at screening 
• 
Either treatment-naïve or receiving treatment with disease-modifying therapies, 
including prior use of IFN-β-1a (Avonex®, Rebif®), IFN-β-1b (Betaseron®/Betaferon), 
or glatiramer acetate (Copaxone®) 
• 
At least one clinically documented relapse in the past year and/or at least one 
T1-weighted Gd-enhancing lesion in the past year and/or at least one new T2 lesion 
in the past year at the time of enrollment 
 


 
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Inclusion Criteria Specific to RMS Cohort Arm 4 
• 
Must meet inclusion criteria for the RMS cohort  
• 
Separate signed Informed Consent Form for the RMS Delayed Time to Start 
Control Arm (Arm 4) 
• 
Must be willing to remain on the same dose and regimen of current standard of 
care, or no treatment if treatment-naïve, for 12 weeks after study enrollment 
– 
The treating and/or study physician must agree that the patient is eligible to 
remain on the same dose and regimen of their current standard of care at 
screening, or to receive no treatment if the patient is treatment-naïve, for 
12 weeks after study enrollment. 
 
Inclusion Criteria Specific to PPMS Patients 
• 
Diagnosis of PPMS in accordance with the 2010 revised McDonald criteria 
(Polman et al. 2011; Appendix 7)  
• 
EDSS score of 3.0 − 6.5 points, inclusive, at screening 
• 
Disease duration from the onset of MS symptoms: 
– 
Less than 10 years in patients with an EDSS at screening ≤ 5.0  
• 
Documented history of at least one of the following laboratory findings in CSF: 
– 
Elevated IgG Index 
– 
One or more IgG OCBs detected by isoelectric focusing 
 
4.1.2 
Exclusion Criteria 
General Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Diagnosis of secondary progressive MS without relapses for at least 1 year 
• 
History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, 
tuberculosis) 
• 
History of recurrent aspiration pneumonia requiring antibiotic therapy 
• 
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) 
• 
History of or currently active primary or secondary immunodeficiency  
• 
History of coagulation disorders  
• 
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 


 
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• 
Known presence or history of other neurologic disorders, including but not limited to, 
the following: 
– 
History or known presence of progressive multifocal leukoencephalopathy 
(PML) 
– 
History or known presence of CNS or spinal cord tumor (e.g., meningioma, 
glioma) 
– 
History or known presence of potential metabolic causes of myelopathy (e.g., 
untreated vitamin B12 deficiency) 
– 
History or known presence of infectious causes of myelopathy (e.g., syphilis, 
Lyme disease, HTLV-1, herpes zoster myelopathy) 
– 
History of genetically inherited progressive CNS degenerative disorder (e.g., 
hereditary paraparesis; mitochondrial encephalopathy, lactic acidosis, and 
stroke-like episodes [MELAS]) 
– 
History or known presence of systemic autoimmune disorders, potentially 
causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody 
syndrome, Sjögren’s syndrome, Behçet’s disease) 
– 
History or known presence of sarcoidosis 
– 
Neuromyelitis optica 
– 
Ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or 
ischemia of the spinal cord 
– 
Severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression) 
• 
Significant, uncontrolled disease, such as cardiovascular (including cardiac 
arrhythmia), pulmonary (including chronic obstructive pulmonary disease), renal, 
hepatic, endocrine, gastrointestinal, or any other significant disease 
• 
Congestive heart failure (according to New York Heart Association III or IV 
functional severity) 
• 
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  
• 
Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study 
• 
Contraindications for, or intolerance to, oral or IV corticosteroids, including IV 
methylprednisolone, according to the country label, including: 
– 
Psychosis not yet controlled by a treatment 
– 
Hypersensitivity to any of the treatment drug constituents 
• 
Contraindication for LP 


 
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• 
Previous treatment with B cell-targeted therapies (e.g., rituximab, ocrelizumab, 
atacicept, belimumab, or ofatumumab) 
• 
Previous treatment with natalizumab (Tysabri®), alemtuzumab, anti-CD4 agents, 
cladribine, teriflunomide, cyclophosphamide, mitoxantrone, azathioprine, 
mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone 
marrow transplantation 
• 
Treatment with fingolimod (Gilenya®), dimethyl fumarate (Tecfidera®), or similar 
treatment within 6 months prior to enrollment 
• 
Receipt of a live vaccine within 6 weeks prior to enrollment 
– 
Vaccinations before baseline:  In rare cases where a live vaccine must be 
administered by the patient’s physician, the screening period may need to be 
prolonged but cannot exceed 12 weeks. 
• 
Systemic corticosteroid therapy within 4 weeks prior to baseline 
– 
The screening period may be extended (but cannot exceed 8 weeks) for 
patients who have used systemic corticosteroids for their MS before screening.  
• 
Previous or concurrent treatment with any investigational agent or treatment with 
any experimental procedure for MS (e.g., treatment for chronic cerebrospinal 
venous insufficiency) 
• 
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]) or hepatitis C (HepCAb)  
– 
AST or ALT ≥ 2.0 upper limit of normal (ULN) 
– 
Platelet count < 100,000/μL (< 100 × 109/L) 
– 
ANC < 1.5 × 103/μL 
– 
Abnormal lymphocyte count (below LLN) 
Re-testing before baseline:  in rare cases in which the screening laboratory 
samples are rejected by the laboratory (e.g., hemolyzed sample) or the results 
are not assessable (e.g., indeterminate) or abnormal, the tests need to be 
repeated.  Any abnormal screening laboratory value that is clinically relevant 
should be retested in order to rule out any progressive or uncontrolled 
underlying condition.  The last value before randomization must meet study 
criteria.  In such circumstances, the screening period may need to be prolonged 
but should not exceed 8 weeks. 
• 
Inability to complete an MRI (contraindications for MRI include but are not restricted 
to weight ≥ 140 kg, pacemaker, cochlear implants, intracranial vascular clips, surgery 
within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior 
to the time of the intended MRI, contraindication to gadolinium, etc.)   
• 
Lack of peripheral venous access 


 
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• 
Pregnant or lactating, or intending to become pregnant during the study 
– 
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug. 
 
Exclusion Criteria Specific to RMS Patients 
• 
Diagnosis of PPMS or SPMS without relapses 
 
4.2 
METHOD OF DETERMINATION OF THE TIME OF 
LUMBAR PUNCTURE 
Patients in Arms 1−3 of the RMS cohort will be randomized into each of the three arms 
at 1:1:1 ratio according to the timing of the second LP at Week 12, 24, or 52 following 
the first dose of ocrelizumab (see Table 1).  An independent interactive voice/web 
response system (IxRS) provider will conduct randomization and maintain the treatment 
assignment code.  Enrolled patients will be stratified by the previous disease-modifying 
therapy (DMT) treatment status (DMT-naïve vs. DMT-experienced).  Therefore, the 
proportion of DMT-naïve patients will be approximately equal in each of three arms.    
A fourth RMS arm with delayed treatment start (Arm 4) will not be a part of the 
randomization and will be recruited separately.   
All patients in the PPMS cohort will receive the second LP at 52 weeks and therefore 
will not be randomized.   
Enrollment of the PPMS cohort and/or the RMS control arm (Arm 4) is open to all 
sites choosing to participate. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Ocrelizumab 
Ocrelizumab will be supplied by the Sponsor as a liquid formulation containing 
30-mg/mL ocrelizumab in 20 mM sodium acetate at pH 5.3, with 4% trehalose and 
0.02% polysorbate 20.  The drug product is provided as a single-use liquid formulation in 
a 15-cc, type I USP, glass vial fitted with a 20-mm, fluoro-resin, laminated stopper and 
an aluminum seal with a flip-off plastic cap and contains a nominal 300 mg ocrelizumab.  
No preservative is used as each vial is designed for single use. 
The ocrelizumab drug product must be diluted before administration.  Solutions of 
ocrelizumab for IV administration are prepared by dilution of the drug product into an 
infusion bag containing 0.9% sodium chloride to a final drug concentration of 1 to 
2 mg/mL. 
Ocrelizumab may contain fine translucent and/or reflective particles associated with 
enhanced opalescence.  Do not use the solution if discolored or if the solution contains 
discrete foreign particulate matter. 


 
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The infusion solution must be administered using an infusion set with an in-line, sterile, 
non-pyrogenic, low-protein-binding filter (pore size of up to 0.2 micrometer). 
The prepared infusion solution of ocrelizumab is physically and chemically stable for 
24 hours at 2−8°C and subsequently 8 hours at room temperature.  The prepared 
infusion solution should be used immediately.  If not used immediately, it can be stored 
up to 24 hours at 2−8°C.  Infusion solution must be completely administered to the 
patient within 32 hours of preparation (not exceeding 24 hours at 2−8°C and 8 hours at 
room temperature).  In the event an IV infusion cannot be completed the same day, the 
remaining solution should be discarded. 
For information on the formulation and handling of ocrelizumab, see the 
Ocrelizumab Investigator's Brochure. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Ocrelizumab 
For the RMS cohort, dose 1 of ocrelizumab will be administered as two 300-mg IV 
infusions (600 mg total) separated by 14 days (i.e., Day 1 [Week 1] and Day 15 
[Week 3]).  Subsequent doses will be administered as one 600-mg IV infusion every 
24 weeks for a maximum of 3 doses (see Table 2).   
For the PPMS cohort, ocrelizumab 600 mg will be administered as two 300-mg IV 
infusions separated by 14 days at a scheduled interval of every 24 weeks (see Table 3).   
Although ocrelizumab may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator.  Ocrelizumab infusions 
should always be administered in a hospital or clinic environment under close 
supervision of the investigator or a medically qualified staff member.  It is anticipated 
that the patient will need to stay at the hospital or clinic for a full day for the infusion 
visits. 
Each ocrelizumab infusion should be given as a slow IV infusion over approximately 
150 minutes (2.5 hours) for the 300-mg dose and approximately 240 minutes (4 hours) 
for the 600-mg dose.  To reduce potential IRRs, all patients will receive prophylactic 
treatment with 100 mg of methylprednisolone (or equivalent IV steroid), administered by 
slow IV infusion, to be completed approximately 30 minutes before the start of each 
ocrelizumab infusion.  
It is also strongly recommended that the infusion is accompanied by prophylactic 
treatment with an analgesic/antipyretic such as acetaminophen/paracetamol (1 g) and 
an IV or oral antihistamine (such as IV diphenhydramine 50 mg or equivalent dose of 
alternative) 30 − 60 minutes prior to the start of an infusion to reduce potential IRRs.  
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should be given appropriate warnings concerning drowsiness and potential impairment 
of ability to drive or operate machinery. 
Since transient hypotension may occur during ocrelizumab infusion, the investigator may 
wish to withhold anti-hypertensive medications 12 hours prior to ocrelizumab infusion.  
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.  
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. 
See the Ocrelizumab Investigator’s Brochure for detailed instructions on drug 
preparation, storage, and administration.  
An overview of the ocrelizumab dosing is presented in Table 2 and Table 3.   
Table 2 
Overview of Ocrelizumab Dosing:  RMS Cohort  
1st Dose a,c 
Subsequent Dose(s) b,c 
 
Day 1  
Infusion 
Day 15 
Infusion 
 
Ocrelizumab  
300 mg IV 
300 mg IV 
600 mg IV 
IV = intravenous; RMS = relapsing multiple sclerosis. 
Note:  Before each infusion of ocrelizumab, 100 mg of methylprednisolone IV will be 
administered to reduce the potential for infusion-related reactions.  Each treatment period has a 
duration of 24 weeks.   
a The first dosing will consist of two IV infusions separated by 14 days (i.e., Days 1 and 15). 
b Beginning with the second dose, a single infusion of ocrelizumab will be administered. 
c Prior to the next infusion, a clinical evaluation will be performed to ensure that the patient 
remains eligible for retreatment. 
 


 
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Table 3 
Overview of Ocrelizumab Dosing:  PPMS Cohort 
1st Dose a 
Subsequent Dose(s) a 
Group 
Day 1 Infusion 
Day 15 Infusion 
First Infusion 
Next Infusion 
(14 days later) 
Ocrelizumab 
300 mg IV 
300 mg IV 
300 mg IV 
300 mg IV 
IV = intravenous; PPMS = primary progressive multiple sclerosis. 
Note:  Before each infusion of ocrelizumab, 100 mg of methylprednisolone IV (or equivalent IV 
steroid) will be administered to reduce the potential for infusion-related reactions.  Each 
treatment period has a duration of 24 weeks.  
a Prior to the next infusion, a clinical evaluation will be performed to ensure that the patient 
remains eligible for retreatment.  
 
Because of possible need to vary infusion rates depending on tolerance of the infusion, 
the total infusion time may exceed the time stated.  Unless an IRR occurs 
necessitating discontinuation, the entire contents of the infusion bag must be 
administered to the patient. 
Guidelines for treatment discontinuation are provided in Section 4.6.3. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.3.3 
Methylprednisolone  
Premedicate with 100 mg of methylprednisolone (or an equivalent) approximately 
30 minutes prior to each ocrelizumab infusion to reduce the frequency and severity of 
IRRs.  
Any overdose or incorrect administration of methylprednisolone should be noted on the 
Methylprednisolone Administration eCRF.  Adverse events associated with an overdose 
or incorrect administration of methylprednisolone should be recorded on the 
Adverse Event eCRF. 
4.3.4 
Other Prophylactic Treatment 
Additional premedication with an antihistaminic drug (e.g., diphenhydramine) is 
recommended approximately 30 − 60 minutes before each infusion of ocrelizumab to 
further reduce the frequency and severity of IRRs.  The addition of an antipyretic (e.g., 
acetaminophen/paracetamol) may also be considered. 
4.3.5 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (ocrelizumab) will be provided by the 
Sponsor where required by local health authority regulations.  The study site will 


 
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acknowledge receipt of IMPs, 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 returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction 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. 
4.3.6 
Post-Trial Access to Ocrelizumab 
The Sponsor (Genentech, a member of the Roche Group) will offer post-trial access to 
the study drug (ocrelizumab) free of charge to eligible patients in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, as 
outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after completing the study if any of 
the following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for MS 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for MS 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 


 
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4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 4 weeks prior to screening to the study completion/discontinuation visit.  All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  
Medications used after treatment discontinuation should be recorded during the Safety 
Follow-up Period. 
4.4.1 
Permitted Therapy  
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
• 
Anti-hypertensive medications   
– 
Since transient hypotension may occur during ocrelizumab infusion, the 
investigator may wish to withhold anti-hypertensive medications 12 hours prior 
to ocrelizumab infusion. 
• 
IV or oral corticosteroids 
– 
Patients who experience a relapse may receive treatment with IV or oral 
corticosteroids, if judged to be clinically appropriate by the investigator. Such 
patients should not discontinue treatment solely based on the occurrence of a 
relapse, unless the patient or investigator feels he or she has met the criteria 
for withdrawal (Section 4.6.3). 
 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the program and for at least 7 days 
prior to initiation of ocrelizumab, unless otherwise specified below: 
• 
Therapies for MS other than systemic corticosteroids 
• 
Immunosuppressants, lymphocyte-depleting agents, or lymphocyte-trafficking 
blockers while patient is B-cell depleted 
 
See the Ocrelizumab Investigator’s Brochure for a more detailed safety profile. 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of activities for the RMS cohort Arms 1−3, 
Appendix 2 for the schedule of activities for the RMS cohort Arm 4, and Appendix 3 for 
the schedule of activities for the PPMS cohort. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  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. 
4.5.2 
Medical History and Demographic Data 
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, use of any previous MS medication 
should be recorded.  
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
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 per the schedule of 
activities.  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. 
Height and weight will be measured at screening.  After the screening visit, only weight 
will be measured per the schedule of activities.  
4.5.4 
Vital Signs 
Vital signs should be performed at all visits.  Vital signs will include the measurements of 
heart rate, systolic and diastolic blood pressure, and temperature. 
Vital signs should be taken within 45 minutes prior to the premedication 
methylprednisolone infusion.  In addition, vital signs should be obtained prior to the 
ocrelizumab infusion then every 15 minutes for the first hour, followed by every 
30 minutes until 1 hour after the end of the infusion.   
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms. 
4.5.5 
Assessment of Disability 
Disability in MS will be measured by the EDSS, which will be assessed at timepoints 
according to the appropriate schedule of activities.   
The EDSS is based on a standard neurological examination, incorporating seven 
functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, 


 
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and cerebral [or mental], plus “other”) rated and scored as Functional Systems (FS) 
scores.  Each FS score is an ordinal clinical rating scale ranging from 0 to 5 or 6.  These 
ratings are then used in conjunction with observations and information concerning 
ambulation and use of assistive devices to determine the EDSS score.  The EDSS is a 
disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death) (see 
Appendix 4). 
4.5.6 
Neurological Examinations 
Neurological examinations will be performed at timepoints according to the appropriate 
schedule of activities and in the case of relapse or early termination so that the 
investigator can assess whether the patient is experiencing a relapse of MS or another 
neurological (non-MS) disorder. 
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/sings (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 (see 
Appendix 6).  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. 
Potential relapses should be recorded throughout the treatment period.  Protocol-defined 
relapse is the occurrence of new or worsening neurological symptoms attributable to 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 
immediately preceded by a stable or improving neurological state for least 30 days.  The 
new or worsening neurological symptoms must be accompanied by objective 
neurological worsening consistent with an increase of at least half a step on the EDSS 
scale, or 2 points on one of the appropriate FS scales, or 1 point on two or more of the 
appropriate FS scales.  The change must affect the selected FS (i.e., pyramidal, 
ambulation, cerebellar, brainstem, sensory, or visual).  Episodic spasms, sexual 
dysfunction, fatigue, mood change, or bladder or bowel urgency or incontinence will not 
suffice to establish a relapse.  Sexual dysfunction and fatigue will not be scored.  
(Note:  Adjudication of protocol-defined relapses will be performed by the Sponsor based 
on pre-specified criteria, applied to data collected by investigator, in a blinded fashion.) 
For patients in the PPMS cohort, disease worsening or improvement over the treatment 
period will also be assessed and is defined as a 20% change in timed 25-foot walk test or 
a 20% change in 9-hole peg test time (see Appendix 3).  


 
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4.5.7 
Brain Magnetic Resonance Imaging 
MRI will be used to monitor CNS lesions and potentially other pathophysiology, such as 
inflammation and neurodegeneration.  Brain MRI scans will be obtained at study visits as 
shown in the schedule of activities and at the study completion/early termination visit.   
MRI scans will be read by a centralized reading center for both efficacy and safety 
endpoints.  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. 
Assessments will include T1-weighted scans before and after injection of multicyclic 
gadolinium contrast agent and may also include, but may not be limited to:  
fluid-attenuated inversion-recovery (FLAIR), proton density-weighted, and T2-weighted 
scans. 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis according to the schedule of activities. 
Pre-infusion laboratory samples may be drawn up to 14 days before the start of infusion 
so that routine laboratory test results are available for review before the infusion, unless 
otherwise specified.   
• 
Hematology (hemoglobin, hematocrit, RBCs, WBC absolute and differential, ANC, 
and quantitative platelet count) 
• 
Serum chemistry (AST, ALT, GGT, total bilirubin, urea, uric acid, creatinine, 
potassium, sodium, calcium, phosphorus)   
• 
Urine dipstick (standard to assess kidney function) 
• 
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. 
• 
Viral serology 
– 
Hepatitis screening 
– 
Must be negative for HBsAg and HepCAb prior to enrollment; if HBcAb is 
positive at screening, HBV DNA 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. 
 


 
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Biomarkers 
• 
Biomarker samples for the following tests should be drawn according to the 
schedule of activities timepoint and will be sent to the study site's local laboratory for 
same-day analysis and processing: 
– 
Blood:  analysis of B and T cells, which may include but will not be limited to 
number, activation status or markers, functional attributes, activity, and/or 
molecular status of cells 
– 
CSF:  analysis of B and T cells, which may include but will not be limited to 
number, activation status or markers, functional attributes, activity, and/or 
molecular status of cells  (supernatant, i.e., non-cellular portion of sample to be 
aliquoted, frozen, and sent to central laboratory and/or Sponsor or designee) 
• 
Biomarker samples for the following tests should be drawn according to the SOA 
timepoint and 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 
laboratory 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 cells, NK cells, and other leukocytes 
– 
Serum sample for PK analysis  
– 
Serum sample for measurement of ADAs to ocrelizumab 
– 
CSF supernatant:  analysis may include but will not be limited to NfL, levels of 
soluble neurodegeneration markers, and/or inflammatory markers; and the 
relationship between ocrelizumab exposure and selected pharmacodynamics 
– 
Serum and plasma:  analysis may include but will not be limited to levels of 
soluble neurodegeneration markers  (i.e., NfL) and/or inflammatory markers 
(i.e., CXCL13); 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):  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 
 
Exploratory biomarker research may include, but will not be limited to, the assessments 
listed above.  Given the complexity and exploratory nature of biomarker analyses, 
results from the analyses will not be shared with investigators or study participants, 
unless required by law. 


 
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In the case of suspected PML, serum or plasma biomarker, PK, or ADA samples may be 
used to assess status of JC virus (JCV) antibodies. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Fluoroscopy can be used, if required, for the LP to draw the CSF.  
Biological samples will be destroyed when the final clinical study report has been 
completed, with the following exceptions: 
• 
Biomarker samples, including CSF, plasma, serum, blood collected for RNA 
extraction, and PBMC samples, will be destroyed no later than 15 years after the 
date of final closure of the clinical database. 
 
4.5.9 
Optional Samples for Roche Clinical Repository 
Genentech is a member of the Roche group and participates in the collection and/or 
submission of biological samples to the Roche Clinical Repository (RCR).  Collection 
and submission of biological samples to the RCR is contingent upon the review and 
approval of the RCR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site is not granted the necessary approval for RCR sampling, this 
section of the protocol will not be applicable at that site. 
4.5.9.1 
Overview of the Roche Clinical Repository 
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 


 
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4.5.9.2 
Sample Collection 
The following samples will be collected for research purposes, including, but not limited 
to, research on inherited or non-inherited biomarkers related to ocrelizumab, RMS, or 
MS: 
• 
Blood for plasma non-heritable protein analysis 
• 
Blood for non-heritable RNA expression profiling 
• 
Blood for DNA collection and genetic analysis 
 
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.  For DNA collection, only a single sample is needed and will be 
obtained at baseline.  However, if the sample collection is missed for any reason, the 
sample may be obtained at any subsequent visit.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.9.3 
Confidentiality 
Confidentiality for All RCR Specimens 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RCR specimens 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. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 


 
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Additional Confidentiality for Specimens Used for Genetic Research 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens collected for genetic research.  
Upon receipt by the RCR, specimens for genetic research are "double-coded" by 
replacing the patient identification number with a new independent number.  Data 
generated from the use of these specimens and all clinical data transferred from the 
clinical database and considered relevant are also labeled with this same independent 
number.  A "linking key" between the patient identification number and this new 
independent number is stored in a secure database system.  Access to the linking key is 
restricted to authorized individuals and is monitored by audit trail.  Legitimate operational 
reasons for accessing the linking key are documented in a standard operating procedure.  
Access to the linking key for any other reason requires written approval from the Pharma 
Repository Governance Committee and Roche's Legal Department, as applicable. 
4.5.9.4 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the DNA Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.9.5 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the DNA Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study ML29966 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study ML29966. 
4.5.9.6 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 


 
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management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  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 RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Criteria for Re-Treatment with Ocrelizumab 
Prior to re-treatment with ocrelizumab, patients will be evaluated for the following 
conditions and laboratory abnormalities.  If any of these are present prior to re-dosing, 
further administration of ocrelizumab should be suspended until these are resolved or 
held indefinitely: 
• 
Life-threatening (Grade 4) infusion-related event that occurred during a previous 
ocrelizumab infusion 
• 
Any significant or uncontrolled medical condition or treatment-emergent, 
clinically significant laboratory abnormality 
• 
Active infection 
• 
Ongoing pregnancy 
 
In addition to the criteria above, patients with PPMS will also be evaluated for: 
• 
 ANC < 1.5 × 103/μL 
 
4.6.2 
Patient Discontinuation 
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.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance, defined as failure to follow dosing instructions or to 
complete program visits 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 


 
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4.6.3 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Ongoing pregnancy:  Please note that the pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of birth, 
and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and newborn complications.   
• 
Life-threating IRR or serious hypersensitivity reaction 
• 
Active hepatitis B infection or reactivation 
• 
PML 
• 
Active tuberculosis, either new onset or reactivation 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.4 
Study and Site 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.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council on Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Ocrelizumab is currently in clinical development for the treatment of MS.  Identified and 
potential risks associated with ocrelizumab treatment will continue to be closely 
monitored throughout the clinical program.  Patient safety during the ocrelizumab 
program is ensured by targeting the most appropriate patient population, stringent safety 


 
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monitoring by the Sponsor, and protocol-specified ocrelizumab treatment interruption 
criteria.  Patients will be evaluated clinically and with standard laboratory tests before the 
study and at regular intervals during the study.  Safety evaluations will consist of medical 
interviews, recording of adverse events, physical examinations, and standard laboratory 
measurements.  Adverse events will be graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). 
Administration of ocrelizumab will be performed in a hospital or clinic environment under 
close supervision of the investigator or a medically qualified staff member with 
immediate availability of full resuscitation facilities.  All adverse events and serious 
adverse events will be recorded during the study and for up to 48 weeks after the last 
dose of ocrelizumab as provided through this study.  Related serious adverse events 
must be collected and reported regardless of the time elapsed from the last study drug 
administration, even if the study has been closed.  If the patient is unable to return for 
the safety follow-up visit, the discontinuation visit information may be collected via phone 
call. 
Safety assessments will include the incidence, nature, and severity of (serious) adverse 
events graded per the NCI CTCAE v4.0.  Safety assessments will be conducted for the 
RMS cohort Arms 1−3 per the schedule of activities in Appendix 1, for the RMS cohort 
Arm 4 per the schedule of activities in Appendix 2, and for the PPMS cohort per the 
schedule of activities in Appendix 3. 
The potential safety issues anticipated in this study, as well as measures intended to 
avoid or minimize these issues, are outlined in the following sections. 
5.1.1 
Risks Associated with Ocrelizumab  
5.1.1.1 
Identified Risks and Adverse Drug Reactions 
5.1.1.1.1 
Infusion-Related Reactions 
All CD20-depleting agents administered via the intravenous route, including 
ocrelizumab, have been associated with acute 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.  These reactions may present as pruritus, rash, urticaria, erythema, throat 
irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal edema, flushing, 
hypotension, pyrexia, fatigue, headache, dizziness, nausea, and tachycardia.  
Patients should be observed for at least one hour after the completion of the infusion for 
any symptom of IRR.  They will be informed about the possibility of delayed 
post-infusion symptoms and instructed to contact their study physician if they develop 
such symptoms. 


 
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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.  
5.1.1.1.2 
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% to 6%, simplex and zoster) than with 
comparators (approximately 3%).  
During the controlled period of the pivotal trials, the proportion of patients with 
serious infections was lower in RMS in the ocrelizumab group (1.3%) than in the 
interferon beta-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 (RA) 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 MS patient treated with ocrelizumab.  
There were no reports of hepatitis B reactivation in MS patients treated with 
ocrelizumab, but it had been reported in one RA patient treated with ocrelizumab.  
HBV screening should be performed in all patients before initiation of treatment with 
ocrelizumab as per local guidelines.  Patients with active hepatitis B virus should not 
be treated with ocrelizumab.  Patients with positive serology should consult liver 
disease experts before the start of treatment and should be monitored and managed 
following local medical standards to prevent hepatitis B reactivation.  
There were no reports of PML in patients treated with ocrelizumab.  JCV infection 
resulting in PML has been observed in patients treated with anti-CD20 antibodies and 
other MS therapies and associated with risk factors (e.g., patient population, 
polytherapy with immunosuppressants).  However, a risk of PML cannot be ruled out.  
Healthcare professionals should be alerted to the 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.  Please refer to Appendix 6 for guidance for 
diagnosis of PML.  
Delay ocrelizumab administration in patients with an active infection until the 
infection is resolved.   


 
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5.1.1.1.3 
Decrease in Immunoglobulins 
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins (Igs) over 
2 years, mainly driven by reduction in IgM, with no observed association with serious 
infections.  The proportion of patients with decrease in Igs below the LLN increased 
over time and with successive dosing.   
5.1.1.1.4 
Delayed Return of Peripheral B Cells 
Treatment with ocrelizumab leads to rapid depletion of CD19+  B cells in blood by 
14 days post-treatment (first timepoint of assessment) as an expected pharmacologic 
effect.  This was sustained throughout the treatment period.  The longest follow-up time 
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 their B cells have repleted. 
5.1.1.2 
Potential Risks 
5.1.1.2.1 
Hypersensitivity Reactions  
No hypersensitivity reactions to ocrelizumab were reported in the controlled clinical 
trials.  
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. 
5.1.1.2.2 
Impaired Response to Vaccination 
The degree of impairment of B cell-dependent humoral response to neoantigens and 
polysaccharide antigens and its clinical relevance are currently unknown in patients 
with MS. 
After treatment with ocrelizumab over 2 years, the proportion of patients with positive 
antibody titers against Streptococcus pneumoniae, mumps, rubella, and varicella were 
generally similar to the proportions at baseline. 
No data are available on the effects of vaccination in patients receiving ocrelizumab.  
Physicians 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. 
The safety of immunization with live or live-attenuated viral vaccines following 
ocrelizumab therapy has not been studied, and vaccination with live-attenuated or live 
vaccines is not recommended while B cells are depleted. 


 
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5.1.1.2.3 
Malignancies including Breast Cancer 
Malignancies are considered a potential risk with ocrelizumab due to the potential 
decreased immune surveillance associated with B-cell depletion in the context of 
treatments that are used long-term to treat chronic diseases.  During the controlled 
treatment period, the incidence rate of malignancies in the ocrelizumab treatment 
groups across the MS program was higher than IFN or placebo groups with overlapping 
confidence intervals.  The incidence rates were within the expected ranges for the MS 
population from epidemiology sources.  The only cluster identified was for breast cancer.  
No firm conclusion can be made to date concerning the risk due to the low number and 
the limited follow-up; hence, the risk remains potential to date.  
5.1.1.2.4 
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, and approximately 1% of the patients had Grade 3 or 
4 neutropenia; and no temporal association with infections was identified.   
Detailed information for all risks can be found in the current Ocrelizumab 
Investigator’s Brochure. 
5.1.2 
Management of Patients Who Experience Specific Adverse 
Events 
Guidelines for management of specific adverse events are outlined in Table 4.  
Additional guidelines are provided in the subsections below. 
Table 4 
Guidelines for Management of Specific Adverse Events 
Event 
Action to Be Taken 
Mild to moderate IRR 
• 
If the event that a patient experiences is a mild to moderate IRR 
(e.g. headache), the infusion rate should be reduced to half the 
rate at the time of the event. 
• 
This reduced rate should be maintained for at least 30 minutes.  
If tolerated, the infusion rate may then be increased according to 
the patient’s initial infusion schedule. 
Severe IRR (or complex of 
flushing, fever, and throat 
pain) 
• 
If a patient experiences a severe IRR or a complex of flushing, 
fever, and throat pain symptoms, the infusion should be 
interrupted immediately and the patient should receive 
symptomatic treatment. 
• 
The infusion should be restarted only after all symptoms have 
resolved. 
• 
The initial infusion rate at restart should be half of the infusion 
rate at the time of onset of the reaction. 


 
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Table 4 
Guidelines for Management of Specific Adverse Events (cont.) 
Life-threatening or 
disabling IRR (e.g., 
anaphylaxis) 
• 
Immediately stop ocrelizumab if there are signs of a 
life-threatening or disabling IRR during an infusion, such as 
acute hypersensitivity or acute respiratory distress syndrome. 
• 
The patient should receive appropriate treatment. 
• 
Permanently discontinue ocrelizumab in these patients. 
IRR = infusion-related reaction. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10  
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as lumbar puncture) 
 


 
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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
– 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Standard adverse events of special interest 
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 (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
– 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
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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. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 − Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported for up to 48 weeks 
after the last dose of study drug.  After this period, the investigator should report any 
serious adverse events that are believed to be related to prior study drug treatment 
(see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  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?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 5 
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 (v4.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 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 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 6): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


 
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Table 6 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
“infusion-related reaction” or “anaphylactic reaction”) on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as “systemic reaction.”  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction eCRF. 
Further details on prevention and management of IRRs are described in 
Section 5.1.1.1.1, Section 5.1.2 (Table 4), and in the Ocrelizumab Investigator’s 
Brochure. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 


 
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constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


 
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5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 


 
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
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 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of MS. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
If the death is attributed to progression of MS, "MS progression" should be recorded on 
the Adverse Event eCRF.   


 
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Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Relapsing Multiple Sclerosis 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on EDSS score.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
Hospitalization following an MS relapse as long as the reason for hospitalization is 
to receive standard treatment with IV methylprednisolone 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
– 
The patient has not experienced an adverse event 
 


 
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The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 


 
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5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
Genentech Medical Monitor contact information: 
Medical Monitor: 
, M.D.  
Telephone No.: 
 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported for up to 48 weeks after the last dose of study drug, regardless 
of causal relation with the investigational product.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 


 
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recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 24 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to study drug.  
The pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy 
Health Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An investigator who 
is contacted by the male patient or his pregnant partner may provide information on the risks of 
the pregnancy and the possible effects on the fetus, to support an informed decision in cooperation 
with the treating physician and/or obstetrician. 
5.4.3.3 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
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All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
48 weeks after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.   
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Ocrelizumab Investigator's Brochure 
• 
Ocrelizumab Core Data Sheet  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This study is designed to assess levels of NfL, levels of lymphocyte populations in CSF, 
and to generate hypotheses about biomarkers of ocrelizumab treatment in patients with 


 
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RMS and PPMS.  Levels of NfL in CSF and levels of lymphocyte populations in CSF will 
be compared to baseline levels.  In addition, Arm 1 of the RMS cohort (second LP at 
12 weeks) will be compared to Arm 4 (second LP at 12 weeks before the first dose of 
study drug). 
In this exploratory biomarker study, the analyses will be mostly descriptive and 
hypothesis-generating.  Unless otherwise specified, statistical tests will be two sided and 
the statistical significance level will be 5%.  Corresponding 95% confidence intervals will 
be presented as appropriate.  No corrections for multiple testing will be applied to the 
primary endpoint analyses, exploratory endpoint analyses, or interim analysis. 
The statistical summaries will be descriptive if not otherwise specified.  For continuous 
variables, the mean, median, standard deviation, 25th and 75th percentiles, minimum and 
maximum will be calculated.  For categorical variables, number and percentage in each 
category will be displayed.  
When establishing statistical significance, the non-parametric method will be applied as 
appropriate, i.e., the Mann-Whitney test will be used between two groups and the 
Kruskal-Wallis test will be used for three or more groups.  For the analysis of continuous 
data, the paired/unpaired t-test and non-parametric test (i.e., the Wilcoxon matched pairs 
test) will be performed as appropriate.  Some variables may be appropriately 
transformed as needed before performing statistical analysis.  The Spearman’s 
rank-correlation coefficient will be used to evaluate the relationship among the levels of 
biomarkers or between levels of biomarkers and clinical parameters. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations for this study are based on the assumed reduction from 
baseline in NfL (Gunnarsson et al. 2011) at Weeks 24 and 52 combined (Arms 2 and 3) 
in the RMS cohort.  Other biomarker measures are not considered for power 
determination.  
Assuming (a) a 30% reduction from pre-treatment NfL (mean [SD] = 860 pg/mL 
[780 pg/mL]) to post-treatment NfL (mean [SD] = 602 pg/mL [310 pg/mL]) and a 
correlation coefficient of 0.6, resulting in an SD of 643 pg/mL for the change from pre- to 
post-treatment, and (b) a desired power of 80% with a Type 1 error of 5%, a sample size 
of 51 patients is required, with approximately 25 patients in Arm 2 and 26 patients in 
Arm 3. 
This is the first study to explore the impact of ocrelizumab on CSF B-cell count.  In a 
study by Piccio et al. (2010), the rate of undetectable B cells in CSF was 74% (21/26) 
after 24−30 weeks of rituximab as an add-on to immunomodulatory therapy.  Based on 
this information and a sample size of 51 patients (Arm 2 and 3 combined), the expected 
95% CI for the CSF B-cell undetectable rate will be:  (0.61, 0.85). 


 
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In the RMS cohort, 15 patients will be included in Arm 1 to explore the possible 
reduction in NfL at Week 12 post-treatment and 15 patients will be assigned to the 
delayed start RMS control arm (Arm 4).  Fifteen patients will be recruited to the PPMS 
cohort.  The above sample sizes are not based on statistical considerations and are 
meant to help explore the changes in biomarkers and generate hypotheses for future 
studies. 
Based on the above, the total sample size for this study will be 96 patients.  The sample 
size will be increased by approximately 10% in order to account for potential missing 
post-treatment CSF information; therefore, the number of patients to be enrolled in the 
RMS cohort will be N = 88 (Arm 1:  16 patients, Arm 2:  28 patients, Arm 3:  28 
patients, and Arm 4:  16 patients), and N = 16 in the PPMS cohort.  Therefore, the total 
number of patients to be enrolled is 104.   
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, ocrelizumab administration, and discontinuations from the study will be 
summarized.  Patient disposition and the incidence of treatment discontinuation for 
reasons other than disease progression will be tabulated.  Major protocol violations, 
including violations of inclusion/exclusion criteria, will also be summarized. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Patients’ demographics, medical history, and neurological examination will be 
summarized.  MS disease history (duration since MS first symptom, duration since MS 
diagnosis), MS disease status (MS treatment naïve or experienced), and MS prior 
treatment (for those being treated) will be summarized.  Also, the baseline measures of 
key CSF biomarkers, MRI, EDSS, or other important endpoints will be summarized.  It 
should be noted that two baseline measures for the RMS control arm (Arm 4) will be 
obtained:  the first at the Week −12 visit, which is 12 weeks before the first infusion of 
ocrelizumab, and the second at the first treatment visit pre-infusion. 
6.4 
ANALYSES 
Statistical analyses will be performed on the analysis population, defined as all enrolled 
patients who (a) received at least one infusion of ocrelizumab, even if the infusion was 
incomplete or (b) received at least one LP.   
6.4.1 
Primary Endpoints 
Primary endpoints for the RMS cohort (Arms 1−3) include: 
• 
Change in levels of NfL in CSF from treatment baseline to post-treatment with 
ocrelizumab 
• 
Change in number of CD19+  B cells in CSF from treatment baseline to 
post-treatment with ocrelizumab  


 
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• 
Change in number of CD3+ T cells in CSF from treatment baseline to post-treatment 
with ocrelizumab 
 
6.4.2 
Exploratory Endpoints 
Exploratory endpoints for the PPMS cohort include: 
• 
Change in levels of NfL in CSF from treatment baseline to post-treatment with 
ocrelizumab 
• 
Change in number of CD19+ B cells in CSF from treatment baseline to 
post-treatment with ocrelizumab  
• 
Change in number of CD3+ T cells in CSF from treatment baseline to 
post-treatment with ocrelizumab 
 
CSF biomarker endpoints for both cohorts may include, but may not be limited to: 
• 
Activation markers, functional attributes, activity, and/or molecular status of cells 
(e.g., proteins, non-heritable RNA levels, etc.) at all collected timepoints before and 
after treatment with ocrelizumab, including optional samples 
• 
Levels of soluble neurodegeneration markers and/or inflammatory markers at all 
collected timepoints before and after treatment with ocrelizumab, including optional 
samples 
 
Blood biomarker endpoints for both cohorts may include, but may not be limited to: 
• 
Change in number of CD19+ B and CD3+ T cells in blood at all collected timepoints 
before and after treatment with ocrelizumab, including at unscheduled visits 
• 
Activation markers, functional attributes, activity, and/or molecular status of PBMCs 
or cell products (e.g., proteins, non-heritable RNA levels) at all collected timepoints 
before and after treatment with ocrelizumab, including at unscheduled visits 
• 
Levels of NfL, levels of soluble neurodegeneration markers, and/or inflammatory 
markers in the peripheral blood serum or plasma at all collected timepoints before 
and after treatment with ocrelizumab, including at unscheduled visits 
 
MRI biomarker endpoints for both cohorts may include, but may not be limited to: 
• 
Total number of T1 Gd-enhanced lesions at all collected timepoints before and after 
treatment with ocrelizumab, including at unscheduled visits  
• 
Change in total T2 lesion volume at all collected timepoints before and after 
treatment with ocrelizumab, including at unscheduled visits 
• 
Total number of new and/or enlarging T2 lesions at all collected timepoints before 
and after treatment with ocrelizumab, including at unscheduled visits 
• 
Changes in regional or total brain volume at all collected timepoints before and after 
treatment with ocrelizumab, including at unscheduled visits 
• 
Total number of leptomeningeal-enhancing regions at all collected timepoints 
before and after treatment with ocrelizumab, including at unscheduled visits 
 


 
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Efficacy endpoints for both cohorts may include, but may not be limited to: 
• 
Change in EDSS score from baseline 
 
Other analyses may include evaluation of the possible associations between the 
changes in biomarkers of neurodegeneration or inflammation and change in MRI or 
efficacy outcome measures, such as reduction in Gd-positive lesions or time to 
worsening as measured by the EDSS score (RMS and PPMS cohort), or the 25-foot 
timed walk or the 9-hole peg test (PPMS cohort only). 
Endpoints for the RMS control arm (Arm 4) will include comparisons between Arm 1 
of the RMS cohort (treatment baseline to second LP at 12 weeks) and Arm 4 
(pre-treatment baseline to treatment baseline, second LP at 12 weeks before the first 
dose of study drug), and may include, but may not be limited to, changes in CSF at all 
collected timepoints including optional samples, blood, and MRI biomarkers or efficacy, 
as outlined above. 
6.4.3 
Pharmacokinetic and Immunogenicity Endpoints 
Pharmacokinetics and immunogenicity may be explored in relation to the 
pharmacodynamics of blood and/or CSF biomarkers in both cohorts.  Serum 
concentration of ocrelizumab may be measured at Weeks 12, 24, 48, and 52; in the case 
of early termination; and at safety follow-up.  The level of ocrelizumab may be measured 
in the CSF at Weeks 12, 24, and/or 52 for the RMS cohort; and at Week 52 for the 
PPMS cohort; and/or in a CSF sample taken at an unscheduled visit or from an optional 
sample.  
Assessment may include, but may not be limited to, the relationship of pharmacokinetics 
in CSF to levels of cells in CSF, or to NfL levels in CSF, and/or compared with serum 
concentration. 
6.5 
SAFETY ANALYSES 
Safety analyses will be performed on the analysis population. 
Safety will be assessed through summaries of adverse events (including incidence rates 
and corresponding 95% CIs) and clinical laboratory abnormalities.  All adverse events 
occurring on or after treatment on Day 1 will be coded, summarized by NCI CTCAE v4.0 
grade, and tabulated by body system and Preferred Term for individual events within 
each body system.  Grade 3 to 5 adverse events, serious adverse events, adverse 
events leading to treatment discontinuation, time to withdrawal of the study due to an 
adverse event, adverse events leading to infusion adjustment, and treatment-related 
events will be summarized.  In addition, all serious adverse events and deaths will be 
listed. 


 
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Associated laboratory parameters, such as hepatic function, renal function, and 
hematology values, will be grouped and presented together.  Marked abnormalities will 
also be flagged.  
Ocrelizumab exposure will be summarized, including duration and dosage.  
6.6 
INTERIM ANALYSIS 
An interim analysis may be performed when approximately 50% of patients have had 
their second LP. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC through 
use of eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event 
of discrepant data, the CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data will be sent directly to the CRO, using 
the CRO's standard procedures to handle and process the electronic transfer of these 
data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used to handle and process the electronic transfer of these 
data.   
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures.  
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 


 
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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 


 
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7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results (including flow cytometry data), and medication inventory 
records, must be retained by the Principal Investigator for at least 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/EC−approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 


 
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The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 


 
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or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 


 
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data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech, a member of the Roche group, and will be 
managed by Genentech and CROs.  CROs will provide clinical operations management, 
data management, biostatistics, and medical monitoring.  
An IxRS will be used to assign patient numbers, monitor enrollment and patient status, 
and to manage study treatment requests and study drug shipments.   
Patient data will be recorded via an EDC system using eCRFs. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 


 
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In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Stashenko P, Nadler LM, Hardy R, et al. Characterization of a human B lymphocyte-
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Stern JN, Yaari G, Vander Heiden JA, et al. B cells populating the multiple sclerosis 
brain mature in the draining cervical lymph nodes. Sci Trans Med 2014;6:248ra107. 
Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. 
Immunol Today 1994;15:450−454. 
Tullman MJ. A review of current and emerging therapeutic strategies in multiple 
sclerosis. Am J Manag Care 2013;19(2 Suppl):S21−27.


 
Ocrelizumab—Genentech, Inc. 
112/Protocol ML29966, Version 4 (Global) 
Appendix 1  
Schedule of Activities the RMS Cohort Arms 1−3  
Screening
 a 
Treatment Period 
Week 
 −4  
1  
(Treat-
ment 
Baseline) 
3 
12 
24 
36 
48 
52 
Day 
 
1 
15 (± 2) 
84 (± 7) 168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-Up c 
Informed 
consent d 
x 
 
 
 
 
 
 
 
 
 
 
Medical 
history & 
demographic 
data e 
x 
 
 
 
 
 
 
 
 
 
 
Review 
inclusion & 
exclusion 
criteria 
x 
x f 
 
 
 
 
 
 
 
 
 
Physical 
examination g 
x 
x f 
x f 
 
x f 
 
x f 
x 
x 
x 
x 
Weight & 
height 
x 
 
 
x h 
 
x h 
 
x h 
 
x h 
x h 
Vital signs i 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x 
x 
x 
Laboratory, Biomarker, and Other Biological Samples 
Hematology, 
chemistry, and 
urinalysis j, k, l 
x 
x f 
 
 
x f 
 
x f 
x 
x 
x 
x 


Appendix 1  
Schedule of Activities for the RMS Cohort Arms 1−3 (cont.) 
Ocrelizumab—Genentech, Inc. 
113/Protocol ML29966, Version 4 (Global) 
Screening
 a 
Treatment Period 
Week 
 −4  
1  
(Treat-
ment 
Baseline) 
3 
12 
24 
36 
48 
52 
Day 
 
1 
15 (± 2) 
84 (± 7) 168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-Up c 
Pregnancy 
test m 
x 
x f 
 
 
x f 
x 
x f 
x 
 
x 
x 
Hepatitis 
screening n 
x 
 
 
 
 
 
 
 
 
 
 
Hepatitis B 
virus DNA 
test n 
x 
(x) 
 
 
(x) 
 
(x) 
 
 
(x) 
(x) 
Quantitative Ig 
(total Ig, IgG, 
IgM, and IgA)  
x 
 
 
 
x f 
 
x f 
 
 
x 
x 
Local/on-site 
CSF specimen 
(LP) o, p 
 
x f 
 
x 
x f 
 
 
x 
x q 
 
 
Local/on-site 
blood flow 
cytometry 
sample r 
 
x f 
 
x 
x f 
 
 
x 
x 
 
 
Blood 
TBNK/B-cell 
subset panel r 
 
x f 
x f 
x 
x f 
x 
x f 
x 
x  
x 
x 


Appendix 1  
Schedule of Activities for the RMS Cohort Arms 1−3 (cont.) 
Ocrelizumab—Genentech, Inc. 
114/Protocol ML29966, Version 4 (Global) 
Screening
 a 
Treatment Period 
Week 
 −4  
1  
(Treat-
ment 
Baseline) 
3 
12 
24 
36 
48 
52 
Day 
 
1 
15 (± 2) 
84 (± 7) 168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-Up c 
Plasma 
 
x f 
x f 
x 
x f 
x 
x f 
x 
x  
x 
 
Serum 
 
x f 
x f 
x 
x f 
x 
x f 
x 
x  
x 
 
PBMC  
 
x f 
x f 
x 
x f 
x 
x f 
x 
x  
x 
 
RNA  
 
x f 
x f 
x 
x f 
 
 
x 
x  
x 
 
Serum sample 
for PK 
 
x f 
 
x 
x f 
 
x f 
x 
 
x 
x 
Serum sample 
for ADAs 
 
x f 
 
 
x f 
 
x f 
 
 
x 
x 
Neurological Assessments 
EDSS 
x 
x f, j 
 
x 
x f 
x 
x f 
x 
x 
x 
x 
Neurological 
exam s 
x 
x f 
 
x 
x f 
 
x f 
x 
x 
x 
x 
Recording of 
relapse  
x 
x f 
x  
x 
x f 
x 
x f 
x 
x 
x 
x 
Brain MRI o, p 
 
x f, t 
 
x 
x f 
 
 
x 
x q 
x 
 
Safety Assessments 
Adverse  
events u 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Appendix 1  
Schedule of Activities for the RMS Cohort Arms 1−3 (cont.) 
Ocrelizumab—Genentech, Inc. 
115/Protocol ML29966, Version 4 (Global) 
Screening
 a 
Treatment Period 
Week 
 −4  
1  
(Treat-
ment 
Baseline) 
3 
12 
24 
36 
48 
52 
Day 
 
1 
15 (± 2) 
84 (± 7) 168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-Up c 
Concomitant 
treatment 
review 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x 
x 
x v 
Premedication and Study Drug Administration 
Methylpred-
nisolone pre-
medication w 
 
x f 
x f 
 
x f 
 
x f 
 
 
 
 
Ocrelizumab 
administration  
x 
 
x 
x 
 
x 
 
x 
 
 
 
 
Optional RCR Sample Collection y 
Plasma y 
 
x f 
x f 
x 
x f 
x 
x f 
x 
x 
x 
 
RNA y 
 
x f 
x f 
x 
x f 
 
 
x 
x 
x 
 
DNA y, z 
 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
 
 
 
 


Appendix 1  
Schedule of Activities for the RMS Cohort Arms 1−3 (cont.) 
Ocrelizumab—Genentech, Inc. 
116/Protocol ML29966, Version 4 (Global) 
ADAs = anti-drug antibodies; CSF = cerebrospinal fluid; 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; Ig = immunoglobulin; 
LP = lumbar puncture; MRI = magnetic resonance imaging; MS = multiple sclerosis; NfL = neurofilament light; PBMC = peripheral blood 
mononuclear cell; PCR = polymerase chain reaction; PK = pharmacokinetic; PML = progressive multifocal leukoencephalopathy; RCR = Roche 
Clinical Repository; RMS = relapsing multiple sclerosis; TBNK = T cells, B cells, and natural killer cells. 
Note:  (x) indicates that an assessment will only be done if needed. 
a The screening window is up to 4 weeks prior to baseline.  However, the screening window can be extended up to 8 weeks prior to baseline per 
the exclusion criteria for systemic corticosteroid therapy and/or laboratory abnormalities. 
b In the case of MS relapse during the study, the patient should have an unscheduled visit and will be asked to receive an optional LP at the time 
of relapse.  The patient will have another LP at the originally scheduled time based on their randomization, or if a relapse occurs after they have 
already given the second LP, the relapse LP will remain optional.  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 The Safety Follow-up Period will begin only if the patient discontinues from treatment early or completes the study and does not continue on 
ocrelizumab treatment (i.e., commercially available or from another source).  Patients will be assessed in safety follow-up every 24 weeks for 48 
weeks following the last infusion of ocrelizumab.  After 48 weeks, if the peripheral blood B-cell count remains depleted, monitoring of the patient 
should continue at 24-week intervals until the B-cell count has returned to the baseline value or to the lower limit of the normal range, whichever 
is lower (see Appendix 8).   
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, use of any previous MS medication should be recorded.  Demographic data will include age, sex, and self-reported 
race/ethnicity.   
f To be obtained/performed before administration of ocrelizumab (i.e., pre-dose).  
g 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. 
h After the screening visit, only weight will be measured. 
i Vital signs will include the measurements of heart rate, systolic and diastolic blood pressure, and temperature.  Vital signs should be taken within 
45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the ocrelizumab infusion 
then every 15 minutes for the first hour, followed by every 30 minutes until 1 hour after the end of the infusion.   


Appendix 1  
Schedule of Activities for the RMS Cohort Arms 1−3 (cont.) 
Ocrelizumab—Genentech, Inc. 
117/Protocol ML29966, Version 4 (Global) 
j If the screening assessment has been conducted within 14 days prior to baseline dosing, it does not need to be conducted again prior to 
baseline dosing. 
k Results should be available prior to dosing (may be taken up to 14 days prior to dosing) to ensure patient eligibility per the investigator’s 
discretion (see Section 4.6.1). 
l Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute and differential, ANC, and quantitative platelet count.  Chemistry will 
include AST, ALT, GGT, total bilirubin, urea, uric acid, creatinine, potassium, sodium, calcium, and phosphorus.  Standard urinalysis will be used 
to assess kidney function. 
m Serum β-hCG must be performed at screening in women of childbearing potential.  Subsequently, urine β-hCG (sensitivity ≥ 25 mIU/mL) must be 
collected.  On infusion visits, the urine pregnancy test should be performed prior to methylprednisolone infusion in all women of childbearing 
potential.  If positive, ocrelizumab should be withheld and pregnancy status confirmed with serum β-hCG test.   
n 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.    
o CSF specimen will be obtained at Week 1 (baseline, pre-dose) and at either Week 12, 24 (pre-dose), or 52 according to randomization; AND at 
an unscheduled visit in case of relapse (two CSF samples per patient, unless consent for optional relapse sample is given).  The collection of the 
CSF specimen should precede the brain MRI.  
p The brain MRI requires 2 business days to be quality checked before dosing of ocrelizumab.  In order to facilitate scheduling before an 
ocrelizumab dose, the CSF specimen collection, followed by the brain MRI, may precede the administration of ocrelizumab by up to 7 business 
days. 
q To be obtained/performed optionally in case of relapse or suspected relapse.   
r Local blood flow cytometry and blood TBNK/B-cell subset panel samples (where indicated at the same timepoints as CSF, including optional 
relapse CSF) should be collected on the same day and as close as possible in time to the CSF sample, prior to ocrelizumab administration by up 
to 7 days. 
s Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be 
recorded throughout the treatment period.  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/sings (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 (see Appendix 6).  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. 


Appendix 1  
Schedule of Activities for the RMS Cohort Arms 1−3 (cont.) 
Ocrelizumab—Genentech, Inc. 
118/Protocol ML29966, Version 4 (Global) 
t If an MRI was obtained during the 4-week screening period then that MRI can be used as the baseline brain MRI and the brain MRI does not 
need to be repeated at baseline (Day 1). 
u Adverse events will be reported throughout the study and for up to 48 weeks after the last dose of ocrelizumab as provided through this study.  If 
the patient is unable to return for the safety follow-up visit, the discontinuation visit information may be captured via phone call.   
v Medications used after treatment discontinuation should be recorded during the Safety Follow-up Period. 
w All patients must receive prophylactic treatment with 100 mg of methylprednisolone (or equivalent), administered by slow IV infusion, to be 
completed approximately 30 minutes before the start of each ocrelizumab infusion. 
x Ocrelizumab will be administered at Weeks 1, 3, 24, and 48.  The first dose will be administered as two infusions of 300 mg given on Day 1 and 
Day 15.  The subsequent doses will be given as single 600-mg infusions.y For patients consenting to optional RCR sampling only.  Not 
applicable in countries not participating in RCR sampling. 
z For DNA collection, only a single sample is needed and will be obtained at baseline.  However, if the sample collection is missed for any reason, 
the sample may be obtained at any subsequent visit. 
 


 
Ocrelizumab—Genentech, Inc. 
119/Protocol ML29966, Version 4 (Global) 
Appendix 2  
Schedule of Activities for the RMS Cohort Arm 4 
Screen-
ing a 
Treatment Period 
Week 
 −16  
 −12 
(Pre-
treatment 
Baseline) 
1 
(Treat-
ment 
Baseline)
3 
12 
24 
36 
48 
52 
Day 
 −112 
 −84 (± 7) 
1 
15 (± 2)
84 (± 7)
168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-
Up c  
Informed 
consent d 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history & 
demographic 
data e 
x 
 
 
 
 
 
 
 
 
 
 
 
Review 
inclusion & 
exclusion 
criteria 
x 
x 
x f 
 
 
 
 
 
 
 
 
 
Physical 
examination g 
x 
x 
x f 
x f 
 
x f 
 
x f 
x 
x 
x 
x 
Weight & 
height 
x 
x h 
x h 
 
x h 
 
x h 
 
x h 
 
x h 
x h 
Vital signs i 
x 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x 
x 
x 


 
 
Appendix 2  
Schedule of Activities for the RMS Cohort Arm 4 (cont.) 
Ocrelizumab—Genentech, Inc. 
120/Protocol ML29966, Version 4 (Global) 
Screen-
ing a 
Treatment Period 
Week 
 −16  
 −12 
(Pre-
treatment 
Baseline) 
1 
(Treat-
ment 
Baseline)
3 
12 
24 
36 
48 
52 
Day 
 −112 
 −84 (± 7) 
1 
15 (± 2)
84 (± 7)
168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-
Up c  
Laboratory, Biomarker, and Other Biological Samples 
Hematology, 
chemistry, and 
urinalysis j, k, l 
x 
x  
x f 
 
 
x f 
 
x f 
x 
x 
x 
x 
Pregnancy 
test m 
x 
x  
x f 
 
 
x f 
x 
x f 
x 
 
x 
x 
Hepatitis 
screening n 
x 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B 
virus DNA 
test n 
x 
(x) 
(x) 
 
 
(x) 
 
(x) 
 
 
(x) 
(x) 
Quantitative 
Ig (total Ig, 
IgG, IgM, and 
IgA)  
x 
 
 
 
 
x f 
 
x f 
 
 
x 
x 
Local/on-site 
CSF specimen  
(LP) o 
 
x 
x f, p 
 
x q 
 
 
 
 
x q 
 
 


 
 
Appendix 2  
Schedule of Activities for the RMS Cohort Arm 4 (cont.) 
Ocrelizumab—Genentech, Inc. 
121/Protocol ML29966, Version 4 (Global) 
Screen-
ing a 
Treatment Period 
Week 
 −16  
 −12 
(Pre-
treatment 
Baseline) 
1 
(Treat-
ment 
Baseline)
3 
12 
24 
36 
48 
52 
Day 
 −112 
 −84 (± 7) 
1 
15 (± 2)
84 (± 7)
168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-
Up c  
Local/on-site 
blood flow 
cytometry 
sample r 
 
x 
x f 
 
x 
x f 
 
 
x 
x 
 
 
Blood 
TBNK/B-cell 
subset panel r 
 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x  
x 
x 
Plasma 
 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x  
x 
 
Serum 
 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x  
x 
 
PBMC  
 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x  
x 
 
RNA  
 
x 
x f 
x f 
x 
x f 
 
 
x 
x  
x 
 
Serum sample 
for PK 
 
 
x f 
 
x 
x f 
 
x f 
x 
 
x 
x 
Serum sample 
for ADAs 
 
 
x f 
 
 
x f 
 
x f 
 
 
x 
x 
Neurological Assessments 
EDSS 
x 
x j 
x f 
 
x 
x f 
x 
x f 
x 
x 
x 
x 


 
 
Appendix 2  
Schedule of Activities for the RMS Cohort Arm 4 (cont.) 
Ocrelizumab—Genentech, Inc. 
122/Protocol ML29966, Version 4 (Global) 
Screen-
ing a 
Treatment Period 
Week 
 −16  
 −12 
(Pre-
treatment 
Baseline) 
1 
(Treat-
ment 
Baseline)
3 
12 
24 
36 
48 
52 
Day 
 −112 
 −84 (± 7) 
1 
15 (± 2)
84 (± 7)
168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-
Up c  
Neurological 
exam s 
x 
x 
x f 
 
x 
x f 
 
x f 
x 
x 
x 
x 
Recording of 
relapse  
x 
x 
x f 
x  
x 
x f 
x 
x f 
x 
x 
x 
x 
Brain MRI o, p 
 
x s, t 
x f 
 
x 
x f 
 
 
x 
x q 
x p 
 
Safety Assessments 
Adverse  
events u 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
treatment 
review 
x 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x 
x 
x v 
Premedication and Study Drug Administration 
Methylpred-
nisolone pre-
medication w 
 
 
x f 
x f 
 
x f 
 
x f 
 
 
 
 
Ocrelizumab 
administration 
x 
 
 
x 
x 
 
x 
 
x 
 
 
 
 


 
 
Appendix 2  
Schedule of Activities for the RMS Cohort Arm 4 (cont.) 
Ocrelizumab—Genentech, Inc. 
123/Protocol ML29966, Version 4 (Global) 
Screen-
ing a 
Treatment Period 
Week 
 −16  
 −12 
(Pre-
treatment 
Baseline) 
1 
(Treat-
ment 
Baseline)
3 
12 
24 
36 
48 
52 
Day 
 −112 
 −84 (± 7) 
1 
15 (± 2)
84 (± 7)
168 (± 7) 252 (± 7) 336 (± 7) 364 (± 7)
Unsched-
uled Visit 
(due to 
relapse) b  
Early 
Termination 
Visit 
Safety 
Follow-
Up c  
Optional RCR Sample Collection y 
Plasma y 
 
x 
x f 
x f 
x 
x f 
x 
x f 
x 
x 
x 
 
RNA y 
 
x 
x f 
x f 
x 
x f 
 
 
x 
x 
x 
 
DNA y, z 
 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
 
ADAs = anti-drug antibodies; CSF = cerebrospinal fluid; 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; Ig = immunoglobulin; 
LP = lumbar puncture; MRI = magnetic resonance imaging; MS = multiple sclerosis; PBMC = peripheral blood mononuclear cell; 
PCR = polymerase chain reaction; PK = pharmacokinetic; PML = progressive multifocal leukoencephalopathy; RCR = Roche Clinical Repository; 
RMS = relapsing multiple sclerosis; TBNK = T cells, B cells, and natural killer cells. 
Note:  (x) indicates that an assessment will only be done if needed. 
a The screening window is up to 4 weeks prior to Week −12.  However, the screening window can be extended up to 8 weeks prior to Week −12 
per the exclusion criteria for systemic corticosteroid therapy and/or laboratory abnormalities. 
b In the case of MS relapse during the study and after a patient has already given 2 LPs at the start, the patient should have an unscheduled 
visit and will be asked to receive an optional LP at the time of relapse. If the patient comes into the clinic for an unscheduled visit for reasons 
other than relapse, procedures should be performed per standard of care.    


 
 
Appendix 2  
Schedule of Activities for the RMS Cohort Arm 4 (cont.) 
Ocrelizumab—Genentech, Inc. 
124/Protocol ML29966, Version 4 (Global) 
c The Safety Follow-up Period will begin only if the patient discontinues from treatment early or completes the study and does not continue on 
ocrelizumab treatment (i.e., commercially available or from another source).  Patients will be assessed in safety follow-up every 24 weeks for 
48 weeks following the last infusion of ocrelizumab.  After 48 weeks, if the peripheral blood B-cell count remains depleted, monitoring of the 
patient should continue at 24-week intervals until the B-cell count has returned to the baseline value or to the lower limit of the normal 
range, whichever is lower (see Appendix 8).  
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, use of any previous MS medication should be recorded.  Demographic data will include age, 
sex, and self-reported race/ethnicity.   
f To be obtained/performed before administration of ocrelizumab (i.e., pre-dose).   
g 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. 
h After the screening visit, only weight will be measured. 
i Vital signs will include the measurements of heart rate, systolic and diastolic blood pressure, and temperature.  Vital signs should be taken 
within 45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the 
ocrelizumab infusion then every 15 minutes for the first hour, followed by every 30 minutes until 1 hour after the end of the infusion.   
j If the screening assessment has been conducted within 14 days prior to baseline dosing, it does not need to be conducted again prior to 
baseline dosing. 
k Results should be available prior to dosing (may be taken up to 14 days prior to dosing) to ensure patient eligibility per the investigator’s 
discretion (see Section 4.6.1). 
l Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute and differential, ANC, and quantitative platelet count.  Chemistry 
will include AST, ALT, GGT, total bilirubin, urea, uric acid, creatinine, potassium, sodium, calcium, and phosphorus.  Standard urinalysis 
will be used to assess kidney function. 
m Serum β-hCG must be performed at screening in women of childbearing potential.  Subsequently, urine β-hCG (sensitivity ≥ 25 mIU/mL) 
must be collected.  On infusion visits, the urine pregnancy test should be performed prior to methylprednisolone infusion in all women of 
childbearing potential.  If positive, ocrelizumab should be withheld and pregnancy status confirmed with serum β-hCG test.   


 
 
Appendix 2  
Schedule of Activities for the RMS Cohort Arm 4 (cont.) 
Ocrelizumab—Genentech, Inc. 
125/Protocol ML29966, Version 4 (Global) 
n 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.    
o CSF specimen will be obtained at Week  −12 (pre-treatment baseline) and Week 1(treatment baseline, pre-dose); optionally at 12 weeks post-
ocrelizumab dose; AND at an unscheduled visit in case of relapse (two CSF samples per patient, unless consent for optional 12-week post-dose 
or relapse sample is given).  The collection of the CSF specimen should precede the brain MRI.   
p The brain MRI requires 2 business days to be quality checked before dosing of ocrelizumab.  In order to facilitate scheduling before an 
ocrelizumab dose, the CSF specimen collection, followed by the brain MRI, may precede the administration of ocrelizumab by up to 7 business 
days.  
q To be obtained/performed optionally at 12 weeks post-ocrelizumab dose and/or in case of relapse or suspected relapse.   
r Local blood flow cytometry and blood TBNK/B-cell subset panel samples (where indicated at the same timepoints as CSF, including optional 
12-week post-dose or relapse CSF) should be collected on the same day and as close as possible in time to the CSF sample, even if CSF is 
collected prior to ocrelizumab administration by up to 7 days. 
s Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should 
be recorded throughout the treatment period.  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/sings (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 (see 
Appendix 6).  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. 
t If an MRI was obtained during the 4-week screening period then that MRI can be used as the baseline brain MRI and the brain MRI does not 
need to be repeated at pre-treatment baseline (Day 1). 
u Adverse events will be reported throughout the study and for up to 48 weeks after the last dose of ocrelizumab as provided through this study.  
If the patient is unable to return for the safety follow-up visit, the discontinuation visit information may be captured via phone call.   
v Medications used after treatment discontinuation should be recorded during the Safety Follow-up Period. 
w All patients must receive prophylactic treatment with 100 mg of methylprednisolone (or equivalent), administered by slow IV infusion, to be 
completed approximately 30 minutes before the start of each ocrelizumab infusion. 
x Ocrelizumab will be administered at Weeks 1, 3, 24, and 48.  The first dose will be administered as two infusions of 300 mg given on Day 1 
and Day 15.  The subsequent doses will be given as single 600-mg infusions. 
y For patients consenting to optional RCR sampling only.  Not applicable in countries not participating in RCR sampling. 
z For DNA collection, only a single sample is needed and will be obtained at baseline.  However, if the sample collection is missed for any 
reason, the sample may be obtained at any subsequent visit. 


 
Ocrelizumab—Genentech, Inc. 
126/Protocol ML29966, Version 4 (Global) 
Appendix 3  
Schedule of Activities for the PPMS Cohort 
Screening a 
Treatment Period 
Week 
–4 
1  
(Treat-
ment 
Baseline) 
3 
12 
24 
26 
36 
48 
50 
52 
Day 
 
1 
15 
(± 2) 
84  
(± 7) 
168 
(± 7) 
182 
(± 7) 
252 
(± 7) 
336 
(± 7) 
350 
(± 7) 
364 
(± 7) 
Unsched-
uled 
Visit  
(due to 
relapse)
b 
Early 
Termin-
ation 
Visit 
Safety 
Follow-
Up  
c 
Informed consent d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & 
demographic data e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion & 
exclusion criteria 
x 
x f 
 
 
 
 
 
 
 
 
 
 
 
Physical examination g 
x 
x f 
x f 
 
x f 
x f 
 
x f 
x f 
x 
x 
x 
x 
Weight & height 
x 
 
 
x h 
 
 
x h 
 
 
x h 
 
x h 
x h 
Vital signs i 
x 
x f 
x f 
x 
x f 
x f 
x 
x f 
x f 
x 
x 
x 
 
Laboratory Assessments 
Hematology, chemistry, 
and urinalysis j, k, l 
x 
x f 
 
 
x f 
 
 
x f 
 
x 
x 
x 
x 
Pregnancy test m 
x 
x f 
 
 
x f 
 
x 
x f 
 
x 
 
x 
x 
Hepatitis screening n 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B virus DNA 
test n 
x 
(x) 
 
 
(x) 
 
 
(x) 
 
 
 
(x) 
(x) 
Quantitative Ig (total 
Ig, IgG, IgM, and IgA)  
x 
 
 
 
x f 
 
 
x f 
 
 
 
x 
x 


 
 
Appendix 3  
Schedule of Activities for the PPMS Cohort (cont.) 
Ocrelizumab—Genentech, Inc. 
127/Protocol ML29966, Version 4 (Global) 
Screening a 
Treatment Period 
Week 
–4 
1  
(Treat-
ment 
Baseline) 
3 
12 
24 
26 
36 
48 
50 
52 
Day 
 
1 
15 
(± 2) 
84  
(± 7) 
168 
(± 7) 
182 
(± 7) 
252 
(± 7) 
336 
(± 7) 
350 
(± 7) 
364 
(± 7) 
Unsched-
uled 
Visit  
(due to 
relapse)
b 
Early 
Termin-
ation 
Visit 
Safety 
Follow-
Up  
c 
Local/on-site CSF 
specimen 
(LP) o, p 
 
x f 
 
 
 
 
 
 
 
x 
x 
 
 
Local/on-site blood flow 
cytometry sample  
 
x f, q 
 
x 
x f 
 
 
 
 
x q 
x q 
 
 
Blood TBNK/B-cell 
subset panel q 
 
x f 
x f 
x 
x f 
 
x 
x f 
 
x 
x 
x 
x 
Plasma 
 
x f 
x f 
x 
x f 
 
x 
x f 
 
x 
x 
x 
 
Serum 
 
x f 
x f 
x 
x f 
 
x 
x f 
 
x 
x 
x 
 
PBMC  
 
x f 
x f 
x 
x f 
 
x 
x f 
 
x 
x 
x 
 
RNA  
 
x f 
x f 
x 
x f 
 
 
 
 
x 
x 
x 
 
Serum sample for PK 
 
x f 
 
x 
x f 
 
 
x f 
 
x 
 
x 
x 
Serum sample for 
ADAs 
 
x f 
 
 
x f 
 
 
x f 
 
 
 
x 
x 
Neurological Assessments 
EDSS score 
x 
x f, j 
 
x 
x f 
 
x 
x f 
 
x 
x 
x 
x 
25-foot timed walk test 
x 
x f 
 
x 
x f 
 
x 
x f 
 
x 
x 
x 
 


 
 
Appendix 3  
Schedule of Activities for the PPMS Cohort (cont.) 
Ocrelizumab—Genentech, Inc. 
128/Protocol ML29966, Version 4 (Global) 
Screening a 
Treatment Period 
Week 
–4 
1  
(Treat-
ment 
Baseline) 
3 
12 
24 
26 
36 
48 
50 
52 
Day 
 
1 
15 
(± 2) 
84  
(± 7) 
168 
(± 7) 
182 
(± 7) 
252 
(± 7) 
336 
(± 7) 
350 
(± 7) 
364 
(± 7) 
Unsched-
uled 
Visit  
(due to 
relapse)
b 
Early 
Termin-
ation 
Visit 
Safety 
Follow-
Up  
c 
9-hole peg test 
x 
x f 
 
x 
x f 
 
x 
x f 
 
x 
x 
x 
 
Neurological 
examination r 
x 
x f 
 
x 
x f 
 
 
x f 
 
x 
x 
x 
x 
Recording of potential 
relapses 
x 
x f 
x 
x 
x f 
x 
x 
x f 
x 
x 
x 
x 
x 
Brain MRI o, p 
 
x f, s 
 
x 
x f 
 
 
 
 
x 
x 
x 
 
Safety Assessments 
Adverse event 
assessment t 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant treatment 
review 
x 
x f 
x f 
x 
x f 
x 
x 
x f 
x 
x 
x 
x 
x u 
Premedication and Study Drug Administration 
Methylprednisolone  
premedication v 
 
x 
x 
 
x 
x 
 
x 
x 
 
 
 
 
Ocrelizumab 
administration w 
 
x 
x 
 
x 
x 
 
x 
x 
 
 
 
 
Optional RCR Sample Collection x 
Plasma x  
 
x f 
x f 
x 
x f 
 
x 
x f 
 
x 
x 
x 
 


 
 
Appendix 3  
Schedule of Activities for the PPMS Cohort (cont.) 
Ocrelizumab—Genentech, Inc. 
129/Protocol ML29966, Version 4 (Global) 
Screening a 
Treatment Period 
Week 
–4 
1  
(Treat-
ment 
Baseline) 
3 
12 
24 
26 
36 
48 
50 
52 
Day 
 
1 
15 
(± 2) 
84  
(± 7) 
168 
(± 7) 
182 
(± 7) 
252 
(± 7) 
336 
(± 7) 
350 
(± 7) 
364 
(± 7) 
Unsched-
uled 
Visit  
(due to 
relapse)
b 
Early 
Termin-
ation 
Visit 
Safety 
Follow-
Up  
c 
RNA x 
 
x f 
x f 
x 
x f 
 
 
 
 
x 
x 
x 
 
DNA x, y 
 
x 
(x) 
(x) 
(x) 
 
(x) 
(x) 
 
(x) 
(x) 
(x) 
 
CSF = cerebrospinal fluid; 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 antibody; Ig = immunoglobulin; IV = intravenous; LP = lumbar puncture; MRI = magnetic 
resonance imaging; MS = multiple sclerosis; PCR = polymerase chain reaction; PML = progressive multifocal leukoencephalopathy; PPMS = primary progressive 
multiple sclerosis; TBNK = T cells, B cells, and natural killer cells. 
Note:  (x) indicates that an assessment will be performed only if indicated. 
a The screening window is up to 4 weeks prior to baseline.  However, the screening window can be extended up to 8 weeks prior to baseline per the 
exclusion criteria for systemic corticosteroid therapy and/or laboratory abnormalities. 
b In the case of MS relapse during the study, the patient should have an unscheduled visit and will be asked to receive an optional LP at the time of relapse.  The 
patient will have another LP at the originally scheduled time based on their randomization, or if a relapse occurs after they have already given the second LP, 
the relapse LP will remain optional.  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 The Safety Follow-up Period will begin only if the patient discontinues from treatment early or completes the study and does not continue on 
ocrelizumab treatment (i.e., commercially available or from another source).  Patients will be assessed in safety follow-up every 24 weeks for 
48 weeks following the last infusion of ocrelizumab.  After 48 weeks, if the peripheral blood B-cell count remains depleted, monitoring of the 
patient should continue at 24-week intervals until the B-cell count has returned to the baseline value or to the lower limit of the normal 
range, whichever is lower (see Appendix 8).   
d Written informed consent will be obtained from all patients during screening in order to be eligible. 


 
 
Appendix 3  
Schedule of Activities for the PPMS Cohort (cont.) 
Ocrelizumab—Genentech, Inc. 
130/Protocol ML29966, Version 4 (Global) 
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, use 
of any previous MS medication should be recorded.  Demographic data will include age, sex, and self-reported race/ethnicity.   
f To be obtained/performed before administration of ocrelizumab (i.e., pre-dose). 
g 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 General Medical History and Baseline Conditions eCRF.  New or worsened 
clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF.  
h After the screening visit, only weight will be measured. 
i Vital signs will include the measurements of heart rate, systolic and diastolic blood pressure, and temperature.  Vital signs should be taken within 45 minutes 
prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the ocrelizumab infusion then every 15 minutes for 
the first hour, followed by every 30 minutes until 1 hour after the end of the infusion.   
j If the screening assessment has been conducted within 14 days prior to baseline dosing, it does not need to be conducted again prior to baseline dosing.   
k Results must be available and reviewed prior to dosing (may be taken up to 14 days prior to dosing) to ensure patient eligibility per the 
investigator’s discretion (see Section 4.6.1). 
l Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute and differential, ANC, and quantitative platelet count.  Chemistry will include AST, 
ALT, GGT, alkaline phosphatase, amylase, lipase, total protein, albumin, cholesterol, total bilirubin, urea, uric acid, creatinine, random glucose, potassium, 
sodium, calcium, phosphorus, LDH, creatine phosphokinase, and triglycerides.  Urinalysis will include specific gravity, pH, glucose, protein, ketones, and 
blood. 
m Serum β-hCG must be performed at screening in women of childbearing potential.  Subsequently, urine β-hCG (sensitivity ≥ 25 mIU/mL) must be collected.  
On infusion visits, the urine pregnancy test should be performed prior to methylprednisolone infusion in all women of childbearing potential.  If positive, 
ocrelizumab should be withheld and pregnancy status confirmed by a serum β-hCG test. 
n All patients must have negative HBsAg result and negative HepCAb screening tests prior to study enrollment.  If total HBcAb is positive at screening, HBV 
DNA measured by PCR must be negative in order for a patient to be eligible for the study.  For enrolled patients with negative HBsAg and positive total 
HBcAb, HBV DNA (by PCR) must be repeated every 24 weeks during the treatment period.   
o CSF specimen will be obtained at Week 1 (baseline, pre-dose) and Week 52 according to randomization; AND at an unscheduled visit in case of disease 
worsening (two CSF samples per patient, unless consent for optional worsening sample is given).  The collection of the CSF specimen should precede the brain 
MRI. 
p The brain MRI requires 2 business days to be quality checked before dosing of ocrelizumab.  In order to facilitate scheduling before an ocrelizumab dose, the 
CSF specimen collection, followed by the brain MRI, may precede the administration of ocrelizumab by up to 7 business days.  


 
 
Appendix 3  
Schedule of Activities for the PPMS Cohort (cont.) 
Ocrelizumab—Genentech, Inc. 
131/Protocol ML29966, Version 4 (Global) 
q Local blood flow cytometry and blood TBNK/B-cell subset panel samples (where indicated at the same timepoints as CSF, including optional relapse CSF) 
should be collected on the same day and as close as possible in time to the CSF sample, even if CSF is collected prior to ocrelizumab administration by up to 7 
days. 
r Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be recorded 
throughout the treatment period.  Investigators will also screen patients for signs and symptoms of PML by evaluating neurological deficits localized to the 
cerebral cortex, such as cortical symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual defects, hemiparesis, cerebellar 
symptoms/sings (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 (see Appendix 6).  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. 
s If an MRI was obtained during the 4-week screening period then that MRI can be used as the baseline brain MRI and the brain MRI does not need to be 
repeated at baseline (Day 1). 
t Adverse events will be reported throughout the study and for up to 48 weeks after the last dose of ocrelizumab as provided through this study.  If the patient is 
unable to return for the safety follow-up visit, the discontinuation visit information may be captured via phone call. 
u Medications used after treatment discontinuation should be recorded during the Safety Follow-up Period. 
v All patients must receive prophylactic treatment with 100 mg methylprednisolone (or equivalent), administered by slow IV infusion, to be completed 
approximately 30 minutes before the start of each ocrelizumab infusion. 
w Ocrelizumab 600 mg will be administered as two 300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks.   
x For patients consenting to optional RCR sampling only.  Not applicable in countries not participating in RCR sampling. 
y For DNA collection, only a single sample is needed and will be obtained at baseline.  However, if the sample collection is missed for any reason, the sample may 
be obtained at any subsequent visit. 


 
Ocrelizumab—Genentech, Inc. 
132/Protocol ML29966, Version 4 (Global) 
Appendix 4  
Expanded Disability Status Scale 
 


 
 
Appendix 4  
Expanded Disability Status Scale (cont.) 
Ocrelizumab—Genentech, Inc. 
133/Protocol ML29966, Version 4 (Global) 
 
Source:  http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-
Researchers/Clinical-Study-Measures/Functional-Systems-Scores-(FSS)-and-Expanded-Disab 
 
 


 
Ocrelizumab—Genentech, Inc. 
134/Protocol ML29966, Version 4 (Global) 
Appendix 5  
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. 


 
Ocrelizumab—Genentech, Inc. 
135/Protocol ML29966, Version 4 (Global) 
Appendix 6  
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy 
ACTION STEPS IF PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY (PML) IS SUSPECTED:  
• 
If the clinical presentation is suggestive of PML, further investigations should include 
brain magnetic resonance imaging (MRI) evaluation as soon as possible.  If MRI 
evaluation reveals lesions suspicious for PML (see Figure 1), a lumbar puncture 
with evaluation of the cerebrospinal fluid (CSF) for the detection of JC virus (JCV) 
DNA should be undertaken.  A diagnosis of PML can potentially be made by 
evaluating clinical and MRI findings plus the identification of JCV in the CSF.  
• 
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 MS, a 
brain MRI scan that includes fluid-attenuated inversion recovery (FLAIR) 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 for differences in lesion characteristics that 
may help differentiate between PML and multiple sclerosis [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. 
 


 
 
Appendix 6  
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (cont.) 
Ocrelizumab—Genentech, Inc. 
136/Protocol ML29966, Version 4 (Global) 
 
 
CSF = cerebrospinal fluid; JCV = JC virus; MRI = magnetic resonance imaging; MS = multiple 
sclerosis; PML = progressive multifocal leukoencephalopathy. 
 


 
 
Appendix 6  
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (cont.) 
Ocrelizumab—Genentech, Inc. 
137/Protocol ML29966, Version 4 (Global) 
TABLE 1 
 
 
Source:  Kappos et al. 2007. 


 
 
Appendix 6  
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (cont.) 
Ocrelizumab—Genentech, Inc. 
138/Protocol ML29966, Version 4 (Global) 
 
TABLE 2 
 
MRI LESION CHARACTERISTICS TYPICAL OF PML AND MS 
 
Source:  Yousry et al. 2006. 
 
 


 
Ocrelizumab—Genentech, Inc. 
139/Protocol ML29966, Version 4 (Global) 
Appendix 7  
2010 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis 
Clinical 
(attacks)  
Lesions  
Additional Criteria to Make Diagnosis  
2 or more  
Objective clinical evidence of 2 or 
more lesions or objective clinical 
evidence of 1 lesion with 
reasonable historical evidence of a 
prior attack  
None.  Clinical evidence alone will suffice; 
additional evidence desirable but must be 
consistent with MS  
2 or more  
Objective clinical evidence of 1 
lesion  
Dissemination in space, demonstrated by 
• 
 ≥ 1 T2 lesion in at least two MS typical 
CNS regions (periventricular, 
juxtacortical, infratorial, spinal cord);  
OR  
• 
Await further clinical attack implicating a 
different CNS site 
1  
Objective clinical evidence of 2 or 
more lesions  
Dissemination in time, demonstrated by 
• 
Simultaneous asymptomatic contrast-
enhancing and non-enhancing lesions 
at any time;  
OR  
• 
A new T2 and/or contrast-enhancing 
lesions(s) on follow-up MRI, irrespective 
of its timing;  
OR  
• 
Await a second clinical attack 
1  
Objective clinical evidence of 1 
lesion  
Dissemination in space, demonstrated by  
• 
 ≥ 1 T2 lesion in at least two MS typical 
CNS regions (periventricular, 
juxtacortical, infratentorial, spinal cord); 
OR  
• 
Await further clinical attack implicating a 
different CNS site  
AND 
Dissemination in time, demonstrated by  
• 
Simultaneous asymptomatic contrast-
enhancing and non-enhancing lesions 
at any time;  
OR  
• 
A new T2 and/or contrast-enhancing 
lesions(s) on follow-up MIR, irrespective 
of its timing;  
OR  
• 
Await a second clinical attack 


 
 
Appendix 7  
2010 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis (cont.) 
Ocrelizumab—Genentech, Inc. 
140/Protocol ML29966, Version 4 (Global) 
Clinical 
(attacks)  
Lesions  
Additional Criteria to Make Diagnosis  
0 
(progression 
from onset)  
 
One year of disease progression 
(retrospective or prospective) AND at least 2 
out of 3 criteria:  
• 
Dissemination in space in the brain 
based on  ≥ 1 T2 lesion in 
periventricular, juxtacortical or 
infratentorial regions;  
• 
Dissemination in space in the spinal 
cord based on  ≥ 2 T2 lesions;  
OR 
• 
Positive CSF 
2 or more  
Objective clinical evidence of 2 or 
more lesions or objective clinical 
evidence of 1 lesion with 
reasonable historical evidence of a 
prior attack  
None.  Clinical evidence alone will suffice; 
additional evidence desirable but must be 
consistent with MS 
CNS = central nervous system; CSF  = cerebrospinal fluid; MRI = magnetic resonance imaging; 
MS = multiple sclerosis. 
Sources: 
http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Paper-
TipSheet_-2010-Revisions-to-the-McDonald-Criteria-for-the-Diagnosis-of-MS.pdf 
Polman et al. 2011. 


 
Ocrelizumab—Genentech, Inc. 
141/Protocol ML29966, Version 4 (Global) 
Appendix 8  
B-Cell Monitoring Schedule of Activities 
 
Prolonged B-Cell Monitoring a 
Assessment 
Visits Every 24 Weeks  
(±  7 days) b 
Physical examination 
x 
Neurological examination 
x 
Vital signs 
x 
Routine safety laboratory tests c 
x 
Urine pregnancy test 
x 
Hepatitis B virus DNA test d 
x 
Total Ig, IgA, IgG, and IgM levels 
x 
Blood TBNK/B-cell subset panel e 
x 
Recording of potential relapses  
x 
Adverse event assessments 
x 
Concomitant treatment  review 
x 
HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B 
virus; PCR = polymerase chain reaction; TBNK = T cells, B cells, and natural killer cells. 
a Patients whose B-cells have not been repleted after 48 weeks of Safety Follow-up period will 
continue with visits every 24 weeks (± 7 days) until B-cell repletion (prolonged B-cell 
monitoring). 
b Visits will be performed at 24-week intervals counting from the date of last infusion of 
ocrelizumab.   
c Routine safety laboratory tests:  hematology, chemistry, and urinalysis. 
d For enrolled patients with negative HBsAg and positive total HBcAb, HBV DNA (by PCR) 
must be repeated every 12 weeks. 
e Includes CD19 and other circulating B-cell subsets, T cells, natural killer cells, and other 
leukocytes. 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
Offi ci al Titl e:  
A n O p e n -la b el, M ulti c e nt er, Bi o m ar k er St u d y to E x pl or e th e 
M e c h a ni s m o f A cti o n o f O cr eli z u m a b a n d B -C ell Bi ol o g y in P ati e nt s 
w it h R el a p si n g M ulti pl e S cl er o si s o r Pri m ar y Pr o gr e s si v e M ulti pl e 
S cl er o si s  
N C T N u m b er:  
N C T 0 2 6 8 8 9 8 5  
D o c u m e nt  D at e : 
S A P V er si o n 3: 1 8 -J ul -2 0 2 3  
 
 




C O N FI D E N TI A L  
T hi s i s a G e n e nt e c h, I n c. d o c u m e nt t h at c o nt ai n s c o nfi d e nti al i nf or m ati o n.  N ot hi n g h er ei n i s t o b e 
di s cl o s e d w it h o ut writt e n c o n s e nt fr o m G e n e nt e c h, I n c.  
O cr eli z u m a b — G e n e nt e c h,  I n c. 
St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
S T A TI S TI C A L A N A L Y SI S P L A N  
TI T L E:  
A N O P E N -L A B E L, M U L TI C E N T E R, BI O M A R K E R  
S T U D Y T O E X P L O R E T H E M E C H A NI S M O F  
A C TI O N O F O C R E LI Z U M A B A N D B -C E L L  
BI O L O G Y I N P A TI E N T S WI T H R E L A P SI N G  
M U L TI P L E S C L E R O SI S  
P R O T O C O L N U M B E R:  
M L 2 9 9 6 6  
S T U D Y D R U G:  
O cr eli z u m a b ( R O 4 9 6 4 9 1 3)  
V E R SI O N N U M B E R:  
3 
I N D N U M B E R: 
1 0 0, 5 9 3  
E U D R A C T  N U M B E R:  
2 0 1 5 -0 0 4 6 1 6 -3 7  
S P O N S O R:  
G e n e nt e c h, I n c.  
P L A N P R E P A R E D B Y:  
 
D A T E FI N A L:  
7/ 1 8 / 2 02 3  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
3 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
S T A TI S TI C A L  A N A L Y SI S  P L A N  A M E N D M E N T  
R A TI O N A L E  
J u n e 2 0 1 7  
 
S e v er al mi n or u p d at e s h a v e b e e n m a d e f oll o wi n g t h e a p pr o v al of v er si o n 1 of t h e 
St ati sti c al A n al y si s Pl a n ( S A P):  
•  Bi o m ar k er t e st n a m e s h a v e b e e n u p d at e d fr o m “ C D 4 + C D 3 + T c ell 
n u m b er” t o “ C D 4 + T c ell n u m b er”, a n d fr o m “ C D 8 + C D 3 + T c ell n u m b er” t o 
“ C D 8 + T c ell n u m b er”. 
•  Pr ef err e d t er m s of t h e A E SI s ( A E of S p e ci al I nt er e st) h a v e b e e n u p d at e d 
p er M e d D R A c o di n g l at e st v er si o n.  
 
J a n u ar y 2 0 1 8  
 
I n t hi s v er si o n of S A P, u p d at e s ar e m a d e t o s p e cif y a n al y s e s f or bl o o d Nf L d at a. 
Bl o o d Nf L d at a u p t o t h e s a m e d at a c ut off d at e a s t h e I nt eri m A n al y si s 1 (i. e., 
J u n e 1 st 2 0 1 7) will b e s u m m ari z e d a s a n p o st -h o c a n al y si s of t h e I nt eri m A n al y si s 
1 w h e n d at a b e c o m e a v ail a bl e. All a n al y s e s t h at h a v e b e e n c o m pl et e d d uri n g t h e 
I nt eri m A n al y si s 1 (i n cl u di n g ot h er bi o m ar k er/ effi c a c y a n al y s e s, s af et y a n al y s e s 
et c.) will r e m ai n u n c h a n g e d.  
 
T h e St ati sti c al A n al y si s Pl a n w a s al s o a m e n d e d t o i n c or p or at e t h e pr ot o c ol 
v er si o n 5 u p d at e s:  
•  A L o n g -T er m E xt e n si o n p eri o d h a s b e e n a d d e d t o t h e st u d y t o pr o vi d e 
o cr eli z u m a b  a n d t o c oll e ct l o n g -t er m s af et y a n d effi c a c y i nf or m ati o n. 
U p d at e s h a v e b e e n m a d e t o ali g n wit h t h e pr ot o c ol o n t h e st u d y d e si g n 
wit h l o n g t er m e xt e n si o n p eri o d.  
•  U p d at e s h a v e b e e n m a d e t o ali g n wit h t h e pr ot o c ol o n e x pl or at or y 
o bj e cti v e s a n d e n d p oi nt s i n c or p or ati n g t h e l o n g -t er m e xt e n si o n p eri o d.  
•  U p d at e s h a v e b e e n m a d e i n t h e s a m pl e si z e s e cti o n a b o ut a d diti o n al 
p ati e nt s b e e n a d d e d t o t h e P P M S c o h ort.  
 
I n a d diti o n, s c o p e s of t h e pl a n n e d i nt eri m a n d/ or pri m ar y a n al y s e s ar e d e s cri b e d 
i n t hi s v er si o n of t h e SA P.  
A d diti o n al mi n or c h a n g e s h a v e b e e n m a d e t o i m pr o v e cl arit y a n d c o n si st e n c y.   
 
J ul y 2 0 2 3  
U p d at e s f or t hi s v er si o n of t h e S A P i n cl u d e e x p a n di n g t h e vi sit wi n d o w s t o 
i n cl u d e L T E vi sit s d u e t o t h e i m p a ct of t h e C O VI D-1 9 p a n d e mi c. I n a d diti o n, 
i m p ut ati o n r ul e s f or bi o m ar k er s m e a s ur e d b el o w t h e li mit of q u a ntifi c ati o n h a v e 
b e e n d efi n e d. 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
4 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
 T A B L E O F C O N T E N T S  
1. B A C K G R O U N D  
6  
2. S T U D Y D E SI G N  
6  
2. 1 P R O T O C O L S Y N O P SI S  
7  
2. 2 O U T C O M E M E A S U R E S  
7  
2. 2. 1 Pri m ar y E n d p oi nt s  
7  
2. 2. 2 E x pl or at or y E n d p oi nt s  
7  
2. 2. 3 P h ar m a c o ki n eti c O ut c o m e M e a s ur e s  
9  
2. 2. 4 I m m u n o g e ni cit y O ut c o m e M e a s ur e s  
9  
2. 2. 5 S af et y O ut c o m e M e a s ur e s  
9  
2. 3 D E T E R MI N A TI O N O F S A M P L E SI Z E  
1 0  
2. 4 A N A L Y SI S TI MI N G  
1 0  
3. S T U D Y C O N D U C T  
1 1  
3. 1 R A N D O MI Z A TI O N I S S U E S  
1 1  
4. S T A TI S TI C A L M E T H O D S  
1 2  
4. 1 A N A L Y SI S P O P U L A TI O N S  
1 2  
4. 1. 1 I nt e nt -t o-tr e at (I T T) P o p ul ati o n 
1 3  
4. 1. 2 Bi o m ar k er P o p ul ati o n  
1 3  
4. 1. 3 P h ar m a c o ki n eti c -E v al u a bl e P o p ul ati o n  
1 3  
4. 1. 4 S af et y P o p ul ati o n  
1 3  
4. 2 A N A L Y SI S O F S T U D Y C O N D U C T  
1 3  
4. 3 A N A L Y SI S O F T R E A T M E N T G R O U P C O M P A R A BI LI T Y  
1 4  
4. 3. 1 D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s  
1 4  
4. 3. 2 M ulti pl e S cl er o si s Di s e a s e Hi st or y  
1 4  
4. 3. 3 B a s eli n e bi o m ar k er d at a  
1 5  
4. 3. 4 B a s eli n e M RI D at a  
1 5  
4. 4 E F FI C A C Y A N A L Y SI S  
1 5  
4. 4. 1 Pri m ar y E n d p oi nt s  
1 6  
4. 4. 2 E x pl or at or y E n d p oi nt s  
1 7  
4. 4. 2. 1 S u m m ari e s of E x pl or at or y E n d p oi nt s O v er Ti m e  
1 7  
4. 4. 2. 2 C o m p ari s o n b et w e e n Ar m 1 a n d Ar m 4  
1 7  
4. 4. 2. 3 A s s o ci ati o n s A m o n g Bi o m ar k er D at a  
1 7  
4. 4. 3 S e n siti vit y A n al y s e s  
1 8  
4. 4. 4 S u b gr o u p A n al y s e s  
1 8  
4. 5 P H A R M A C O KI N E TI C A N D P H A R M A C O D Y N A MI C A N A L Y S E S  
1 8  
4. 6 S A F E T Y A N A L Y S E S  
1 9  
4. 6. 1 E x p o s ur e of St u d y M e di c ati o n  
1 9  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
5 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
4. 6. 2 A d v er s e E v e nt s  
1 9  
4. 6. 3 L a b or at or y D at a  
2 0  
4. 6. 4 A nti -dr u g  A nti b o di e s ( A D A s)  
2 0  
4. 6. 5 A d v er s e E v e nt of S p e ci al I nt er e st ( A E SI)  
2 0  
4. 6. 6 Vit al Si g n s  
2 0  
4. 7 MI S SI N G D A T A  
2 0  
4. 8 I N T E RI M A N A L Y S E S  
2 0  
4. 9 S C O P E O F P L A N N E D A N A L Y S E S  
2 0  
 
 LI S T O F T A B L E S  
T a bl e  1 O utli n e of A n al y si s Ti mi n g s  
1 1  
T a bl e  2 S c o p e of Pl a n n e d A n al y s e s  
2 2  
 
 LI S T O F A P P E N DI C E S  
A p p e n di x  1 Pr ot o c ol S y n o p si s  
2 3  
A p p e n di x  2 Vi sit Wi n d o wi n g R ul e s  
3 1  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
6 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
1.  
B A C K G R O U N D  
M ulti pl e s cl er o si s ( M S) i s a c hr o ni c, i nfl a m m at or y, d e m y eli n ati n g, a n d 
d e g e n er ati v e di s e a s e of t h e c e ntr al n er v o u s s y st e m ( C N S) t h at aff e ct s 
a p pr o xi m at el y 4 0 0, 0 0 0 p e o pl e i n t h e U nit e d St at e s ( U. S.) a n d 2. 5 milli o n 
w orl d wi d e.   
T h er e r e m ai n s a n u n m et m e di c al n e e d t o d e v el o p m or e eff e cti v e a n d w ell 
t ol er at e d t h er a pi e s f or t h e tr e at m e nt of M S. T o m e et t hi s n e e d, t h e i d e ntifi c ati o n 
of M S di s e a s e bi o m ar k er s r e pr e s e nt s a criti c al o p p ort u nit y t o p ot e nti all y 
u n d er st a n d di s e a s e p at h o g e n e si s, di s e a s e pr o gr e s si o n, a n d t h e m e c h a ni s m of 
a cti o n of a t h er a p e uti c tr e at m e nt.   
O cr eli z u m a b i s a r e c o m bi n a nt h u m a ni z e d a nti -h u m a n m o n o cl o n al a nti b o d y t h at 
s el e cti v el y t ar g et s C D 2 0 -e x pr e s si n g B c ell s. T o b ett er u n d er st a n d t h e 
m e c h a ni s m of a cti o n of o cr eli z u m a b i n M S, t hi s st u d y will a s s e s s k n o w n 
bi o m ar k er s ( O C B s, Nf L, B c ell s, M RI a s a s urr o g at e m ar k er, et c.) a n d e x pl or e 
n e w p ot e nti al bi o m ar k er s a s s o ci at e d wit h r e s p o n s e t o o cr eli z u m a b i n C S F a n d 
p eri p h er al bl o o d.    
R ef er t o t h e pr ot o c ol r e g ar di n g m or e d et ail s of b a c k gr o u n d o n bi o m ar k er s i n M S 
a n d b a c k gr o u n d o n O cr eli z u m a b.  
2.  
S T U D Y D E SI G N  
T hi s i s a n o p e n -l a b el, m ulti c e nt er, bi o m ar k er st u d y c o n d u ct e d at c e nt er s i n 
m ulti pl e c o u ntri e s i n w hi c h all eli gi bl e p ati e nt s will b e e nr oll e d t o a si n gl e 
tr e at m e nt ar m of o cr eli z u m a b.  T h e st u d y will i n cl u d e a n R M S c o h ort a n d a 
P P M S c o h ort. T h e R M S c o h ort i s t h e m ai n c o h ort a n d will i n cl u d e t h e m aj orit y of 
st u d y p arti ci p a nt s.  T h e R M S c o h ort will b e c o m pri s e d of f o ur ar m s, t hr e e of 
w hi c h will h a v e p ati e nt s r a n d o mi z e d i nt o o n e of t hr e e ar m s ( Ar m s  1 3) 
d e p e n di n g o n t h e ti m e of t h eir s e c o n d l u m b ar p u n ct ur e ( L P).  I n Ar m 4, tr e at m e nt 
wit h o cr eli z u m a b will b e d el a y e d f or 1 2  w e e k s aft er t h e fir st L P.  T h e P P M S 
c o h ort will c o m pri s e a h y p ot h e si s -g e n er ati n g p orti o n of t h e tri al, a s l e s s i s k n o w n 
a b o ut P P M S bi o m ar k er s.  
T h e st u d y tr e at m e nt p eri o d i s c o m pri s e d of a M ai n Tr e at m e nt P eri o d a n d a L o n g -
t er m E xt e n si o n P eri o d. F or p ati e nt s w h o c o m pl et e t h e M ai n Tr e at m e nt P eri o d 
a n d c o nti n u e t o r e c ei v e o cr eli z u m a b, a L o n g -t er m E xt e n si o n P eri o d of t h e st u d y 
will b e gi n at W e e k 7 2 a n d a d mi ni st er o cr eli z u m a b e v er y 6 m o nt h s f or u p t o 4 
y e ar s. T h e m ai n tr e at m e nt p eri o d will e n d o n t h e e arli er of t h e d at e s i n w hi c h t h at 
p ati e nt r e c ei v e d t h e W e e k 7 2 d o s e a n d t h e d at e i n w hi c h W e e k 7 2 l a b d at a w er e 
c oll e ct e d  , or t o d at a c ut off d at e or e n d of st u d y d at e if p ati e nt h a s n’t r e c ei v e d t h e 
w e e k 7 2 d o s e. T h e l o n g t er m e xt e n si o n p eri o d f or e a c h p ati e nt will st art fr o m t h e 
e arli e st d a y t h at p ati e nt t a k e s t h e W e e k 7 2 d o s e or W e e k 7 2 l a b d at a i s c oll e ct e d 
till d at a c ut off d at e or e n d of st u d y.  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
7 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
D uri n g t h e M ai n Tr e at m e nt P eri o d of t h e st u d y, t w o L P s will b e dr a w n fr o m e a c h 
p ati e nt. T h e t w o L P s will all o w f or a s s e s s m e nt of bi o m ar k er s i n C S F t h at ar e 
i n di c ati v e of r e s p o n s e t o dr u g, p h ar m a c o ki n eti c/ p h ar m a c o d y n a mi c r el ati o n s hi p s, 
a n d/ or di s e a s e p at h o g e n e si s i n t h e C N S. O pti o n al L P s m a y b e c oll e ct e d u p o n 
p ati e nt’ s a d diti o n al c o n s e nt. S p e cifi c all y:  
P ati e nt s i n t h e R M S c o h ort ( Ar m s 1  3) will r e c ei v e a n L P b ef or e t h e st art of 
d o si n g wit h o cr eli z u m a b.  S u b s e q u e ntl y, t h e s e p ati e nt s will b e r a n d o mi z e d i nt o 
o n e of t hr e e ar m s f or ti mi n g of t h e s e c o n d L P, eit h er W e e k 1 2, 2 4, or 5 2 f oll o wi n g 
t h e fir st d o s e of o cr eli z u m a b.   
P ati e nt s i n Ar m 4 will r e c ei v e t w o L P s, s e p ar at e d b y a 1 2 -w e e k i nt er v al, b ef or e 
a d mi ni str ati o n of t h e fir st d o s e of o cr eli z u m a b.  P ati e nt s i n t hi s ar m will b e a s k e d 
if t h e y ar e willi n g t o gi v e o pti o n al C S F s a m pl e s vi a L P 1 2 w e e k s a n d 5 2 w e e k s 
aft er t h e o cr eli z u m a b d o s e.  
P ati e nt s i n t h e P P M S c o h ort will r e c ei v e a n L P at t h e st art of t h e st u d y b ef or e 
d o si n g wit h o cr eli z u m a b.  S u b s e q u e ntl y, t h e y will r e c ei v e a s e c o n d L P at W e e k 
5 2 f oll o wi n g t h e fir st d o s e of o cr eli z u m a b.  
D uri n g t h e L o n g -t er m E xt e n si o n P eri o d, p ati e nt s will b e a s k e d t o c o n s e nt t o L P s 
p erf or m e d e v er y 2 y e ar s. R ef er t o t h e pr ot o c ol r e g ar di n g m or e d et ail s of st u d y 
d e si g n i n cl u di n g t h e l o n g t er m e xt e n si o n p eri o d.  
2. 1  
P R O T O C O L S Y N O P SI S  
T h e Pr ot o c ol S y n o p si s i s i n A p p e n di x  1.   
2. 2  
O U T C O M E M E A S U R E S  
2. 2. 1  Pri m ar y E n d p oi nt s  
T h e pri m ar y e n d p oi nt s f or t h e R M S c o h ort ( Ar m s 1 -3) i n cl u d e:  
● 
C h a n g e i n l e v el s of Nf L ( p g / m L) i n C S F fr o m tr e at m e nt b a s eli n e t o p o st-
tr e at m e nt  
● 
C h a n g e i n n u m b er of C D 1 9 + B c ell s i n C S F ( c ell n u m b er/ mi cr olit er) fr o m 
tr e at m e nt b a s eli n e t o p o st-tr e at m e nt  
● 
C h a n g e i n n u m b er of C D 3 + T c ell s i n C S F ( c ell n u m b er/ mi cr olit er) fr o m 
tr e at m e nt b a s eli n e t o p o st-tr e at m e nt  
 
 
2. 2. 2  E x pl or at or y E n d p oi nt s  
T h e e x pl or at or y e n d p oi nt s f or R M S Ar m 4 i n cl u d e:  
C h a n g e fr o m fir st L P t o s e c o n d L P c o m p ari n g Ar m 4 t o Ar m 1 i n:  
● 
L e v el s of Nf L  i n C S F  
● 
N u m b er of C D 1 9 + B c ell s i n C S F  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
8 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
● 
N u m b er of C D 3 + T c ell s i n C S F  
● 
L e v el s of Nf L i n bl o o d  
● 
N u m b er of C D 1 9 + B c ell s i n bl o o d  
● 
N u m b er of C D 3 + T c ell s i n bl o o d  
 
T h e e x pl or at or y e n d p oi nt s f or t h e P P M S c o h ort ar e:  
● 
C h a n g e i n l e v el s of Nf L i n C S F fr o m t r e at m e nt b a s eli n e t o p o st-tr e at m e nt  
● 
C h a n g e i n n u m b er of C D 1 9 + B c ell s i n C S F fr o m tr e at m e nt b a s eli n e t o 
p o st -tr e at m e nt  
● 
C h a n g e i n n u m b er of C D 3 + T c ell s i n C S F fr o m tr e at m e nt b a s eli n e t o p o st -
tr e at m e nt  
 
F or b ot h R M S a n d P P M S c o h ort s, ot h er e x pl or at or y e n d p oi nt s i n cl u d e t h e i m p a ct 
of o cr eli z u m a b tr e at m e nt o n ot h er C S F bi o m ar k er s, bl o o d bi o m ar k er s a n d M RI 
bi o m ar k er s li st e d i n t hi s s e cti o n.  
C h a n g e fr o m tr e at m e nt b a s eli n e i n C S F bi o m ar k er s:  
● 
% C D 1 9 + B c ell   
● 
% C D 3 + T c ell   
● 
% C D 4 + ( C D 3 +)  
● 
C D 4 + C D 3 + n u m b er  
● 
% C D 4 - ( C D 3 +) 
● 
C D 4 -C D 3 + n u m b er  
● 
%I g D + C D 2 7 + ( C D 1 9 +)  
● 
I g D + C D 2 7 + C D 1 9 + n u m b er 
● 
%I g D + C D 2 7 - ( C D 1 9 +) 
● 
I g D + C D 2 7-C D 1 9 + n u m b er  
● 
%I g D -C D 2 7 - ( C D 1 9 +) 
● 
I g D-C D 2 7 -C D 1 9 + n u m b er  
● 
%I g D -C D 2 7 + ( C D 1 9 +)  
● 
I g D-C D 2 7 + C D 1 9 + n u m b er  
● 
% C D 1 3 8 + C D 3 8 + (I g D -C D 2 7 +)  
● 
C D 1 3 8 + C D 3 8 +I g D -C D 2 7 + C D 1 9 + n u m b er  
● 
% C D 1 3 8 -C D 3 8 - (I g D-C D 2 7 +)  
● 
C D 1 3 8 -C D 3 8 -I g D C D 2 7 + C D 1 9 + n u m b er 
● 
% C D 1 3 8 -C D 3 8 + (I g D -C D 2 7 +)  
● 
C D 1 3 8 -C D 3 8 +I g D -C D 2 7 + C D 1 9 + n u m b er  
● 
% C D 3 8 + (I g D + C D 2 7 -) 
● 
C D 3 8 +I g D + C D 2 7 -C D 1 9 + n u m b er  
● 
I g G 
● 
I g M 
● 
C X C L 1 3  
● 
C C L 1 9  
● 
Str e m 2  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
9 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
● 
Y K L 4 0  
● 
I L- 6 
C h a n g e fr o m tr e at m e nt b a s eli n e i n Bl o o d bi o m ar k er s:  
● 
% C D 1 9 + B c ell  
● 
% C D 3 + T c ell    
● 
C D 3 + T c ell n u m b er  
● 
C D 4 + T c ell n u m b er  
● 
C D 8 + T c ell n u m b er  
● 
C D 1 9 + B c ell n u m b er  
● 
C D 5 6 + C D 1 6 + N K c ell n u m b er  
● 
C D 4/ C D 8 R ati o  
● 
Nf L  
● 
C X C L 1 3  
● 
I L- 6 
M RI bi o m ar k er s : 
● 
M e a n n u m b er of T 1 G d -e n h a n c e d l e si o n s  
● 
M e a n n u m b er of n e w a n d/ or e nl ar gi n g T 2 l e si o n s  
● 
M e a n T 2 l e si o n v ol u m e  
● 
M e a n R e gi o n al or t ot al br ai n v ol u m e  
● 
M e a n n u m b er of l e pt o m e ni n g e al -e n h a n ci n g r e gi o n s  
 
 
2. 2. 3  P h ar m a c o ki n eti c O ut c o m e M e a s ur e s  
P h ar m a c o ki n eti c s a n d i m m u n o g e ni cit y m a y b e e x pl or e d i n r el ati o n t o t h e 
p h ar m a c o d y n a mi c s of bl o o d a n d/ or C S F bi o m ar k er s i n b ot h c o h ort s. S er u m 
c o n c e ntr ati o n of o cr eli z u m a b m a y b e m e a s ur e d at W e e k s 1 2, 2 4, 4 8, a n d 5 2; i n 
t h e c a s e of e arl y t er mi n ati o n; a n d at s af et y f oll o w -u p. T h e l e v el of o cr eli z u m a b 
m a y b e m e a s ur e d i n t h e C S F at W e e k s 1 2, 2 4, a n d/ or 5 2 f or t h e R M S c o h ort; 
a n d at W e e k 5 2 f or t h e P P M S c o h ort; a n d/ or i n a C S F s a m pl e t a k e n at a n 
u n s c h e d ul e d vi sit or fr o m a n o pti o n al s a m pl e.  
A s s e s s m e nt m a y i n cl u d e, b ut m a y n ot b e li mit e d t o, t h e r el ati o n s hi p of 
p h ar m a c o ki n eti c s i n C S F t o l e v el s of c ell s i n C S F, or t o Nf L l e v el s i n C S F, a n d/ or 
c o m p ar e d wit h s er u m c o n c e ntr ati o n.  
 
2. 2. 4  I m m u n o g e ni cit y O ut c o m e M e a s ur e s 
● 
I n ci d e n c e of a nti-dr u g a nti b o di e s ( A D A s) t o o cr eli z u m a b.  
2. 2. 5  S af et y O ut c o m e M e a s ur e s  
● 
E x p o s ur e t o o cr eli z u m a b, i n cl u di n g i nf or m ati o n s u c h a s d ur ati o n a n d 
d o s a g e  
● 
I n ci d e n c e of  
● 
Tr e at m e nt e m er g e nt a d v er s e e v e nt s  
● 
S eri o u s tr e at m e nt e m er g e nt a d v er s e e v e nt s  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 0 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
● 
Tr e at m e nt e m er g e nt a d v er s e e v e nt s of s p e ci al i nt er e st  
● 
Tr e at m e nt e m er g e nt a d v er s e e v e nt s l e a di n g t o wit h dr a w al of tr e at m e nt  
● 
F at al a d v er s e e v e nt s  
● 
I nf u si o n-r el at e d r e a cti o n s (I R R) 
● 
Li sti n g of l a b a b n or m aliti e s a s n e e d e d  
 
 
2. 3  
D E T E R MI N A TI O N O F S A M P L E SI Z E  
T h e s a m pl e si z e c al c ul ati o n s f or t hi s st u d y ar e b a s e d o n t h e a s s u m e d r e d u cti o n 
fr o m b a s eli n e i n Nf L at W e e k s 2 4 a n d 5 2 c o m bi n e d ( Ar m s 2 a n d 3) i n t h e R M S 
c o h ort.  Ot h er bi o m ar k er m e a s ur e s ar e n ot c o n si d er e d f or p o w er d et er mi n ati o n.  
A s s u mi n g ( a) a 3 0 % r e d u cti o n fr o m pr e -tr e at m e nt Nf L ( m e a n [ S D] =  8 6 0 p g/ m L 
[ 7 8 0 p g/ m L]) t o p o sttr e at m e nt Nf L ( m e a n [ S D]  =  6 0 2 p g/ m L [ 3 1 0 p g/ m L]) a n d a 
c orr el ati o n c o effi ci e nt of  0. 6, r e s ulti n g i n a n S D of 6 4 3 p g/ m L f or t h e c h a n g e fr o m 
pr e - t o p o st-tr e at m e nt, a n d ( b) a d e sir e d p ow er of 8 0 % wit h a T y p e 1 err or of 5 %, 
a s a m pl e si z e of 5 1 p ati e nt s i s r e q uir e d, wit h a p pr o xi m at el y 2 5 p ati e nt s i n Ar m 2 
a n d 2 6 p ati e nt s i n Ar m  3.  
T hi s i s t h e fir st st u d y t o e x pl or e t h e i m p a ct of o cr eli z u m a b o n C S F B -c ell c o u nt.  
I n a st u d y b y Pi c ci o et al. (2 0 1 0 ), t h e r at e of u n d et e ct a bl e B c ell s i n C S F w a s 
7 4 % ( 2 1/ 2 6) aft er 2 4  3 0 w e e k s of rit u xi m a b a s a n a d d -o n t o i m m u n o m o d ul at or y 
t h er a p y.  B a s e d o n t hi s i nf or m ati o n a n d a s a m pl e si z e of 5 1 p ati e nt s ( Ar m 2 a n d 
3 c o m bi n e d),  t h e e x p e ct e d 9 5 %  CI f or t h e C S F B c ell u n d et e ct a bl e r at e will b e:  
( 0. 6 1, 0. 8 5). 
I n t h e R M S c o h ort, 1 5 p ati e nt s will b e i n cl u d e d i n Ar m 1 t o e x pl or e t h e p o s si bl e 
r e d u cti o n i n Nf L at W e e k 1 2 p o st-tr e at m e nt a n d 1 5 p ati e nt s will b e a s si g n e d t o 
t h e d ela y e d st art R M S c o ntr ol ar m ( Ar m 4).  At l e a st 1 5 p ati e nt s will b e r e cr uit e d 
t o t h e P P M S c o h ort.  T h e a b o v e s a m pl e si z e s ar e n ot b a s e d o n st ati sti c al 
c o n si d er ati o n s a n d ar e m e a nt t o h el p e x pl or e t h e c h a n g e s i n bi o m ar k er s a n d 
g e n er at e h y p ot h e s e s f or f ut ur e s t u di e s. 
B a s e d o n t h e a b o v e, t h e t ot al s a m pl e si z e f or t hi s st u d y will b e at l e a st 9 6 
p ati e nt s.  T h e s a m pl e si z e will b e i n cr e a s e d b y a p pr o xi m at el y 1 0 % i n or d er t o 
a c c o u nt f or p ot e nti al mi s si n g p o st -tr e at m e nt C S F i nf or m ati o n; t h er ef or e, t h e 
n u m b er of p ati e n t s t o b e e nr oll e d i n t h e R M S c o h ort will b e N =  8 8 ( Ar m 1:  1 6 
p ati e nt s, Ar m 2:  2 8 p ati e nt s, Ar m 3:  2 8 p ati e nt s, a n d Ar m 4:  1 6 p ati e nt s).  
T h e P P M S c o h ort will e nr oll at l e a st 1 6 p ati e nt s, a n d a d diti o n al P P M S p ati e nt s 
w er e all o w e d t o e nr oll t o c oll e ct m or e i nf or m ati o n o n bi o m ar k er s. T h e t ot al 
s a m pl e si z e of t h e P P M S c o h ort m a y a p pr o xi m at e 3 0 p ati e nt s. T h er ef or e, t h e 
t ot al n u m b er of p ati e nt s t o b e e nr oll e d i s at l e a st 1 0 4, a n d m a y r e a c h 
a p pr o xi m at el y 1 3 0 p ati e nt s.  
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 1 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
2. 4  
A N A L Y SI S TI MI N G  
F or p u bli c ati o n p ur p o s e , a n i nt eri m a n al y si s (I nt eri m A n al y si s 1, d et ail s s p e cifi e d 
i n S A P v er si o n 1) h a s b e e n c o n d u ct e d b a s e d o n a cli ni c al d at a c ut off d at e 
( C C O D) of J u n e 1 st, 2 0 1 7. Bi o m ar k er d at a c oll e ct e d fr o m R R M S Ar m 1 a n d Ar m 
2 p ati e nt s w er e s u m m ari z e d b a s e d o n a v ail a bl e d at a. Bl o o d Nf L a n al yt e d at a 
w a s n ot a v ail a bl e at t h e ti m e of I nt eri m A n al y si s 1, a p o st -h o c a n al y si s m a y b e 
c o n d u ct e d f or bl o o d Nf L d at a wit h C C O D of J u n e 1 st 2 0 1 7 u p o n it s a v ail a bilit y.  
T a bl e 1 s h o w s t h e ti mi n g of pl a n n e d i nt eri m a n d fi n al a n al y s e s f or t h e m ai n st u d y 
a n d L T E p eri o d. A d diti o n al i nt eri m a n al y s e s m a y al s o b e p erf or m e d f or i nt er n al 
e x pl or ati o n a n d/ or p u bli c ati o n p ur p o s e s. N o f or m al a dj u sti n g of al p h a l e v el i s 
n e c e s s ar y f or t h e m ulti pl e i nt eri m a n al y s e s, a s n o d e ci si o n s will b e m a d e 
r e g ar di n g st u d y c o n d u ct b a s e d o n t h e i nt eri m a n al y s e s r e s ult s.  
T a bl e  1 
O utli n e of A n al y si s Ti mi n g s  
A n al y si s  
Ti mi n g of A n al y si s  
I nt eri m A n al y si s 1 
A p pr o xi m at el y 5 0 % of p ati e nt s h a v e h a d t h eir s e c o n d 
L P ( C C O D J u n e 1 st 2 0 1 7) R ef er t o S A P f or I A 1 f or 
a n al y si s d et ail s  
I nt eri m A n al y si s 2 
A d diti o n I A pl a n n e d f or p u bli c ati o n n e e d s. E. g., w h e n 
R M S Ar m 1 -4 p ati e nt s c o m pl et e 2 n d  L P.  
I nt eri m A n al y si s 3 
(I nt er n al r e vi e w) 
A p pr o xi m at el y 5 0 % of P P M S p ati e nt s h a d t h eir 2 n d  L P  
Fi n al A n al y si s  
R M S a n d P P M S p ati e nt s c o m pl et e M ai n Tr e at m e nt 
P eri o d  
L T E Fi n al A n al y si s  
All p ati e nt s c o m pl et e t h e L T E p eri o d ( 4 -Y e ar s u m m ar y) 
& S af et y F oll o w -u p a s s e s s m e nt s  
 
3.  
S T U D Y C O N D U C T  
3. 1  
R A N D O MI Z A TI O N I S S U E S  
P ati e nt s i n Ar m s 1 -3 of t h e R M S c o h ort will b e r a n d o mi z e d i nt o e a c h of t h e t hr e e 
ar m s at 1: 1: 1 r ati o w h er e t h e ti mi n g of t h e s e c o n d L P will b e at W e e k 1 2, 2 4, or 
5 2, r e s p e cti v el y, f oll o wi n g t h e fir st d o s e of O cr eli z u m a b. A n i n d e p e n d e nt 
i nt er a cti v e v oi c e/ w e b r e s p o n s e s y st e m (I X R S) pr o vi d er will c o n d u ct 
r a n d o mi z ati o n a n d m ai nt ai n t h e tr e at m e nt a s si g n m e nt c o d e. R a n d o mi z ati o n will 
b e str atifi e d b y t h e pr e vi o u s di s e a s e -m o dif yi n g t h er a p y ( D M T) tr e at m e nt st at u s 
( D M T-n aï v e v s. D M T -e x p eri e n c e d). T h er ef or e, t h e pr o p o rti o n of D M T-n aï v e 
p ati e nt s will b e a p pr o xi m at el y e q u al i n e a c h of t hr e e ar m s.  
I n t h e e v e nt t h at o n e of t h e r a n d o mi z e d ar m s ( e. g., Ar m 1) r e a c h e d t h e pl a n n e d 
t ar g et p ati e nt e nr oll m e nt ( e. g., ~ 1 6 p ati e nt s i n Ar m 1), s u b s e q u e nt n e w p ati e nt s 
will b e r a n d o mi z e d i nt o t h e r e m ai ni n g ar m s ( e. g., Ar m 2 a n d 3) at a 1: 1 r ati o.  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 2 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
Ar m 4 of t h e R M S c o h ort wit h d el a y e d tr e at m e nt will n ot b e p art of t h e 
r a n d o mi z ati o n a n d will b e r e cr uit e d s e p ar at el y. 
 
4.  
S T A TI S TI C A L M E T H O D S  
T hi s st u d y i s d e si g n e d t o a s s e s s l e v el s of Nf L, l e v el s of l y m p h o c yt e p o p ul ati o n s 
i n C S F, a n d t o g e n er at e h y p ot h e s e s a b o ut bi o m ar k er s of o cr eli z u m a b tr e at m e nt 
i n p ati e nt s wit h R M S a n d P P M S. L e v el s of Nf L i n C S F a n d l e v el s of l y m p h o c yt e 
p o p ul ati o n s i n C S F will b e c o m p ar e d t o b a s eli n e l e v el s. I n a d diti o n, Ar m 1  of t h e 
R M S c o h ort (fir st L P at fir st d o s e a n d s e c o n d L P at 1 2 w e e k s) will b e c o m p ar e d 
t o Ar m 4 (fir st L P at 1 2 w e e k s b ef or e a n d s e c o n d L P at t h e fir st d o s e of st u d y 
dr u g).  
I n t hi s e x pl or at or y bi o m ar k er st u d y, t h e a n al y s e s will b e m o stl y d e s cri pti v e a n d 
h y p ot h e si s -g e n er ati n g. U nl e s s ot h er wi s e s p e cifi e d, st ati sti c al t e st s will b e t w o -
si d e d a n d t h e st ati sti c al si g nifi c a n c e l e v el will b e 5 %. C orr e s p o n di n g 9 5 % 
c o nfi d e n c e i nt er v al s will b e pr e s e nt e d a s a p pr o pri at e. N o c orr e cti o n s f or m ulti pl e 
t e sti n g will b e a p pli e d t o t h e pri m ar y e n d p oi nt a n al y s e s, e x pl or at or y e n d p oi nt 
a n al y s e s, or i nt eri m a n al y s e s.  
T h e st ati sti c al s u m m ari e s will b e d e s cri pti v e if n ot ot h er wi s e s p e cifi e d. F or 
c o nti n u o u s v ari a bl e s, t h e m e a n, m e di a n, st a n d ar d d e vi ati o n, 2 5t h a n d 7 5t h 
p er c e ntil e s , mi ni m u m a n d m a xi m u m will b e c al c ul at e d. F or c at e g ori c al v ari a bl e s, 
n u m b er a n d p er c e nt a g e i n e a c h c at e g or y will b e di s pl a y e d.  
W h e n e st a bli s hi n g st ati sti c al si g nifi c a n c e, t h e n o n -p ar a m etri c m et h o d will b e 
a p pli e d a s a p pr o pri at e, i. e., t h e M a n n -W hit n e y t e s t will b e u s e d b et w e e n t w o 
gr o u p s a n d t h e Kr u s k al -W alli s t e st will b e u s e d f or t hr e e or m or e gr o u p s. F or t h e 
a n al y si s of c o nti n u o u s d at a, t h e p air e d/ u n p air e d t -t e st a n d n o n-p ar a m etri c t e st 
(i. e., t h e Wil c o x o n m at c h e d p air s t e st) will b e p erf or m e d a s a p pr o pri at e. S o m e 
v ari a bl e s m a y b e a p pr o pri at el y tr a n sf or m e d a s n e e d e d ( e. g., l o g tr a n sf or m ati o n 
of C S F Nf L l e v el, C D 1 9 + B c ell a n d C D 3 + T c ell n u m b er s) b ef or e p erf or mi n g 
st ati sti c al a n al y si s. T h e S p e ar m a n’ s r a n k -c orr el ati o n c o effi ci e nt will b e u s e d t o 
e v al u at e t h e r el ati o n s hi p a m o n g t h e l e v el s of bi o m ar k er s or b et w e e n l e v el s of 
bi o m ar k er s a n d cli ni c al p ar a m et er s.  
4. 1  
A N A L Y SI S P O P U L A TI O N S  
O n e p ati e nt p o p ul ati o n will b e d efi n e d f or t h e p ur p o s e of t h e s af et y a n al y si s, a n d 
tw o  p ati e nt p o p ul ati o n s will b e d efi n e d f or t h e effi c a c y a n al y si s. All pri m ar y 
effi c a c y a n al y s e s will b e p erf or m e d u si n g t h e i nt e nt -t o-tr e at (I T T) p o p ul ati o n. T h e 
bi o m ar k er p o p ul ati o n w a s u s e d i n t h e I nt eri m A n al y si s 1 o n s u m m ari e s of all 
bi o m ar k er p ar a m et er s. It m a y n ot b e u s e d i n t h e ot h er pl a n n e d a n al y s e s if, b a s e d 
o n t h e ti mi n g of pl a n n e d a n al y s e s, t h e bi o m ar k er p o p ul ati o n will b e 
a p pr o xi m at el y t h e s a m e a s t h e I T T p o p ul ati o n. D e m o gr a p hi c s, b a s eli n e M RI, a n d 
di s e a s e hi st or y will b e s u m m ari z e d u si n g t h e e nr o ll e d p o p ul ati o n, d efi n e d a s all 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 3 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
p ati e nt s w h o w er e e nr oll e d i n t h e st u d y, r e g ar dl e s s of w h et h er t h e y r e c ei v e d a n y 
O cr eli z u m a b.  
 
4. 1. 1  I nt e nt-t o-tr e at (I T T) P o p ul ati o n 
T h e I T T p o p ul ati o n i s d efi n e d a s all p ati e nt s e nr oll e d i n t h e st u d y w h o r e c ei v e d at 
l e ast o n e d o s e of O cr e v u s . S u m m ari e s s u c h a s p ati e nt di s p o siti o n a n d b a s eli n e 
bi o m ar k er s will b e p erf or m e d o n t h e I T T p o p ul ati o n. S u m m ari e s of all pri m ar y 
a n d e x pl or at or y e n d p oi nt s will al s o b e p erf or m e d u si n g t h e I T T p o p ul ati o n.  
P ati e nt s i n t hi s st u d y w er e r a n d o mi z e d/ a s si g n e d i nt o ar m s t o t a k e t h e 2 n d  L P at 
diff er e nt ti mi n g s, w hil e r e c ei vi n g t h e s a m e tr e at m e nt. I n or d er t o s u m m ari z e t h e 
eff e ct of o cr eli z u m a b o n bi o m ar k er s o v er ti m e m or e a c c ur at el y, p ati e nt s will b e 
s u m m ari z e d b y t h e a ct u al “ ar m” d e p e n di n g o n w h e n t h e p ati e nt a ct u all y r e c ei v e d 
t h e 2n d  L P.  
 
4. 1. 2  Bi o m ar k er P o p ul ati o n  
A Bi o m ar k er p o p ul ati o n i s d efi n e d a s all e nr oll e d p ati e nt s w h o ( a) r e c ei v e d at 
l e a st o n e i nf u si o n of O cr eli z u m a b, e v e n if t h e i nf u si o n w a s i n c o m pl et e a n d ( b) 
r e c ei v e d t w o L P s. S u m m ari e s of bi o m ar k er s i n t hi s p o p ul ati o n w er e p erf or m e d i n 
I nt eri m A n al y si s 1. 
4. 1. 3  P h ar m a c o ki n eti c -E v al u a bl e P o p ul ati o n  
T h e d efi niti o n of p h ar m a c o ki n eti c e v al u a bl e p o p ul ati o n will b e s p e cifi e d i n a 
s e p ar at e a n al y si s pl a n t o g et h er wit h t h e p h ar m a c o ki n eti c e n d p oi nt s, if a p pli c a bl e.  
4. 1. 4  S af et y P o p ul ati o n  
S af et y p o p ul ati o n i s d efi n e d a s all e nr oll e d p ati e nt s w h o r e c ei v e d at l e a st o n e 
i nf u si o n of o cr eli z u m a b, e v e n if t h e i nf u si o n w a s i n c o m pl et e. S u m m ar y of s af et y 
o ut c o m e m e a s ur e s will b e p erf or m e d u si n g t h e s af et y p o p ul ati o n. P ati e nt s  will b e 
s u m m ari z e d b y t h e a ct u al “ ar m” d e p e n di n g o n w h e n t h e p ati e nt a ct u all y r e c ei v e d 
t h e 2n d  L P.  
4. 2  
A N A L Y SI S O F S T U D Y C O N D U C T  
T h e f oll o wi n g i nf or m ati o n o n p ati e nt di s p o siti o n will b e s u m m ari z e d u si n g t h e I T T 
p o p ul ati o n b y t h e a ct u al ar m:  
● 
N u m b er a n d p er c e nt a g e of p ati e nt s w h o r e c ei v e d o cr eli z u m a b tr e at m e nt 
d uri n g t h e M ai n Tr e at m e nt P eri o d a n d t h e L o n g -t er m E xt e n si o n P eri o d. 
● 
N u m b er a n d p er c e nt a g e of p ati e nt s w h o r e c ei v e d L P at e a c h s c h e d ul e d 
vi sit.  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 4 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
● 
N u m b er a n d p er c e nt a g e of p ati e nt s w h o c o m pl et e d t h e M ai n Tr e at m e nt 
P eri o d a n d t h e L o n g -t er m E xt e n si o n P eri o d of t h e st u d y. 
● 
R e a s o n f or st u d y di s c o nti n u ati o n. At i nt eri m a n al y si s, p ati e nt s w h o h a v e n ’t 
fill e d o ut t h e St u d y C o m pl eti o n C R F b y t h e C C O D of a n al y s e s will b e c o n si d er e d 
a s “ o n g oi n g” i n st u d y.  
● 
R e a s o n f or di s c o nti n u ati o n fr o m o cr eli z u m a b d uri n g M ai n Tr e at m e nt 
P eri o d a n d t h e L o n g -t er m E xt e n si o n P eri o d. At i nt eri m a n al y si s, p ati e nt s w h o 
h a v e n't  fill e d o ut t h e O cr eli z u m a b C o m pl eti o n/ Di s c o nti n u ati o n C R F b y t h e ti m e 
C C O D will b e c o n si d er e d a s “ o n g oi n g” o n tr e at m e nt.  
● 
S u m m ari e s or li sti n g of m aj or pr ot o c ol vi ol ati o n s.  
 
4. 3  
A N A L Y SI S O F T R E A T M E N T G R O U P C O M P A R A BI LI T Y 
F or c o nti n u o u s v ari a bl e s, t h e m e a n, m e di a n, S D, mi ni m u m, a n d m a xi m u m will b e 
c al c ul at e d. F or c at e g ori c al v ari a bl e s, n u m b er a n d p er c e nt a g e i n  e a c h c at e g or y 
will b e di s pl a y e d. T h e u nit s/ c at e g ori e s t o b e u s e d ar e i n di c at e d wit hi n t h e 
br a c k et s a n d s e p ar at e d b y c o m m a s.  
E x c e pt w h er e st at e d, all a s s e s s m e nt s of tr e at m e nt gr o u p c o m p ar a bilit y will utili z e 
t h e d at e of t h e b a s eli n e vi sit ( n ot t h e d at e of t h e s cr e e ni n g vi sit) a s t h e r ef er e n c e 
p oi nt i n ti m e, u nl e s s ot h er wi s e st at e d. F or Ar m 4, t h e tr e at m e nt b a s eli n e will b e 
u s e d w h e n c o m p ari n g t o ot h er ar m s.  
Bi o m ar k er v al u e s f or Ar m 4 at pr e -tr e at m e nt b a s eli n e will b e s u m m ari z e d 
s e p ar at el y a n d c o m p ar e d t o Ar m 1 b a s eli n e v al u e s.  
 
4. 3. 1  D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s  
T h e f oll o wi n g p ati e nt d e m o gr a p hi c s a n d b a s eli n e c h ar a ct eri sti c s will b e 
s u m m ari z e d:  
A g e ( y e ar s)  
A g e ( y e ar s) gr o u p: ( a g e c at e g ori e s < 4 0, ≥ 4 0, a n d a g e c at e g ori e s < 1 8, > = 1 8 − 
< 4 0, > = 4 0 −= < 5 5,  > 5 5)  
G e n d er  
S elf r e p ort e d r a c e a n d et h ni cit y  
F e m al e a n d m al e r e pr o d u cti v e st at u s e s  
R e gi o n ( U S A, C a n a d a, E U)  
B a s eli n e H ei g ht, w ei g ht, a n d B MI  
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 5 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
4. 3. 2  M ulti pl e S cl er o si s Di s e a s e Hi st or y  
P ati e nt di s e a s e hi st or y s u m m ari e s will i n cl u d e t h e f oll o wi n g v ari a bl e s:  
D u r ati o n si n c e M S fir st s y m pt o m s (i n y e ar s), c at e g ori c al ( = < 3, > 3 - = < 5, > 5 - 
= < 1 0 a n d > 1 0).  
M S di a g n o si s c at e g ori e s ( R R M S, S P M S, P P M S)  
D ur ati o n si n c e M S di a g n o si s (i n y e ar s), c at e g ori c al ( = < 3, > 3 - = < 6, > 6 - = < 9  
a n d > 9; = < 2, > 2 - = < 5, > 5 - = < 1 0  a n d > 1 0).  
Pr e vi o u s di s e a s e -m o dif yi n g t h er a p y ( D M T) tr e at m e nt st at u s ( D M T -n aï v e v s. 
D M T -e x p eri e n c e d)  
N u m b er of pr e vi o u s u ni q u e D M T s  
N u m b er of s wit c h e s of pr e vi o u s D M T s  
L a st D M T b ef or e st u d y e nr oll m e nt   
D ur ati o n of l a st D M T  
R e a s o n s f or e nr oll m e nt eli gi bilit y  
B a s eli n e E D S S (r o u n d e d) a n d c at e g ori c al ( 0 -< 3, 3 - < 4, 4 -< 6, > = 6)  
 
4. 3. 3  B a s eli n e bi o m ar k er d at a  
P ati e nt b a s eli n e C S F a n d bl o o d bi o m ar k er d at a s u m m ari e s will i n cl u d e t h e 
v ari a bl e s d e s cri b e d i n S e cti o n s 2. 2. 1 a n d 2. 2. 2. T h e s u m m ari e s m a y al s o b e 
d o n e b y:  
Pr e vi o u s di s e a s e -m o dif yi n g t h er a p y ( D M T) tr e at m e nt st at u s ( D M T -n aï v e v s. 
D M T -e x p eri e n c e d).  
 
4. 3. 4  B a s eli n e M RI D at a  
P ati e nt b a s eli n e M RI d at a s u m m ari e s will b e d o n e a s f oll o w s:  
N u m b er of G d -e n h a n ci n g T 1 l e si o n s at b a s eli n e a n d c at e g ori c al ( 1, 2, 3, 4 -8, 9 -
2 0, > 2 0)  
N u m b er of T 2 l e si o n s at b a s eli n e a n d c at e g ori c al ( 0 -3, 4 -5, 6 -9, > 9)  
V ol u m e of T 2 l e si o n s at b a s eli n e  
Br ai n v ol u m e at b a s eli n e  
 
4. 4  
E F FI C A C Y A N A L Y SI S  
All bi o m ar k er a s s e s s m e nt s ( s c h e d ul e d or u n s c h e d ul e d) will b e s u m m ari z e d aft er 
a p pl yi n g vi sit wi n d o w s. S u m m ar y  of t h e vi sit wi n d o wi n g r ul e s c a n b e f o u n d i n 
A p p e n di x 2.  S e e M o d ul e 3 f or f ull vi sit wi n d o w s p e cifi c ati o n s. If m ulti pl e v al u e s 
of t h e s a m e p ar a m et er o c c ur wit hi n t h e s a m e ti m e wi n d o w f or bl o o d bi o m ar k er s 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 6 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
or r e g ul ar l a b v al u e s, t h e w or st v al u e f or t h at p ar a m et er will b e pr e s e nt e d i n t h e 
s u m m ar y t a bl e. If m ulti pl e M RI s c a n s o c c ur wit hi n t h e s a m e ti m e wi n d o w, t h e 
s c a n cl o s e st t o t h e s c h e d ul e d vi sit d at e will b e i n cl u d e d i n t h e a n al y si s.  
 
All s u m m ari e s will b e d o n e b a s e d o n t h e I T T p o p ul ati o n a n d s u m m ari e s will b e 
pr o vi d e d b y t h e a ct u al ar m, a s d et er mi n e d b y t h e a ct u al ti mi n g of 2 n d  L P:  
 
F or p ati e nt s r a n d o mi z e d t o Ar m 1 -3,  
 
If t h e s e c o n d L P d at e i s mi s si n g t h e n p ati e nt i s i n cl u d e d i n t h e ar m w h er e 
ori gi n all y r a n d o mi z e d t o;  
 
El s e:  
 
St u d y D a y of s e c o n d L P  
( = d at e of t h e 2 n d L P – 1 st i nf u si o n 
st art d at e + 1)  
Tr e at m e nt Ar m  
≤1 2 6  
Ar m 1  
1 2 7 -2 6 6  
Ar m 2  
≥2 6 7  
Ar m 3  
 
P ati e nt s r a n d o mi z e d t o Ar m 4 will b e s u m m ari z e d a s Ar m 4 r e g ar dl e s s of t h e 
ti mi n g of 2n d  L P.  
 
U nl e s s ot h er wi s e s p e cifi e d a n d w h er e a p pr o pri at e, st ati sti c al t e st s, if a n y, will b e 
p erf or m e d at t h e t w o -si d e d 5 % si g nifi c a n c e l e v el. C orr e s p o n di n g 9 5 % c o nfi d e n c e 
i nt er v al s will b e pr e s e nt e d a s a p pr o pri at e.  N o c orr e cti o n s f or m ulti pl e t e sti n g will 
b e a p p li e d.  
 
F or bi o m ar k er s m e a s ur e d b el o w t h e l o w er li mit of q u a ntifi c ati o n ( L L O Q), n u m eri c 
v al u e s will b e i m p ut e d u si n g h alf of t h e L L O Q.  
 
4. 4. 1  Pri m ar y E n d p oi nt s  
F or R M S c o h ort ar m 1 -3, t h e f oll o wi n g v al u e s at tr e at m e nt b a s eli n e a n d p o st -
b a s eli n e vi sit s, a n d c h a n g e s a n d p er c e nt c h a n g e s fr o m tr e at m e nt b a s eli n e t o 
p o st -b a s eli n e vi sit s will b e s u m m ari z e d b y ar m:  
● 
L e v el s of Nf L i n C S F  
● 
N u m b er of C D 1 9 + B c ell s i n C S F  
● 
N u m b er of C D 3 + T c ell s i n C S F  
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 7 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
T h e m e di a n (I Q R) v al u e at pr e -tr e at m e nt b a s eli n e, tr e at m e nt b a s eli ne a n d p o st -
b a s eli n e vi sit s will b e pl ott e d o v er ti m e a n d c ol or c o d e d b y e a c h ar m. S c att er 
p oi nt s of d at a will b e l ai d o v er t h e m e di a n (I Q R) pl ot.  
 
4. 4. 2  E x pl or at or y E n d p oi nt s  
4. 4. 2. 1  
S u m m ari e s of E x pl or at or y E n d p oi nt s O v er Ti m e  
F or R M S p ati e nt s i n Ar m 4, v al u e s at pr e -tr e at m e nt b a s eli n e a n d tr e at m e nt 
b a s eli n e, a n d c h a n g e a n d p er c e nt c h a n g e fr o m tr e at m e nt b a s eli n e t o p o st -
b a s eli n e vi sit s will b e s u m m ari z e d.  
F or R M S p ati e nt s i n ar m s 1 -3 a n d P P M S p ati e nt ar m, C S F bi o m ar k er e n d p oi nt s, 
bl o o d bi o m ar k er e n d p oi nt s a n d M RI bi o m ar k er e n d p oi nt s st at e d i n S e cti o n 2. 2. 2 
will b e s u m m ari z e d o v er ti m e f oll o wi n g t h e s a m e r ul e a s t h e pri m ar y effi c a c y 
e n d p oi nt, a s st at e d i n S e cti o n 4. 4. 1. T h e m e di a n (I Q R) v al u e of C S F a n d bl o o d 
bi o m ar k er s at pr e -tr e at m e nt b a s eli n e, tr e at m e nt b a s eli n e a n d po st- b a s eli n e vi sit s 
will b e pl ott e d o v er ti m e a n d c ol or c o d e d b y e a c h ar m. S c att er p oi nt s of d at a will 
b e l ai d o v er t h e m e di a n (I Q R) pl ot f or bl o o d Nf L l e v el, C D 1 9 + B c ell a n d C D 3 + T 
c ell n u m b er s.  
M e a n ( S D) of M RI bi o m ar k er e n d p oi nt s will b e s u m m ari z e d o v er ti m e.  
F or bl o o d bi o m ar k er s, p ati e nt ar m s will al s o b e p o ol e d t o l o o k at t h e eff e ct of 
o cr eli z u m a b o v er ti m e.  
 
4. 4. 2. 2  
C o m p ari s o n b et w e e n Ar m 1 a n d Ar m 4  
F or p ati e nt s i n Ar m 4, c h a n g e s fr o m pr e -tr e at m e nt b a s eli n e t o tr e at m e nt b a s eli n e 
will b e c o m p ar e d t o Ar m 1 c h a n g e fr o m tr e at m e nt b a s eli n e t o W e e k 1 2 t hr o u g h 
a n A N C O V A m o d el a dj u sti n g f or b a s eli n e D M T st at u s ( D M T n aï v e v s. D M T 
e x p eri e n c e d) a n d b a s eli n e bi o m ar k er l e v el f or t h e f oll o wi n g e n d p oi nt s:  
● 
C S F C D 1 9 + B c ell, C D 3 + T c ell a n d Nf L  
● 
Bl o o d C D 1 9 + B c ell, C D 3 + T c ell a n d Nf L  
 If d at a ar e hi g hl y s k e w e d, A N C O V A m o d el will b e b a s e d o n p er c e nt c h a n g e s.  
 
4. 4. 2. 3  
A s s o ci ati o n s A m o n g Bi o m ar k er D at a  
T h e f oll o wi n g a s s o ci ati o n s will b e a s s e s s e d s e p ar at el y f or e a c h ar m at e a c h 
s c h e d ul e d vi sit:  
● 
C S F wit h bl o o d Nf L, C D 1 9 + B c ell s, a n d C D 3 +  T c ell s.  
● 
c h a n g e i n C S F Nf L l e v el s, C D 1 9 + B c ell s, C D 3 +  T c ell s wit h c h a n g e s i n 
T 1 G d -e n h a n c e d l e si o n s fr o m tr e at m e nt b a s eli n e t o p o st -b a s eli n e s c h e d ul e d 
vi sit s f or ar m s 1 -3 p ati e nt s, a n d fr o m pr e -tr e at m e nt b a s eli n e t o tr e at m e nt 
b a s eli n e vi sit f or ar m  4 p ati e nt s.  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 8 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
● 
br ai n v ol u m e wit h C S F Nf L l e v el s.   
● 
c h a n g e i n C S F Nf L l e v el s wit h n e w/ e nl ar gi n g T 2 G d -e n h a n c e d l e si o n s.  
● 
bl o o d Nf L wit h C S F C D 1 9 + B c ell s, C D 3 + T c ell s.  
● 
bl o o d Nf L wit h T 1 G d -e n h a n c e d l e si o n s.  
● 
c h a n g e i n bl o o d Nf L wit h n e w a n d/ or e nl ar gi n g T 2 l e si o n s. 
T h e S p e ar m a n’ s r a n k c orr el ati o n c o effi ci e nt will b e u s e d t o e v al u at e t h e 
r el ati o n s hi p a m o n g t h e l e v el s of bi o m ar k er s or b et w e e n l e v el s of bi o m ar k er s a n d 
cli ni c al p ar a m et er s. B a s eli n e v al u e s a cr o s s p ati e nt ar m s m a y b e p o ol e d w h e n 
a p pr o pri at e. S c att er pl ot s of t h e t w o -b y -t w o a s s o ci ati o n s m a y al s o b e c o n str u ct e d 
t o ai d i n t h e i nt er pr et ati o n of t h e c o effi ci e nt s. 
T h e f oll o wi n g a s s o ci ati o n s will b e a s s e s s e d b y M a n n -W hit n e y t e st:  
● 
B a s eli n e C S F Nf L i n D M T -e x p eri e n c e d p ati e nt s v er s u s D M T -n aï v e 
p ati e nt s.  
● 
B a s eli n e C S F Nf L l e v el s i n p ati e nt s wit h 0, 1 a n d > 1 b a s eli n e T 1 G d -
e n h a n c e d l e si o n s.  
● 
P er c e nt c h a n g e i n C S F Nf L i n p ati e nt s h a vi n g at l e a st o n e r el a p s e e v e nt 
v er s u s p ati e nt s wit h o ut r el a p s e d uri n g t h e st u d y.  
● 
P er c e nt c h a n g e i n C S F Nf L i n D M T -e x p eri e n c e d p ati e nt s v er s u s D M T -
n aï v e p ati e nt s.  
 
4. 4. 3  S e n siti vit y A n al y s e s  
D u e t o p ot e nti all y s k e w e d di stri b uti o n of t h e bi o m ar k er e n d p oi nt s, a s e n siti vit y 
a n al y si s u si n g t h e n o n -p ar a m etri c M a n n -W hit n e y t e st m a y b e p erf or m e d a s 
a p pr o pri at e.  
F or e a c h of t h e pri m ar y e n d p oi nt s a n d e x pl or at or y e n d p oi nt s li st e d b el o w, a n 
A N C O V A m o d el a dj u sti n g f or b a s eli n e D M T st at u s, b a s eli n e bi o m ar k er l e v el a n d 
ot h er c o v ari at e s, s u c h a s b a s eli n e G d + T 1 l e si o n s c at e g or y ( 0, 1, > 1) a n d a g e, 
m a y b e c o n d u ct e d, pr o vi di n g s uffi ci e nt s a m pl e si z e i n e a c h c o v ari at e c at e g or y:  
● 
C S F Nf L, C D 1 9 + B c ell a n d C D 3 + T c ell  
● 
Bl o o d Nf L, C D 1 9 + B c ell a n d C D 3 + T c ell  
 
 
 
4. 4. 4  S u b gr o u p A n al y s e s  
T h e pri m ar y effi c a c y e n d p oi nt s ( c h a n g e i n l e v el s of Nf L  i n C S F, c h a n g e i n 
n u m b er of C D 1 9 + B c ell s a n d c h a n g e i n n u m b er of C D 3 + T c ell s i n C S F) will b e 
f urt h er s u m m ari z e d f or D M T-n aï v e a n d D M T -e x p eri e n c e d p ati e nt s s e p ar at el y, 
a n d f or p ati e nt s w h o e x p eri e n c e d at l e a st o n e r el a p s e d uri n g t h e st u d y a n d 
p ati e nt s e x p eri e n c e d n o r el a p s e s e p ar at el y.  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
1 9 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
4. 5  
P H A R M A C O KI N E TI C A N D P H A R M A C O D Y N A MI C A N A L Y S E S  
D et ail s of p h ar m a c o ki n eti c a n d p h ar m a c o d y n a mi c s a n al y s e s will b e d e s cri b e d i n 
a M o d eli n g a n d Si m ul ati o n A n al y si s Pl a n a n d r e s ult s will b e r e p ort e d s e p ar at el y.  
4. 6  
S A F E T Y A N A L Y S E S  
S af et y a n al y s e s will b e p erf or m e d o n t h e s af et y p o p ul ati o n. S u m m ari e s of 
a d v er s e e v e nt s will b e g e n er at e d b y s u m m ari zi n g t h e i n ci d e n c e of tr e at m e nt -
e m er g e nt a d v er s e e v e nt s o nl y. Tr e at m e nt -e m er g e nt e v e nt s ar e d efi n e d a s t h o s e 
a d v er s e e v e nt s wit h o b s er v e d or  i m p ut e d o n s et d at e o n or aft er t h e st art d at e of 
st u d y tr e at m e nt. O nl y w h er e t h e m o st e xtr e m e i nt e n sit y i s gr e at er t h a n t h e i niti al 
i nt e n sit y will e v e nt s wit h a n o n s et d at e pri or t o t h e st art of st u d y tr e at m e nt ( a n d 
wit h a n e n d d at e o n or aft er t h e st art of st u d y tr e at m e nt) b e c o n si d er e d tr e at m e nt 
e m er g e nt. A n a d v er s e e v e nt wit h a c o m pl et el y mi s si n g n o n -i m p ut e d st art d at e 
will b e a s s u m e d t o b e tr e at m e nt e m er g e nt u nl e s s t h e a d v er s e e v e nt h a s a 
c o m pl et e n o n -i m p ut e d e n d d at e t h at i s pri or t o st art of st u d y tr e at m e nt. Pr ot o col -
d efi n e d r el a p s e s o v er t h e st u d y p eri o d will al s o b e s u m m ari z e d f or t h e s af et y 
p o p ul ati o n.  
 
4. 6. 1  E x p o s ur e of St u d y M e di c ati o n  
O cr eli z u m a b  e x p o s ur e d uri n g t h e m ai n tr e at m e nt p eri o d will b e s u m m ari z e d, 
i n cl u di n g d ur ati o n a n d d o s a g e. T h e m ai n tr e at m e nt p eri o d i s d efi n e d i n S e cti o n 2. 
A c c or di n gl y, t h e d ur ati o n i s c al c ul at e d a s f oll o w s:  
F or p ati e nt s w h o r e c ei v e d W e e k 7 2 d o s e d uri n g t h e l o n g t er m  e xt e n si o n p eri o d, 
t h e d ur ati o n of o cr eli z u m a b e x p o s ur e d uri n g t h e m ai n tr e at m e nt p eri o d = ( D at e 
pri or t o W e e k 7 2 d o s e – d at e of fir st d o s e) + 1  
F or p ati e nt s w h o di d n ot r e c ei v e W e e k 7 2 d o s e, t h e d ur ati o n = (t h e e arli er of 
C C O D/ c o m pl eti n g/ di s c o nti n ui n g tr e at m e nt − d at e of fir st d o s e) + 1 
O cr eli z u m a b e x p o s ur e d uri n g t h e l o n g t er m e xt e n si o n tr e at m e nt p eri o d will al s o 
b e s u m m ari z e d f or p ati e nt s w h o r e c ei v e d W e e k 7 2 d o s e, i n cl u di n g d ur ati o n a n d 
d o s a g e. T h e l o n g t er m e xt e n si o n tr e at m e nt p eri o d i s d efi n e d i n S e cti o n 2. 
A c c or di n gl y, t h e d ur ati o n i s c al c ul at e d a s (t h e e arli er of C C O D/ d at e of 
c o m pl eti n g/ di s c o nti n ui n g l o n g t er m e xt e n si o n tr e at m e nt − d at e of W e e k 7 2 d o s e) 
+ 1.  
O cr eli z u m a b e x p o s ur e f or t h e e ntir e st u d y will b e s u m m ari z e d a n d c al c ul at e d a s 
t h e ( d at e of l a st d o s e - d at e of fir st d o s e) + 1.  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 0 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
4. 6. 2  A d v er s e E v e nt s  
Tr e at m e nt e m er g e nt a d v er s e e v e nt s a n d s eri o u s tr e at m e nt e m er g e nt a d v er s e 
e v e nt s will b e c o d e d, s u m m ari z e d o v er all a n d b y N CI C T C A E v 4. 0 gr a d e, a n d 
t a b ul at e d b y b o d y s y st e m a n d Pr ef err e d T er m f or i n di vi d u al e v e nt s wit hi n e a c h 
b o d y s y st e m.  
T h e n u m b er a n d p er c e nt a g e of p ati e nt s wit h at l e a st o n e I R R, a n d t h e i nt e n sit y 
( hi g h e st gr a d e f or e a c h p ati e nt) will b e s u m m ari z e d i n t ot al a n d b y d o s e c y cl e 
( p ati e nt s wit h m ulti pl e e v e nt s wit hi n a n i nf u si o n will c o u nt o nl y o n c e). I n a d diti o n, 
t h e t ot al n u m b er of I R R s will b e s u m m ari z e d ( m ulti pl e e v e nt s will b e c o u nt e d) i n 
t ot al a n d b y d o s e c y cl e.  
 
4. 6. 3  L a b or at or y D at a  
S u bj e ct li sti n g of a b n or m aliti e s i n s el e ct e d s af et y l a b s will b e pr o vi d e d if n e e d e d.  
 
4. 6. 4  A nti -dr u g A nti b o di e s ( A D A s)  
T h e n u m b er a n d p er c e nt a g e of p ati e nt s t h at d e v el o p e d A D A s will b e 
s u m m ari z e d.  
4. 6. 5  A d v er s e E v e nt of S p e ci al I nt er e st ( A E SI)  
All r e p ort e d A E SI will b e s u m m ari z e d o v er all a n d b y N CI C T C A E v 4. 0 gr a d e, a n d 
t a b ul at e d b y s p e cifi c M e d D R A b u c k et t er m s a n d pr ef err e d t er m s. T h e f oll o wi n g 
t y p e s of e v e nt s ar e of s p e ci al i nt er e st: 
● 
Dr u g -i n d u c e d li v er i nj ur y 
● 
S u s p e ct e d tr a n s mi s si o n of a n i nf e cti o u s a g e nt vi a pr o d u ct  
 
4. 6. 6  Vit al Si g n s  
Vit al si g n s a n d p h y si c al e x a mi n ati o n r e s ult s will b e pr e s e nt e d i n p ati e nt li sti n g s if 
d e e m e d n e c e s s ar y.  
4. 7  
MI S SI N G D A T A  
Mi s si n g d at a will n ot b e i m p ut e d f or effi c a c y a n al y s e s. F or p arti al d at e s u s e d f or 
s u m m ari e s s u c h a s tr e at m e nt e m er g e nt a d v er s e e v e nt s, r ef er t o t h e D A P m o d ul e 
3 f or i m p ut ati o n of p arti al d at e s.  
4. 8  
I N T E RI M A N A L Y S E S 
Gi v e n t h e h y p ot h e si s -g e n er ati n g n at ur e a n d p u bli c ati o n i nt e nt of t hi s st u d y, 
s e v er al i nt eri m a n al y s e s ar e pl a n n e d a s li st e d i n T a bl e 1, S e cti o n 2. 4 a n d n o 
f or m al m ulti pli cit y a dj u st m e nt i s n e c e s s ar y. T h e i nt eri m a n al y s e s will b e 
p erf or m e d a n d i nt er pr et e d b y m e m b er s of t h e S p o n s or st u d y t e a m a n d 
a p pr o pri at e s e ni or m a n a g e m e nt p er s o n n el. N o d e ci si o n will b e m a d e o n st u d y 
c o n d u ct b a s e d o n t h e i nt eri m a n al y s e s.  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 1 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
4. 9  
S C O P E O F P L A N N E D A N A L Y S E S  
I nt eri m A n al y si s 1 w a s li mit e d t o p ati e nt s i n t h e R M S c o h ort s Ar m s 1 -3 w h o w er e 
e nr oll e d b y t h e C C O D. Bi o m ar k er a n al y s e s w er e li mit e d t o t h e Bi o m ar k er 
P o p ul ati o n.  
I nt eri m A n al y si s 2 will b e li mit e d t o p ati e nt s i n t h e R M S c o h ort Ar m s  1 4. O nl y 
d at a d uri n g t h e M ai n Tr e at m e nt P eri o d ( d efi n e d i n S e cti o n 2, b ef or e r e c ei vi n g 
W e e k 7 2 tr e at m e nt) will b e s u m m ari z e d at t hi s i nt eri m a n al y si s, w hi c h a p pli e s t o 
p ati e nt di s p o siti o n i nf or m ati o n, effi c a c y e n d p oi nt s a n d s af et y e n d p oi nt s.  
T h e Fi n al A n al y si s will i n cl u d e all p ati e nt s ( R M S c o h ort Ar m s 1 -4 a n d P P M S 
c o h ort). O nl y d at a d uri n g t h e M ai n  Tr e at m e nt P eri o d will b e s u m m ari z e d.  
T h e L T E Fi n al St u d y A n al y si s will i n cl u d e all p ati e nt s a n d all d at a c oll e ct e d 
d uri n g t h e L o n g T er m E xt e n si o n P eri o d a n d t h e S af et y F oll o w U p p eri o d.  
T h e e n d p oi nt s t h at will b e i n cl u d e d i n e a c h of t h e a n al y s e s a n d t h e a n al y si s 
p o p ul ati o n s ar e s p e cifi e d i n T a bl e 2. S p e cifi c li st of pl a n n e d o ut p ut s will b e 
a v ail a bl e i n S A P M o d ul e 2.  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 2 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
T a bl e  2 
S c o p e of Pl a n n e d A n al y s e s  
 
E n d p oi nt  
I nt eri m 
A n al y si s 1  
I nt eri m 
A n al y si s 2  
Fi n al A n al y si s  
L T E Fi n al 
A n al y si s  
Di s p o siti o n & 
B a s eli n e 
D e m o gr a p hi c s, 
c h ar a ct eri sti c s 
X  
( R M S  E nr oll e d 
P o p ul ati o n, 
Bi o m ar k er 
P o p ul ati o n)  
X  
( R M S E nr oll e d 
P o p ul ati o n)  
X  
( E nr oll e d 
P o p ul ati o n)  
X  
( E nr oll e d 
P o p ul ati o n)  
Effi c a c y 
E n d p oi nt s 
( d e p e n d o n 
d at a 
a v ail a bilit y)  
X  
( R M S 
Bi o m ar k er 
P o p ul ati o n)  
X  
S el e ct e d 
bi o m ar k er s a s 
s p e cifi e d i n 
S A P M o d ul e 2.  
( R M S E nr oll e d 
P o p ul ati o n)  
X  
( E nr oll e d 
P o p ul ati o n, 
P er -Pr ot o c ol 
P o p ul ati o n)  
X  
( E nr oll e d 
P o p ul ati o n, 
P er -Pr ot o c ol 
P o p ul ati o n)  
P h ar m a c o ki n eti
c ( d e p e n d o n 
d at a 
a v ail a bilit y)  
N ot Pl a n n e d  
D e p e n d o n 
d at a a v ail a bilit y  
X 
( P h ar m a c o ki n et
i c E v al u a bl e 
P o p ul ati o n)  
X 
( P h ar m a c o ki n et
i c E v al u a bl e 
P o p ul ati o n)  
E x p o s ur e, A E, 
I R R 
X  
( R M S S af et y 
P o p ul ati o n)  
X  
( R M S S af et y 
P o p ul ati o n)  
X  
( S af et y 
P o p ul ati o n)  
X  
( S af et y 
P o p ul ati o n)  
A D A  
N ot Pl a n n e d  
N ot Pl a n n e d  
X  
( S af et y 
P o p ul ati o n)  
X  
( S af et y 
P o p ul ati o n)  
Vit al Si g n s a n d 
G e n er al 
L a b or at or y 
D at a  
N ot Pl a n n e d  
N ot Pl a n n e d  
X  
( S af et y 
P o p ul ati o n)  
X  
( S af et y 
P o p ul ati o n)  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 3 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
A P P E N DI X  1 
P R O T O C O L S Y N O P SI S  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
   
  
 
 
  
 
  
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
   
   
 
 
  
  
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
   
 
 
 
 
  
  
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
  
 
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 4 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
 
  
  
 
 
    
 
 
  
 
   
 
 
 
 
 
 
  
  
  
  
  
  
 
  
 
 
 
 
 
  
  
 
 
   
 
  
  
   
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
 
 
  
   
  
 
   
 
 
 
  
 
 
  
 
 
    
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
 
 
 
  
      
 
 
 
  
  
 
     
  
 
  
 
     
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
  
   
  
 
 
 
  
 
   
 
 
 
 
 
    
  
 
 
 
 
 
    
 
 
   
   
 
    
  
 
 
  
  
  
  
  
   
 
 
 
  
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
   
 
  
  
 
 
 
 
     
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
      
 
 
  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
    
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
   
 
 
   
  
 
 
  
 
 
 
 
  
 
    
  
 
   
 
  
  
    
 
 
  
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
    
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
  
 
    
  
  
  
 
  
 
 
    
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
  
  
 
 
 
 
 
 
 
  
 
  
    
   
 
 
 
 
 
  
  
     
 
  
 
 
 
   
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
    
  
 
 
  
 
 
    
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 5 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
   
 
 
  
 
 
 
 
 
 
 
  
 
 
  
    
 
 
 
  
 
 
  
 
 
 
   
 
 
 
  
 
 
  
 
 
 
 
 
 
 
   
   
    
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
  
 
  
  
  
  
 
  
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
    
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
  
 
 
 
  
 
 
 
 
  
  
  
   
  
 
 
 
  
  
  
    
  
    
  
  
   
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
    
  
  
   
  
 
  
    
 
 
 
 
  
  
    
  
  
 
   
 
 
 
 
  
 
 
  
 
  
    
 
 
  
  
  
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
  
 
 
  
 
   
  
 
 
   
 
 
 
    
  
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
     
 
 
  
  
  
 
  
 
   
  
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
   
 
 
 
 
 
   
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
 
  
  
  
 
 
  
   
 
  
  
  
  
 
    
   
 
 
 
 
 
  
 
  
 
   
  
 
 
 
 
    
 
 
 
 
  
 
  
   
 
 
  
  
  
  
   
 
 
  
  
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 6 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
 
   
 
 
 
 
 
     
 
   
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
  
 
 
 
  
  
   
  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
     
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
    
 
 
 
 
 
 
 
 
  
 
   
 
 
    
  
  
 
 
  
   
 
 
 
 
     
  
  
 
 
  
 
 
 
 
 
   
 
 
 
  
  
 
  
 
  
 
   
 
 
  
    
 
 
  
 
 
   
  
    
   
  
  
 
  
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
  
 
 
  
 
   
   
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
  
  
  
  
  
 
 
 
   
 
 
 
    
    
 
   
 
  
 
 
 
 
  
  
  
  
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
  
  
   
 
 
  
  
  
 
  
  
 
 
 
 
   
 
  
   
 
 
   
  
  
   
 
 
 
 
 
  
  
 
 
 
 
  
    
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
  
  
  
  
 
 
   
  
  
  
    
  
 
 
  
    
  
  
 
  
  
 
 
 
    
  
  
   
  
    
 
  
  
   
 
 
  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 7 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
 
  
  
  
 
 
  
 
 
 
  
 
 
 
  
 
 
  
  
 
  
 
 
 
   
  
 
 
   
 
 
 
 
 
  
  
  
  
   
 
  
 
   
 
 
 
 
  
  
 
 
  
 
 
 
  
  
    
   
  
 
 
 
    
 
 
 
 
   
      
 
 
  
 
   
 
   
 
 
 
 
  
  
   
 
 
  
    
   
 
  
  
 
 
 
 
   
 
  
 
 
 
 
    
  
  
   
 
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
    
    
 
 
 
 
 
 
 
   
 
 
  
  
 
 
 
   
  
  
  
  
  
 
 
   
 
 
  
  
 
 
 
 
 
 
 
 
  
 
  
  
  
    
 
   
  
    
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
  
 
 
 
   
  
 
 
  
 
   
  
   
 
  
  
 
 
 
   
 
 
  
 
 
 
 
 
   
 
 
 
 
 
  
  
  
    
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
  
  
 
  
  
 
  
 
  
 
 
  
 
 
  
  
 
 
      
 
  
 
 
  
 
  
  
  
  
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
  
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 8 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
 
 
 
 
  
  
  
  
    
 
  
 
 
 
  
  
  
    
  
 
 
  
  
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
  
 
 
  
  
  
 
   
 
 
 
 
 
 
 
  
   
 
 
 
    
 
 
 
 
 
 
  
 
  
   
 
 
 
   
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
   
 
 
 
 
  
 
   
 
    
 
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
  
    
  
  
 
 
  
 
 
 
 
 
  
  
 
   
 
  
   
 
 
  
 
 
 
 
 
  
  
 
   
 
 
 
 
  
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
  
 
 
 
 
 
 
  
 
 
   
  
    
 
 
    
 
  
   
 
    
 
  
  
 
 
 
 
   
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
   
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
  
  
  
 
  
  
 
 
 
 
 
    
 
 
 
  
   
 
 
 
 
 
 
 
 
  
 
 
 
 
   
  
  
  
 
 
 
 
 
  
    
   
 
 
 
 
  
    
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
   
 
  
 
  
 
  
  
   
  
 
  
  
 
 
 
 
 
 
  
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
2 9 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
    
 
 
  
 
  
 
  
  
 
 
  
 
 
 
 
 
 
  
    
  
  
 
 
  
   
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
   
    
 
 
  
 
 
 
  
 
  
 
 
  
 
 
  
  
  
 
 
   
  
 
  
  
 
 
 
 
   
 
   
 
  
 
 
 
    
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
  
  
 
 
   
 
  
 
  
 
 
 
 
 
 
 
  
 
  
  
 
 
  
 
 
 
 
 
 
   
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
  
  
 
 
  
    
 
  
  
  
 
 
 
 
  
  
   
 
  
 
 
  
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
  
  
 
 
  
  
 
  
  
 
 
 
  
 
 
 
 
 
 
 
  
  
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
    
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
   
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
   
  
 
  
  
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
    
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
   
 
 
 
 
  
  
   
    
 
 
 
 
 
 
 
 
   
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
  
 
 
 
    
     
 
 
 
 
 
 
  
 
 
 
 
 
  
   
 
  
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
  
 
 
   
  
    
 
   
 
  
 
 
  
 
 
 
 
  
  
   
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
3 0 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
 
   
 
  
   
    
    
 
    
   
  
 
 
 
   
  
 
 
    
   
   
  
 
   
  
 
  
 
  
 
 
 
   
  
   
 
  
  
   
   
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
    
 
 
 
  
    
 
 
 
   
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
  
 
 
  
  
    
 
  
 
 
   
 
  
 
  
 
  
 
 
  
  
 
 
  
  
  
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
   
    
  
  
  
 
 
 
 
  
  
  
 
   
  
 
 
 
 
 
 
 
  
  
 
  
 
  
  
 
  
 
 
 
  
 
  
 
   
 
 
 
  
  
  
    
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
3 1 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
A P P E N DI X 2  
VI SI T WI N D O WI N G F O R M AI N T R E A T M E N T A N D L T E P E RI O D  
 
Vi sit wi n d o w f or vit al si g n a n d bl o o d bi o m ar k er s ( Ar m 1 -4 & P P M S):  
R e p ort Vi sit 
L a b el  
N o mi n al st u d y 
d a y s (fr o m 
b a s eli n e)  
Vi sit wi n d o w  
( i n t er m s of st u d y d a y s 
fr o m b a s eli n e) 
N ot e s  
W e e k -1 2 ( Ar m 
4)  
-8 4  
< -1 4  
 
B a s eli n e ( Ar m 
1- 3 & P P M S)  
1  
< = 1  
A N L F L f or t h e  r e c or d 
m o st cl o s e t o d a y 1 if 
t h er e ar e m ulti pl e 
r e c or d s i n t h e wi n d o w 
B a s eli n e ( Ar m 
4)  
1  
-1 4 - 1  
Gi v e t w o w e e k wi n d o w 
f or b a s eli n e 
W e e k 3  
2 1  
2 < = a n d < = 5 3  
Wi n d o w i s fr o m D a y 2 
u ntil W e e k 7. 5 + 0. 5 d a y  
W e e k 1 2  
8 4  
5 4 < = a n d < = 1 2 6  
Wi n d o w i s fr o m W e e k 
7. 5 + 1. 5  d a y u ntil W e e k 
1 8  
W e e k 2 4  
1 6 8  
1 2 7 < = a n d < = 2 1 0  
Wi n d o w i s fr o m W e e k 
1 8 + 1 d a y u ntil W e e k 
3 0  
W e e k 3 6  
2 5 2  
2 1 1 < = a n d < = 2 9 4  
Wi n d o w i s fr o m W e e k 
3 0 + 1 d a y u ntil W e e k 
4 2  
W e e k 4 8  
3 3 6  
2 9 5 < = a n d < = 3 5 0  
Wi n d o w i s fr o m W e e k 
4 2 + 1 d a y u ntil W e e k 
5 0  
W e e k 5 2  
3 6 4  
3 5 1 - < L T E D a y 1 (if 
e nt er e d L T E)  
3 5 1 – p ati e nt e n d of m ai n 
st u d y d at e (if n ot e nt er e d 
L T E)  
Wi n d o w i s fr o m W e e k 
5 0 + 1 d a y u ntil e n d of 
m ai n st u d y d at e  
W e e k 9 6  
6 7 2  
L T E D a y 1 - < = 8 4 0  
Wi n d o w i s fr o m L T E 
D a y 1 t o W e e k 1 2 0  
W e e k 1 4 4  
1 0 0 8  
> = 8 4 1 a n d < = 1, 1 7 6  
Wi n d o w i s fr o m W e e k 
1 2 0 + 1 d a y u ntil W e e k 
1 6 8  
W e e k 1 9 2  
1 3 4 4  
> = 1, 1 7 7 a n d < = 1, 5 1 2  
Wi n d o w i s fr o m W e e k 
1 6 8 + 1 d a y u ntil W e e k 
2 1 6  
W e e k 2 4 0  
1 6 8 0  
> = 1, 5 1 3  
Wi n d o w i s fr o m W e e k 
2 1 6 t o e n d of L T E  
 
Vi sit wi n d o w f or r e g ul ar l a b: h e m at ol o g y, c h e mi str y a n d uri n al y si s ( Ar m 1 -4 &  
P P M S):  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
3 2 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
R e p ort Vi sit L a b el  
N o mi n al st u d y d a y s 
(fr o m b a s eli n e) 
Vi sit wi n d o w  
( i n t er m s of st u d y 
d a y s fr o m b a s eli n e)  
N ot e s  
S cr e e ni n g ( Ar m 4)  
N/ A  
< = -9 2  
 
S cr e e ni n g ( Ar m s 1 -3 
& P P M S)  
N/ A  
< = -8  
 
W e e k -1 2 ( Ar m 4)  
-8 4  
-9 2 < a n d < = -8  
 
B a s eli n e ( Ar m 4)  
1  
-8 < a n d < = 1  
 
B a s eli n e ( Ar m s 1 -3 & 
P P M S)  
1  
-8 < a n d < = 1  
 
W e e k 2 4  
1 6 8  
2 < = a n d < = 2 5 2  
Wi n d o w i s fr o m d a y 
2 u ntil W e e k 3 6  
W e e k 4 8  
3 3 6  
2 5 3 < = a n d < = 3 5 0  
Wi n d o w i s fr o m 
W e e k 3 6 + 1 d a y u ntil 
W e e k 5 0  
W e e k 5 2  
3 6 4  
3 5 1 - < L T E D a y 1 (if 
e nt er e d L T E)  
3 5 1 – p ati e nt e n d of 
m ai n st u d y d at e (if 
n ot e nt er e d L T E)  
Wi n d o w i s fr o m 
W e e k 5 0 + 1 d a y u ntil 
st art of L T E  
W e e k 7 2  
5 0 4  
L T E D a y 1 - < = 6 2 3  
Wi n d o w i s fr o m L T E 
D a y 1 t o W e e k 8 9  
W e e k 9 6  
6 7 2  
  > = 6 2 4 a n d < = 7 5 6  
Wi n d o w i s fr o m 
W e e k 8 9 + 1 d a y t o 
W e e k 1 0 8  
W e e k 1 2 0  
8 4 0  
> = 7 5 7 a n d < = 9 2 4  
Wi n d o w i s fr o m 
W e e k 1 0 8 + 1 d a y t o 
W e e k 1 3 2  
W e e k 1 4 4  
1 0 0 8  
> = 9 2 5 a n d < = 1, 0 9 2  
Wi n d o w i s fr o m 
W e e k 1 3 2 + 1 d a y t o 
W e e k 1 5 6  
W e e k 1 6 8  
1 1 7 6  
> = 1, 0 9 3 a n d 
< = 1, 2 6 0  
Wi n d o w i s fr o m 
W e e k 1 5 6 + 1 d a y t o 
W e e k 1 8 0  
W e e k 1 9 2  
1 3 4 4  
> = 1, 2 6 1 a n d 
< = 1, 4 2 8  
Wi n d o w i s fr o m 
W e e k 1 8 0 + 1 d a y t o 
W e e k 2 0 4  
W e e k 2 1 6  
1 5 1 2  
> = 1, 4 2 9 a n d 
< = 1, 5 9 6  
Wi n d o w i s fr o m 
W e e k 2 0 4 + 1 d a y t o 
W e e k 2 2 8  
W e e k 2 4 0  
1 6 8 0  
> = 1, 5 9 7  
Wi n d o w i s W e e k 
2 2 8 + 1 d a y t o e n d of 
L T E  
 
Vi sit wi n d o w f or pr e g n a n c y ( Ar m 1 -4 & P P M S):  
R e p ort Vi sit 
L a b el  
N o mi n al st u d y d a y s 
(fr o m b a s eli n e) 
Vi sit wi n d o w  
( i n t er m s of st u d y d a y s 
fr o m b a s eli n e) 
N ot e s  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
3 3 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
S cr e e ni n g 
( Ar m 4) 
N/ A  
< -9 2  
 
S cr e e ni n g 
( Ar m s 1-3 & 
P P M S)  
N/ A  
< = -8  
 
W e e k -1 2 
( Ar m 4) 
-8 4  
-9 1 < = a n d < = -8  
 
B a s eli n e 
( Ar m 4) 
1  
-8 < a n d < = 1  
 
B a s eli n e 
( Ar m s 1-3 & 
P P M S)  
1  
-8 < a n d < = 1  
  
W e e k 2 4  
1 6 8  
2 < = a n d  < = 2 1 0  
Wi n d o w i s fr o m W e e k 
1 8 + 1 d a y u ntil W e e k 3 0  
W e e k 3 6  
2 5 2  
2 1 1 < = a n d < = 2 9 4  
Wi n d o w i s fr o m W e e k 
3 0 + 1 d a y u ntil W e e k 4 2  
W e e k 4 8  
3 3 6  
2 9 5 < = a n d < = 3 5 0  
Wi n d o w i s fr o m W e e k 
4 2 + 1 d a y u ntil W e e k 5 0  
W e e k 5 2  
3 6 4  
3 5 1 - < L T E D a y 1 (if 
e nt er e d L T E)  
3 5 1 – p ati e nt e n d of m ai n 
st u d y d at e (if n ot e nt er e d 
L T E)  
Wi n d o w i s fr o m W e e k 
5 0 + 1 d a y u ntil st art of 
L T E  
 
W e e k 7 2  
5 0 4  
L T E D a y 1 - < = 6 2 3  
Wi n d o w i s fr o m L T E 
D a y 1 t o W e e k 8 9  
W e e k 9 6  
6 7 2  
  > = 6 2 4 a n d < = 7 5 6  
Wi n d o w i s fr o m W e e k 
8 9 + 1 d a y t o W e e k 1 0 8  
W e e k 1 2 0  
8 4 0  
> = 7 5 7 a n d < = 9 2 4  
Wi n d o w i s fr o m W e e k 
1 0 8 + 1 d a y t o W e e k 1 3 2  
W e e k 1 4 4  
1 0 0 8  
> = 9 2 5 a n d < = 1, 0 9 2  
Wi n d o w i s fr o m W e e k 
1 3 2 + 1 d a y t o W e e k 1 5 6  
W e e k 1 6 8  
1 1 7 6  
> = 1, 0 9 3 a n d < = 1, 2 6 0  
Wi n d o w i s fr o m W e e k 
1 5 6 + 1 d a y t o W e e k 1 8 0  
W e e k 1 9 2  
1 3 4 4  
> = 1, 2 6 1 a n d < = 1, 4 2 8  
Wi n d o w i s fr o m W e e k 
1 8 0 + 1 d a y t o W e e k 2 0 4  
W e e k 2 1 6  
1 5 1 2  
> = 1, 4 2 9 a n d < = 1, 5 9 6  
Wi n d o w i s fr o m W e e k 
2 0 4 + 1 d a y t o W e e k 2 2 8  
W e e k 2 4 0  
1 6 8 0  
> = 1, 5 9 7  
Wi n d o w i s W e e k 2 2 8 + 1 
d a y t o e n d of L T E  
 
Vi sit wi n d o w f or M RI bi o m ar k er s ( Ar m 1 -4 & P P M S):  
R e p ort Vi sit L a b el  
N o mi n al st u d y d a y s 
(fr o m b a s eli n e)  
Vi sit wi n d o w  
( i n t er m s of st u d y 
d a y s fr o m b a s eli n e)  
N ot e s  
W e e k -1 2 ( Ar m 4)  
-8 4  
< = -2 8  
  
B a s eli n e ( Ar m 4)  
1  
> -2 8 a n d < = 1  
Gi v e a 4 -w e e k 
wi n d o w f or b a s eli n e 
vi sit  


 
O cr eli z u m a b — G e n e nt e c h, I n c.  
3 4 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
 
B a s eli n e ( Ar m 1 -3 & 
P P M S)  
1  
< = 1  
 
W e e k 1 2  
8 4  
2 < = a n d < = 1 2 6  
Wi n d o w i s fr o m D a y 
2 u ntil W e e k 1 8  
W e e k 2 4  
1 6 8  
1 2 7 < = a n d < = 2 6 6  
Wi n d o w i s fr o m 
W e e k 1 8 + 1 d a y u ntil 
W e e k 3 8  
W e e k 5 2  
3 6 4  
2 6 7 - < L T E D a y 1 (if 
e nt er e d L T E)  
2 6 7 – p ati e nt e n d of 
m ai n st u d y d at e (if 
n ot e nt er e d L T E)  
Wi n d o w i s fr o m 
W e e k 3 8 + 1 d a y  
W e e k 9 6  
6 7 2  
L T E D a y 1 - < = 8 4 0  
Wi n d o w i s fr o m L T E 
D a y 1 t o W e e k 1 2 0  
W e e k 1 4 4  
1 0 0 8  
> = 8 4 1 a n d < = 1, 1 7 6  
Wi n d o w i s fr o m 
W e e k 1 2 0 + 1 d a y t o 
W e e k 1 6 8  
W e e k 1 9 2  
1 3 4 4  
> = 1, 1 7 7 a n d 
< = 1, 5 1 2  
Wi n d o w i s fr o m 
W e e k 1 6 8 + 1 d a y t o 
W e e k 2 1 6  
W e e k 2 4 0  
1 6 8 0  
> = 1, 5 1 3  
Wi n d o w i s fr o m 
W e e k 2 1 6 + 1 d a y t o 
e n d of L T E  
*E arl y wit h dr a w al, B c ell m o nit ori n g a n d s af et y f oll o w u p 1 a n d 2 e x cl u d e d fr o m wi n d o wi n g  
 
Vi sit wi n d o w f or C S F Bi o m ar k er s ( Ar m 1 -4 & P P M S):  
R e p ort Vi sit L a b el  
N o mi n al st u d y d a y s 
(fr o m b a s eli n e) 
Vi sit wi n d o w  
( i n t er m s of st u d y 
d a y s fr o m b a s eli n e)  
N ot e s  
W e e k -1 2 ( Ar m 4)  
-8 4  
< -1 4  
 
B a s eli n e ( Ar m 4)  
1  
-1 4 - 1  
Gi v e a 2 -w e e k 
wi n d o w f or b a s eli n e 
vi sit  
B a s eli n e ( All p ati e nt s 
e x c e pt Ar m 4)  
1  
< = 1  
 
W e e k 1 2 ( All 
p ati e nt s)  
8 4  
2 - 1 2 6  
 
W e e k 2 4 ( All 
p ati e nt s)  
1 6 8  
1 2 7 -2 6 6  
 
W e e k 5 2 ( All 
p ati e nt s)  
3 6 4  
2 6 7 - < L T E D a y 1 (if 
e nt er e d L T E)  
2 6 7 – p ati e nt e n d of 
m ai n st u d y d at e (if 
n ot e nt er e d L T E)  
 
W e e k 1 4 4 ( All 
p ati e nt s)  
1, 0 0 8  
L T E D a y 1 - < = 1, 3 4 4  Wi n d o w i s fr o m L T E 
D a y 1 t o W e e k 1 9 2  


O cr eli z u m a b — G e n e nt e c h, I n c.  
3 5 / St ati sti c al A n al y si s Pl a n M L 2 9 9 6 6  
W e e k 2 4 0 ( All 
p ati e nt s)  
1, 6 8 0  
> = 1, 3 4 5  
Wi n d o w i s fr o m 
W e e k 1 9 2 + 1 d a y t o 
e n d of L T E  
Vi sit wi n d o w f or E D S S:  
R e p ort Vi sit L a b el  
N o mi n al st u d y d a y s 
(fr o m b a s eli n e) 
Vi sit wi n d o w  
( i n t er m s of st u d y 
d a y s fr o m b a s eli n e)  
N ot e s  
S cr e e ni n g ( Ar m 4)  
N/ A  
< = -9 7  
S cr e e ni n g ( Ar m 1 -3 
& P P M S)  
N/ A  
< = -1 3  
W e e k -1 2 Pr e -
B a s eli n e ( Ar m 4)  
-8 4
-9 7 - < = -1 4
Gi v e a 2 -w e e k 
wi n d o w f or b a s eli n e 
vi sit  
B a s eli n e ( Ar m 1 -3 & 
P P M S)  
1  
-1 3 –  < = 1
Gi v e a 2 -w e e k 
wi n d o w f or b a s eli n e 
vi sit  
B a s eli n e ( Ar m 4)  
1  
-1 4 –  < = 1
Gi v e a 2 -w e e k 
wi n d o w f or b a s eli n e 
vi sit  
W e e k 1 2 ( All 
P ati e nt s)  
8 4  
2 < = a n d < = 1 2 6  
Wi n d o w i s fr o m D a y 
2 u ntil  W e e k 1 8  
W e e k 2 4 ( All 
P ati e nt s)  
1 6 8  
1 2 7 < = a n d < = 2 1 0  
W e e k 3 6 ( All 
P ati e nt s)  
2 5 2  
2 1 1 < = a n d < = 2 9 4  
W e e k 4 8 ( All 
P ati e nt s)  
3 3 6  
2 9 5 < = a n d < = 3 5 0  
W e e k 5 2  
3 6 4  
2 6 7 - < L T E D a y 1 (if 
e nt er e d L T E)  
2 6 7 – p ati e nt e n d of 
m ai n st u d y d at e (if 
n ot e nt er e d L T E)  
Wi n d o w  i s fr o m 
W e e k 3 8 + 1 d a y  
W e e k 9 6  
6 7 2  
L T E D a y 1 - < = 8 4 0  
Wi n d o w i s fr o m L T E 
D a y 1 t o W e e k 1 2 0  
W e e k 1 4 4  
1 0 0 8  
> = 8 4 1 a n d < = 1, 1 7 6  
Wi n d o w i s fr o m 
W e e k 1 2 0 + 1 d a y t o 
W e e k 1 6 8  
W e e k 1 9 2  
1 3 4 4  
> = 1, 1 7 7 a n d 
< = 1, 5 1 2  
Wi n d o w i s fr o m 
W e e k 1 6 8 + 1 d a y t o 
W e e k 2 1 6  
W e e k 2 4 0  
1 6 8 0  
> = 1, 5 1 3  
Wi n d o w i s fr o m 
W e e k 2 1 6 + 1 d a y t o 
e n d of L T E  
*E arl y wit h dr a w al, B c ell m o nit ori n g a n d s af et y f oll o w u p 1 a n d 2 e x cl u d e d fr o m wi n d o wi n g