Clinical trial NCT03835728
Conditions: Autoimmune Encephalitis
Sponsor: University of Texas Southwestern Medical Center
Start date: 2019-01-22; Completion date: 2020-10-02
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot study is a randomized, double-blind, placebo controlled study of the efficacy of ocrelizumab in autoimmune encephalitis. Subjects with new diagnosis of autoimmune encephalitis will be invited to enroll in this study. Subjects will be randomized to receive ocrelizumab (an anti-CD20 therapy) or matched placebo, and will undergo three infusions over a six month period. Subjects will complete clinical visits over the study period, during which safety monitoring and neuropsychological assessments will be performed to assess for signs of clinical worsening from encephalitis. The primary outcome of this study is the proportion of patients who fail to complete the twelve month period without clinical worsening, as defined by the protocol. Subjects who experience early clinical worsening during the study may be offered open-label treatment with ocrelizumab at the discretion of the investigators.

Detailed description:

Arms: arm 1: Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24. arm 2: Saline will be used as the matching placebo
Interventions: intervention 1: Ocrelizumab intervention 2: Saline
Intervention descriptions: intervention 1: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months. intervention 2: This will be the matching placebo used in the study.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
                  Official title: Exploratory Study of Efficacy of Ocrelizumab in Autoimmune 
                                         Encephalitis 
                  NCT number: NCT03835728 
                  IRB Approval date: March 21, 2019 (Ver.3.0) 


Form A 
IRB #  
 
26776 
STU  2018-0185 
 
STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
1 
vMar2018 
PROTOCOL FORM / RESEARCH DESCRIPTION 
 
If an item does not apply to your research project, indicate that the question is "not applicable” – do not leave sections blank 
 
Click once on the highlighted entry in each box to provide your response.  Click the item number/letter or word, if hyperlinked, 
for detailed instructions for that question.  If your response requires inserting a table, picture, etc, you may need to first delete the 
box that surrounds the answer and then insert your table or other special document. 
 
 
1.  Purpose and objectives.           List the purpose and objectives: 
 
Purpose:  
 
1) To determine if the use of an immunotherapy that targets CD20 (Ocrelizumab) will prevent 
relapses in patients with autoimmune encephalitis with antibodies to cell-surface proteins.  
2) To identify markers of immune activity that may predict response to CD20 therapy in autoimmune 
encephalitis.  
 
Hypothesis:  
Ocrelizumab will be safe and effective (compared to placebo) in preventing relapse (and improving symptoms) in 
patients with autoimmune encephalitis associated with cell-surface antibodies (NMDAR, LGI1, CASPR2, DPPX) 
antibodies. 
 
 
 
2.  Background. 
• 
Describe past experimental and/or clinical findings leading to the formulation of your study.   
• 
For research involving investigational drugs, describe the previously conducted animal and human studies.   
• 
For research that involves FDA approved drugs or devices, describe the FDA approved uses of this drug/device in 
relation to your protocol.   
• 
Attach a copy of the approved labeling as a product package insert or from the Physician’s Desk Reference.   
You may reference sponsor’s full protocol or grant application (section number and/or title) or if none, ensure background 
includes references. 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
a. 
Background 
Autoimmune encephalitis (AE) is a group of disorders caused by an immune-mediated disruption of 
brain function characterized by seizures, cognitive impairment, movement disorders and behavioral 
changes.  These disorders have been increasingly recognized over the past 10 years as a treatable cause 
of rapidly progressive dementia, intractable seizures or psychosis. The best characterized forms of AE 
are associated with autoantibodies targeting cell surface or synaptic proteins. The most common 
encephalitis autoantibodies are specific for the N-methyl-D-aspartate receptor (NMDAR), leucine rich, 
glioma-inactivated 1 protein (LGI1) and contactin associated protein-like 2 (Caspr2). However, as of 
2017, over a dozen other autoantibodies have been associated with AE and some patients with treatable 
AE have no recognized antibody marker.1, 2 
 
AE affects patients across all age groups, with some forms of the disease preferentially affecting 
pediatric patients. Increasing awareness and clinical experience indicates that AE is not rare as 
previously thought. At UT Southwestern Medical Center, for example, we retrospectively identified 64 


Form A 
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vMar2018 
AE cases over a 6 year period (2010-2015), and this is certainly an underestimation since awareness and 
clinical laboratory diagnostic tests have improved significantly in the past 4 years.   
 
References 
1. 
Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. The 
Lancet Neurology 2016;15:391-404. 
2. 
Dubey D, Sawhney A, Greenberg B, et al. The spectrum of autoimmune encephalopathies. J 
Neuroimmunol 2015;287:93-97. 
3. 
Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in 
patients with anti-NMDA receptor encephalitis: an observational cohort study. The Lancet Neurology 
2013;12:157-165. 
 
 
 
b. 
Current practice 
Despite the burden of this potentially treatable condition, there have been no controlled prospective 
treatment trials for AE. Current treatments for the disease are based on expert opinion, retrospective 
case series, or open label immunotherapy. Most of the therapies utilized in AE are off label uses of 
therapies approved for other disorders, including corticosteroids, intravenous immunoglobulin, plasma 
exchange, “traditional” immunosuppression (e.g. cyclophosphamide), cytokine inhibition (e.g. 
tocilizumab) or B cell depletion (e.g. rituximab). There is particular interest in anti-CD20 therapy 
because of the demonstrated role of B cells in the pathogenesis of antibody-mediated disorders and the 
success of anti-CD20 therapy (ocrelizumab) in the treatment of multiple sclerosis, another autoimmune 
disorder of the brain. Additionally, unpublished data from Dr. Nancy Monson (one of the co-
investigators on this proposal) shows that the characteristics of CSF lymphocytes may be predictive of 
response to therapy.  Specifically, those patients with a large population of autoreactive plasmablasts 
anectodally seem to have a better outcome than those with a large population of mature plasma cells or 
autoreactive memory B-cells. Targeting plasmablasts and other CD20-positive B cells acutely should be 
effective therapy for these disorders and prevent progression. 
 
There is an urgent need to carry out systematic controlled studies to evaluate the efficacy of 
immunotherapy in AE. Retrospective data suggests that a significant number of patients will relapse 
without ongoing immunotherapy.3 However, immunotherapeutic drugs carry serious potential risks, so 
evidence of clinical efficacy is critical in order to offer such treatment to patients. We propose to 
conduct a prospective double-bind placebo-controlled pilot study to evaluate the efficacy of 
ocrelizumab in AE. These results can then be used to design a larger multi-center phase III study for the 
use of this drug in AE patients. This proposed pilot study will also allow the development and 
evaluation of biomarkers for AE which could ultimately be used to guide selection of therapy and 
monitor disease activity. 
  
 


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STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
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3.  Study Design.  
Describe the study design (e.g., single/double blind, parallel, crossover, etc.)  Consider inserting a scheme to visually present the 
study design. 
 
These study is comprised of two phases.  
Phase 1 is a study of biomarkers and clinical features of autoimmune encephalitis. Many of the patients from this 
portion of the study will come from the inpatient setting, though patients meeting the criteria may also be identified as 
outpatients. Individuals fitting criteria for possible autoimmune encephalitis will be invited to participate. Consenting 
patients will have blood and CSF samples collected for antibody testing and testing of B-cell activity. They will also 
undergo a brief formal neuropsychological assessment.  During phase 1, all patients will receive standard of care acute 
therapies for encephalitis (typically high dose IV steroids and plasma exchange at our institution). They will again 
undergo biomarker and neuropsychological assessments within seven days of finishing treatments.  
In Phase 2, individuals with a detectable antibody in serum or CSF associated with autoimmune encephalitis will be 
invited to participate in a randomized double-blinded placebo-controlled trial on the efficacy of ocrelizumab for 
autoimmune encephalitis. Individuals will undergo a screening process to insure they can safely enroll in the trial. They 
will then be randomized in a 1:1 fashion to receive infusion of Ocrelizumab or matched placebo. The drug will be 
administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial 
infusion, and at 6 months. Individuals will attend clinical study visits every 3 months, during which a full panel of tests 
will be performed to assess clinical worsening. 
Individuals who meet the definition of clinical worsening within the first 6 months of enrollment will be offered the 
opportunity to participate in open label treatment with ocrelizumab at the investigator’s discretion.  
The primary outcome this study will be proportion of patients who fail to complete the 12 month study period without 
worsening, as defined in the protocol. Secondary outcomes include the time to treatment failure and change in 
neuropsychological assessment at 6 and 12 months compared to baseline.  
 
 
4.  Research Plan / Description of the Research Methods:   
4.a.  Provide a comprehensive narrative describing the research methods.   
     1) Provide the order in which tests/procedures will be performed,  
     2) Provide the setting for these events and a description of the methods used to protect privacy during the study.   
     3) Provide the plan for data analysis (include as applicable the sample size calculation) 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
We will identify adult patients with clinical features of possible autoimmune encephalitis according to 
consensus criteria adapted from a recent consensus group (Table 1). Patients that meet inclusion/exclusion 
criteria (Table 2) will be invited to participate in phase 1 of this study. Phase 1 is a study of biomarkers 
and clinical features of AE. Consenting patients will have blood and CSF collected for antibody testing 
and biomarker studies before and after initial treatment. Rapid screening for encephalitis autoantibodies 
will be done at UT Southwestern using standard cell-based assay (EuroImmun), and biomarkers for B cell 
activity will be conducted in the laboratory of Dr. Nancy Monson. Patients will also be evaluated with 
quantitative functional measures administered by a neuropsychologist including the Texas functional 
living scale as well as Quality of Life measures.  
 
All patients will receive treatment with the current acute standard of care treatment. At UT Southwestern, 
this consists of treatment with iv solumedrol (1000mg daily for 5 days) and plasma exchange (5 exchanges 


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vMar2018 
typically given every other day). Biomarker testing and functional assessment will be repeated within one 
week of completing this initial treatment. 
 
Table 1: Diagnostic criteria for possible autoimmune encephalitis (AE) 
1. Reasonable exclusion of alternative causes  
2. Subacute onset (< 3 months) of memory deficits, altered consciousness, and/or 
psychiatric symptoms  
3. One or more of the following:  
• CSF pleocytosis (>5 cells/µl corrected, if necessary, for traumatic lumbar 
puncture) 
• EEG with epileptiform or focal slow wave abnormalities involving temporal 
lobes 
• Brain abnormalities on T2/FLAIR MRI restricted to the mesial temporal 
(limbic) lobes 
• Associated dyskinesias (faciobrachial dystonic movements or orofacial 
dyskinesias) 
 
 
Table 2: Inclusion/Exclusion criteria (Study Phase 1) 
Inclusion criteria 
1. Age 18 or greater 
2. Able to obtain informed consent from patient or appropriate designee 
3. Possible autoimmune encephalitis as defined by Table 1 
Exclusion criteria 
1. Prior immunosuppression treatment in past year (prior treatment steroids is allowed) 
2. Treatment with intravenous immunoglobulin in past year 
 
Subjects completing Phase 1 must be re-screened to subsequently participate in Phase 2 of this study.  
Phase 2 of the study is the double-blind placebo-controlled trial for which we are requesting funding 
support through Genentech. 
 
Patients who meet the inclusion/exclusion criteria (Table 3) will be eligible to participate in the 
randomized double-blind placebo-controlled treatment trial.  Subjects who meet the eligibility criteria for 
the treatment trial can participate even if they were not enrolled in Phase1 of this study.  Patients will be 
consented separately for the treatment trial.   
 
 
 
Table 3: Inclusion/Exclusion criteria (Treatment Trial) 
Inclusion criteria 
1. Age 18 or greater 
2. Able to obtain informed consent from patient or appropriate designee 
3. Possible autoimmune encephalitis as defined by Table 1 
4. Completed initial treatment with iv steroids (at least 3000mg solumedrol) and plasma 
exchange (at least 3 exchanges) within the past 4 weeks 


Form A 
IRB #  
 
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STU  2018-0185 
 
STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
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vMar2018 
5. Presence of one (or more) of the following autoantibodies in serum or CSF 
• NMDA receptor 
• LGI1 
• CASPR2 
• DPPX 
 
Exclusion criteria 
1. Prior immunosuppression treatment in past year (other than steroids and plasma 
exchange) 
2. Treatment with intravenous immunoglobulin in past year 
3. Active malignancy requiring chemotherapy 
4. Pregnancy 
5. Evidence of active hepatitis or tuberculosis infection 
6. Medical condition that (in investigators opinion) precludes the use of ocrelizumab 
 
 
Patients in Phase 2 (treatment trial) will be evaluated with neuropsychological functional measures at 
baseline and during treatment (every 3 months).  The complete battery of tests listed in Table 4 can be 
completed in about 40 minutes.  The Texas Functional Living Scale (TFLS) and self-reported ADL score 
are part of the clinical outcome assessment.   
 
 
 
Table 4: Neuropsychological testing battery 
Test 
Rationale 
Texas Functional Living Scale 
(TFLS) 
Objective measure of functional ability/instrumental 
ADLs  
Lawton & Brody Instrumental 
Activities of Daily Living (IADL) 
Rating Scale 
Self-report measure of instrumental IADLs 
Patient and informant administrations  
Symbol-digit Modalities Test 
(SDMT) 
Written and /or oral processing speed 
Trail Making Test Parts A & B 
(TMT) 
Visuomotor processing speed (TMTA) and set 
shifting/divided attention (TMTB) 
Controlled Oral Word Association 
Test (FAS) 
Phonemic verbal fluency 
Hopkins Verbal Learning Test-
Revised (HVLT-R) 
Episodic verbal memory  
Test of Premorbid Functioning 
(TOPF) 
Estimate for premorbid intellectual ability 
Montreal Cognitive Assessment 
(MOCA) 
Commonly used multimodality bedside cognitive test 
 


Form A 
IRB #  
 
26776 
STU  2018-0185 
 
STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
6 
vMar2018 
The TFLS is a validated instrumented functional test administered by a trained assessor.  The score reflects 
ability to perform activities of daily living and higher level tasks.  The 50 point raw score is converted to a 
T score (0 – 100) based on normative data. A change in T score of 5 points corresponds to a change of 0.5 
standard deviations in the TFLS and is considered a significant meaningful change.  The IADL is a simple 
8 point self-administered questionnaire; a change of one point is considered significant.  
After baseline procedures, subjects will be randomized to receive either intravenous ocrelizumab or 
matched placebo in a 1:1 ratio.  Investigators, patients and treating physicians will be blinded to the 
treatment assignment. Patients will receive an initial dose of 300mg study medication followed by a 
second dose of 300mg 2 weeks later.  Study medications will be handled and allocated by the research 
pharmacy, and infusions given in either the inpatient or outpatient clinical trials infusion center at UT 
Southwestern.  At 6 months, patients who remain in the study will receive an additional dose of study 
medication (ocrelizumab 600mg or matched placebo). 
Subjects will be monitored closely throughout the study with clinical assessments at months 1, 2, 3, 6, 9, 
and 12 as well as telephone assessments every 2 weeks between clinical visits.  
 
Outcome assessment 
The primary outcome of the treatment trial will be the proportion of patients who fail to complete the 12 
month study without clinical worsening. Secondary outcomes will be time to treatment failure and change 
in TFLS scores at 6 and 12 months compared to baseline. We anticipate that patients treated with 
ocrelizumab will be much less likely to show clinical worsening compared to placebo.  
 
 
 
 
 
 
 
 
 
 
We also anticipate that ocrelizumab-treated subjects will show higher functional scores. 
 
The criteria for the primary endpoint, treatment failure, is described in Table 5. At each clinical study visit, 
subjects will complete the global impression and IADL questionnaire, and the full panel of assessment 
tests will be performed every 3 months.  Between study visits, the study coordinator will contact the 
subject every 2 weeks by telephone to inquire about adverse events and clinical status.  If a subject or 
caregiver reports clinical worsening, the subject will complete the IADL questionnaire.  Subjects with 
concern for clinical worsening will be brought in for unscheduled clinical assessment and completion of 
the TFLS. 
 
Subjects who meet criteria for treatment failure will complete the final study visit procedures (12 month 
visit).  At the investigators’ discretion, subjects with early treatment failure during the first 6 months will 
be offered open label treatment with ocrelizumab (one dose of 600mg) or may proceed with best available 
alternative treatment in consultation with their primary doctors. 
 
Table 5: Definition of clinical worsening (treatment failure) 
1. Clinician or patient/caregiver perception of clinical decline 
2. Worsening of patient/family reported IADL (by one point or more) 
3. One of the following additional features: 
- 
Significant worsening of Texas Functional Living Scale (by ≥ 5 T points, 0.5 st 
deviation) 
- 
Other clinical worsening leading to hospitalization 
 


Form A 
IRB #  
 
26776 
STU  2018-0185 
 
STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
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vMar2018 
Estimated number of subject 
 
We expect to identify up to 60 patients eligible for the phase 1 biomarker study, and we plan to enroll 22 
patients in the double-blind treatment study (phase 2).  Based on our previous retrospective studies, we 
anticipate that we can achieve this enrollment in 12-18 months.   
 
Based on our own experience and case reports related to rituximab, we will be expecting a large effect 
size.  Assuming a relapse rate of 15-20% in the ocrelizumab group and an 75-80% relapse rate in the 
placebo group, a sample size of 22 achieves 80% power to detect an effect size (W) of 0.6 (20% vs 80%) 
using a 1 degree of freedom Chi-Square Test with a significance level (alpha) of 0.05. This sample size 
would have a 73% power to detect and effect size of 0.55 and 65% power to detect and effect size of 0.5 
 
With 22 subjects, the Chi Square for this effect size would be significant (p=0.03) even for an effect size 
of 46% (e.g. 3 treatment failures out of 11 in the ocrelizumab group and 8 treatment failures in placebo 
group). 
 
Setting for each phase:  
 
For phase 1, subjects may be initially enrolled during hospitalization at Zale Lipshy Hospital or Clements 
University Hospital. Patients identified in the neurology clinics of the investigators may also be identified.  
 
For phase 2, all  visits and drug administrations will occur in the Clinical Research Units at UT 
Southwestern Medical Center.  
 
Schedule of Phase 2 Study Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Study Week 
(Study Month) 
Screening/Baseline 
0 
2  
4 
(1) 
6 
8  
(2) 
10  
12 
(3) 
16 
(4) 
20 
(5) 
24 (6) 
infusion # 
 
1 
300mg 
2 
300mg 
 
 
 
 
 
 
 
3 
600mg 
Informed Consent   
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria   
X 
 
 
 
 
 
 
 
 
 
 
Medical History   
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (females 
only) 
X 
 
 
 
 
 
 
 
 
 
 
Telephone Contact 
 
 
 
 
X 
 
X 
 
X 
X 
 
Vital signs, physician exam   
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Concomitant Medications   
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events   
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labs (CBC/CD19) 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Safety Labs (Quantiferon, 
Hepatitis & JCV Serology) 
X 
 
 
 
 
 
 
 
 
 
 
Serum AE Ab 
X 
 
 
X 
 
 
 
X 
 
 
X 
Serum/CSF for B cell 
testing (Biorepository) 
X 
 
 
 
 
 
 
 
 
 
 
Subject/Caregiver 
Impression 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure Frequency Report 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinician Global Impression  
X 
 
X 
X 
 
X 
 
X 
 
 
X 
Testing4 - TFLS 
X 
 
 
X 
 
 
 
X 
 
 
X 


Form A 
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26776 
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STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
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vMar2018 
Testing4- IADL 
X 
 
X 
X 
X3 
X 
X3 
X 
X3 
X3 
X 
X3 
X3
Testing4– SDMT 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Testing4- TMT 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Testing4– FAS 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Testing4– HVLT-R 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Testing4– TOPF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Testing4- MOCA 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Study Drug Administration 
(placebo/ocrelizumab)   
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
1 If subject terminates study early (reaches progression endpoint) 
2Telephone contact/assessments will take place every 2 weeks between scheduled clinic visit 
3The IADL questionnaire will be completed at telephone  contact if the patient/caregiver impression 
suggests clinical worsening 
4TFLS: Texas Functional Living Scale; IADL: Lawton & Brody Instrumental Activities of Daily Living 
Rating Scale; SDMT: Symbol-digit Modalities Test; TMT: Trail Making Test Parts A & B; FAS: 
Controlled Oral Word Association Test; HVLT-R: Hopkins Verbal Learning Test-Revised; TOPF: Test of 
Premorbid Functioning; MOCA: Montreal Cognitive Assessment 
 
 
 
4.b.  List of the study intervention(s) being tested or evaluated under this protocol 
 
N/A -  this study does not test or evaluate an intervention.    Skip to item 4.d. 
# 
Study intervention(s) being tested or evaluated under the protocol 
 
 
 
Add or delete rows as needed 
 
Affiliate 
 
Place a check next to 
institution(s) where 
the  
intervention will be 
performed 
Local Standard 
Practice?  
Indicate whether the 
intervention is 
considered 
acceptable practice 
locally for applicable 
institutions 
1 
Administration of drug Ocrelizumab 
☒ UTSW 
☐ Yes 
☐ PHHS 
☐ Yes 
☐CMC 
☐ Yes 
☐THR 
☐ Yes 
☐TSRH 
☐ Yes 
☐ Other: _____ 
☐ Yes 
 


Form A 
IRB #  
 
26776 
STU  2018-0185 
 
STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
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vMar2018 
 
 
 
 
 
4.c.  Risk:Benefit Analysis of study interventions being tested or evaluated under this protocol 
For each study intervention identified in section 6b above, complete a risk:benefit analysis table. 
 
(Two tables are provided, copy & paste additional tables as needed or delete both tables if this study does not test an 
intervention) 
 


Form A 
IRB #  
 
26776 
STU  2018-0185 
 
STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
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vMar2018 
4.c. 
Study Intervention #1 
Administration of Ocrelizumab 
List each group exposed to this 
intervention on a separate line. 
 
We anticipate that patients receiving ocrelizumab will have a reduced rate of 
worsening compared to placebo.  
Experimental Arm (group randomized to 
ocrelizumab) 
Open Label Arm (patients with early 
worsening who opt to receive drug open 
label) 
 
4.d. List ALL other research procedures or components not listed in table 4.b. 
        The combination of Tables 4b and 4d should account for all of the research 
procedures that will take place during this study. 
 
Consider grouping similar procedures under a single component (e.g., blood work, CT = safety 
assessments) 
 
 
 
# 
Research component 
• 
individual 
procedures 
 
example: 
Eligibility Assessments 
• 
History and 
physical 
• 
Questionnaire 
• 
Laboratory tests 
Add or delete rows as needed 
Column A 
Local Standard 
Practice Indicate the 
number of times each 
procedure will be 
performed as stipulated 
in the research plan that 
would be performed if 
the participant were not 
participating in the 
study. 
Column B 
Research Only  
Indicate the number of times 
each procedure will be 
performed solely for research 
purposes (meaning that the 
participant would not undergo 
the same number of 
procedures or would not 
undergo the procedure(s) at 
the same frequency if they 
were not participating in the 
study) 
Column D 
Risks 
If you are requesting a Waiver of Informed 
Consent, complete the table below. 
 
List the reasonably expected risks for each procedure 
or group of procedures under the following categories 
as appropriate: 
• Serious and likely; 
• Serious and less likely; 
• Serious and rare; 
• Not serious and likely; 
• Not serious and less likely 
1 
Phase 1 assessments 
 
 
 
 
History and Physical 
x 
 
 
 
Antibody testing (serum and 
CSF) 
 
X 
 
 
Biomarker testing (serum and 
CSF)  
 
 
X 
 
 
Neuropsychological 
Assessment 
 
x 
 
2 
Phase 2 Elligibility 
 
 
 
 
History and Physical  
x 
 
 
 
Laboratory testing (safety labs 
for ocrelizumab) 
 
X 
 
 
Laboratory Testing (antibody 
testing) 
 
X 
 
 
Questionnaires 
 
X 
 
 
Neuropsychological testing 
 
x 
 
3 
Drug Adminstration 
 
 
 
 
History and Physical Exam 
 
x 
 
 
Questionnaire (Advserse 
Events)  
 
x 
 
4 
Clinic Visits 
 
 
 
 
History and Physical 
 
x 
 


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IRB #  
 
26776 
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STU2018-0185, Vernino, Form A1, NS, 01-23-19 (1) 
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vMar2018 
 
Questionnaires (Adverse 
Events, seizure frequency, 
impression) 
 
x 
 
 
Laboratory Testing (safety 
labs for ocrelizumab 
 
x 
 
 
Neuropsychological Testing 
 
x 
 
 
5 Telephone Visits  
 
 
 
 
Questionnaires (Adverse 
Events, seizures, impression) 
 
x 
 
 
Testing (IADL) 
 
x 
 
 
 
 
5.  Safety Precautions.  (Describe safeguards to address the serious risks listed above.) 
a.  Describe the procedures for protecting against or minimizing any potential risks for each of the more than minimal risk 
research procedures listed above. 
 
Laboratory monitoring (blood work for blood counts, CD19, and autoantibody testing) will be 
done at study visits. Since the subject, principal investigator and study personnel must remain blinded 
to treatment assignment, the laboratory results will be reviewed by an independent safety monitor 
(physician) who has no contact with the research subjects.   
 
In addition, throughout the study, participates will be regularly contacted (either during clinical visits, 
or during telephone visits) and specifically asked about adverse events.  
 
b.  Where appropriate, discuss provisions for ensuring necessary medical or professional intervention in the event of adverse 
events, or unanticipated problems involving subjects. 
The sponsor (Genetech) will be independently review all AE & SAE for this study. They provided a 
safety data exchange agreement    Will the safeguards be different between/among groups?   
Yes 
No 
If yes, describe here