Comparing the Risk and Severity of Infusion-Related Reactions in Patients Premedicated With Cetirizine Versus Diphenhydramine Prior to Ocrelizumab Infusions
Phase: PHASE3
Conditions: Multiple Sclerosis, Infusion Reaction
Sponsor: Providence Health & Services

 
CONFIDENTIAL 
 
This is a Providence Health & Services document that contains 
confidential information. It is intended solely for the recipient clinical 
investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical 
investigations; any other proposed use requires written consent from 
Providence Health & Services. 
 
Protocol: PRECEPT  
 
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PROTOCOL 
STUDY TITLE: 
Comparing the Risk and Severity of Infusion-
Related Reactions in Patients Premedicated with 
Cetirizine versus Diphenhydramine Prior to 
Ocrelizumab Infusions (PRECEPT) 
SUPPORT PROVIDED BY: 
Genentech, Inc. 
INVESTIGATOR: 
Kyle Smoot, MD 
9135 SW Barnes Road, Suite 461 
Portland, OR 97225 
Phone – 503.216.1150 
Fax – 503.216.1039 
SUB-INVESTIGATORS: 
Stanley Cohan, MD, PhD 
Justine Brink, DO, MPH 
Vitalie Lupu, MD, FAAN, MSCS 
Leah Gaedeke, MSN, FNP-BC 
INSTITUTION: 
Providence Health & Services 
Providence Brain & Spine Institute 
9155 SW Barnes Rd, STE 317, Portland, OR 97225 
STUDY NUMBER: 
ML41308  
PROTOCOL VERSION/DATE: 
Version 4.0/19MAY2021 
                                                                                                                                                 

 
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TABLE OF CONTENTS 
Page 
1. 
INTRODUCTION ........................................................................................................ 
3 
2. 
OBJECTIVES ............................................................................................................. 
3 
2.1 
Primary Objectives ..................................................................................... 
3 
2.2 
Secondary Objectives ................................................................................. 
3 
3. 
STUDY DESIGN ........................................................................................................ 
3 
3.1 
Description of the Study ............................................................................. 
3 
3.2 
Rationale for Study Design ......................................................................... 
4 
3.3 
Outcome Measures .................................................................................... 
4 
3.3.1 Primary Outcome Measure ................................................................ 
4 
3.3.2 Secondary Outcome Measures .......................................................... 
4 
3.4 
Safety Plan ................................................................................................. 
4 
3.5 
Compliance with Laws and Regulations ..................................................... 
6 
4. 
MATERIALS AND METHODS .................................................................................... 
6 
4.1 
Patients ...................................................................................................... 
6 
4.1.1 Patient Selection……………………………………………........... .........       6 
4.1.2 Inclusion Criteria ................................................................................ 
6 
4.1.3 Exclusion Criteria ............................................................................... 
6 
4.2 
Method of Treatment Assignment ............................................................... 
7 
4.3 
Study Treatment ......................................................................................... 
7 
4.3.1 Packaging, Preparation, Storage, Handling, Dosage, and 
Administration  ................................................................................... 
7 
4.3.2 Dosage Modification .......................................................................... 
8 
4.4 
Concomitant and Excluded Therapy ........................................................... 
8 
4.5 
Study Assessments .................................................................................... 
8 
4.5.1 Assessments during Treatment ......................................................... 
8 
4.6 
Discontinuation of Therapy ......................................................................... 
10 
4.7 
Patient Discontinuation ............................................................................... 
11 
4.8 
Study Discontinuation ................................................................................. 
11 
4.9 
Statistical Methods .....................................................................................  11 
4.9.1 Analysis of the Conduct of the Study ................................................. 
11 
4.9.2 Analysis of Treatment Group Comparability ....................................... 
11 
4.9.3 Efficacy Analysis ................................................................................ 
11 
4.9.4 Safety Analysis .................................................................................. 
12 
4.9.5 Missing Data ...................................................................................... 
12 
4.9.6 Determination of Sample Size ............................................................ 
12 
4.10     Data Quality Assurance .............................................................................. 
12 
5. 
REPORTING OF ADVERSE EVENTS ....................................................................... 
12 
5.1 
Assessment of Safety ................................................................................. 
15 
5.2 
Methods and Timing for Assessing and Recording Safety Variables .......... 
15 
5.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ........... 
16 
5.4       MedWatch 3500A Reporting Guidelines ..................................................... 
22 
5.5 
Study Close Out ......................................................................................... 
23 
5.6 
Queries ....................................................................................................... 
23 
5.7 
Signal Management and Risk Management ............................................... 
24 
5.8 
Compliance with Pharmacovigilance Agreement/Audit ............................... 
24 
6. 
INVESTIGATOR REQUIREMENTS ........................................................................... 
25 
6.1 
Study Initiation ............................................................................................ 
25 
6.2  
Informed Consent ....................................................................................... 
25 
6.3  
Institutional Review Board or Ethics Committee Approval……………..... ....     25 

 
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6.4 
Study Monitoring Requirements.................................................................. 
25 
6.5 
Data Collection ........................................................................................... 
26 
6.6 
Study Medication Accountability ................................................................. 
26 
6.7 
Disclosure and Publication of Data ............................................................. 
26 
6.8 
Retention of Records .................................................................................. 
26 
 
APPENDIX A: Study Flowchart…………………………………………………………….      27 
APPENDIX B: Safety Reporting Cover Sheet………………………………………. 
     28 
APPENDIX C: Clinical Trial Pregnancy Reporting Form………………………………...     29 
 
REFERENCES……………………………………………………………………….………      33 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. 
INTRODUCTION 
Ocrelizumab (OCR), a humanized monoclonal antibody that selectively binds to and 
destroys CD20-expressing lymphocytes (B-cell lymphocytes), has demonstrated robust 
efficacy in reducing relapse rate, sustained disability worsening, and MRI indicators of 
disease activity in patients with relapsing multiple sclerosis (RMS)1. For patients with 
primary progressive MS (PPMS), OCR demonstrated reduction in disability progression 
compared to patients receiving the placebo treatment2. The medication is well-tolerated 
with upper respiratory infections being the most common potential side effect followed 
by infusion-related reactions (IRRs). At least one infusion reaction occurred in 34.3% of 
the patients in OPERA I and OPERA II1. The majority of the infusion reactions were 
mild to moderate and occurred with the first infusion of dose 1. In the clinical trials, all 
patients were pre-medicated with 100mg of methylprednisolone, and per the protocol, 
an analgesic/antipyretic such as acetaminophen and an IV or oral antihistamine such as 
diphenhydramine 50mg were recommended to use prior to starting OCR to minimize 
IRRs. However, drowsiness is commonly associated with diphenhydramine; therefore, a 
newer antihistamine such as cetirizine may be tolerated better without an increase in 
IRRs. 
 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this pilot study is to evaluate whether there is some evidence 
that cetirizine is non-inferior to diphenhydramine in limiting the proportion and severity 
of reactions from OCR infusions. 
 
2.2 
SECONDARY OBJECTIVE 
The secondary objective of this study is to evaluate patient treatment satisfaction after 
receiving cetirizine and diphenhydramine as premedication for OCR infusions. 
 
3.     STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This 6-month randomized controlled pilot study will determine whether there is some 
evidence that cetirizine is better tolerated than diphenhydramine without an increase in 
IRRs. Fifty-two patients, 26 patients per arm, will be randomized in a 1:1 ratio to receive 
cetirizine or diphenhydramine as premedication prior to OCR infusions on day 0 (1st 
half dose of 300mg), day 14 (2nd half dose of 300mg) and week 24 (1st full dose of 
600mg). Neurological exams and the estimated Expanded Disability Status Scale 
(EDSS) will be obtained at screening and week 24, as well as premature termination 
visits, if applicable. Stanford Sleepiness Scale (SSS), and the Visual Analog Scale – 
Fatigue (VAS-F) will be administered at screening, baseline, day 14, and week 24. 
Modified Fatigue Impact Scale (MFIS) and Multiple Sclerosis Impact Scale (MSIS-29) 
will be administered at screening and week 24. MSIS-29 and MFIS will also be 
administered at premature termination, if applicable. Treatment Satisfaction 
Questionnaire for Medication (TSQM) will be administered at baseline, day 14, and 
week 24. TSQM, SSS, and VAS-F will be administered within 2 hours after each OCR 
infusion, followed by a phone call on the next business day following each infusion to 
collect and assess infusion reactions or other AEs. 
 

 
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3.2 
RATIONALE FOR STUDY DESIGN 
Shortly after the approval of OCR, we followed the premedication protocol used in 
OPERA I and II which included 100mg of methylprednisolone, 1 gram of 
acetaminophen, and 50mg of IV diphenhydramine. However, many patients 
experienced extreme sedation which caused severe drowsiness and impaired their 
ability to function, drive, or work during and after the infusion, and even the following 
day. As a result, we have decreased the dose of diphenhydramine to 25mg 
administered either IV or orally which has resulted in less, but still marked, drowsiness. 
Newer antihistamines such as cetirizine may be better tolerated; however, there is no 
evidence that they will be as effective in minimizing infusion reactions. 
 
3.3 
OUTCOME MEASURES 
 
3.3.1 Primary Outcome Measure 
The proportion of patients having an infusion-related reaction, as defined by the 
Common Terminology Criteria (CTCAE), version 43 during or after the first-half dose of 
the first infusion on day 0. Infusion-related reactions will be documented at the infusion 
clinic on the day of the infusion and reported by the patient at the follow-up phone call 
the next business day after the infusion. 
 
3.3.2 Secondary Outcome Measures 
The proportion of patients having an infusion-related reaction during or after receiving 
the second half dose infusion on day 14. 
 
The proportion of patients having an infusion-related reaction during or after receiving 
the first full 600mg dose infusion on week 24. 
 
TSQM (Treatment Satisfaction Questionnaire for Medication) score after the infusions 
on day 0, day 14, and week 24. 
 
SSS (Stanford Sleepiness Scale) score after the infusions on day 0, day 14, and week 
24. 
 
VAS-F (Visual Analog Scale for Fatigue) score after the infusions on day 0, day 14, and 
week 24. 
 
MFIS (Modified Fatigue Impact Scale) score at week 24.  
 
Physical and psychological MSIS-29 (Multiple Sclerosis Impact Scale) scores at week 
24. 
 
3.4 
SAFETY PLAN 
Patients will be evaluated by a clinician at the start of the study and at week 24 prior to 
the 600mg OCR infusion. Phone visits will be conducted after each infusion (see 
Section 4.5, Study Assessments, and Appendix A, Study Flowchart). 
A full neurological examination will be conducted at screening and week 24. Any 
worsening or new abnormality (including laboratory results) that is determined by the 
investigator as clinically significant will be recorded as an AE and will be monitored until 
resolution or stabilization. MS related symptoms are not to be reported as AEs unless, 

 
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in the opinion of the investigator, the symptoms are unusually serious and relevant. 
 
The recommendation from the OCR prescribing information dated 12/20204 is to pre-
medicate with 100mg of methylprednisolone (or an equivalent corticosteroid) 
administered 30 minutes prior to each OCR infusion to reduce the frequency and 
severity of infusion-related reactions (IRRs) [see Warnings and Precautions (5.1) in 
prescribing information4].  
 
For this study, all patients will receive 1,000mg of acetaminophen orally and 100mg of 
methylprednisolone via IV 30-60 minutes prior to each infusion. Additionally, patients 
will be randomized to receive either diphenhydramine 25mg orally or cetirizine 10mg 
orally 30-60 minutes prior to each OCR infusion to further reduce the frequency and 
severity of infusion reactions.  
 
Recommended medications to be available if there is an infusion reaction (per treating 
investigator discretion): 
A. Epinephrine – anaphylaxis 
B. Albuterol – bronchospasm or hypoxia 
C. Famotidine 20mg IV – hives, itching, or anaphylaxis 
D. Oxygen therapy – shortness of breath, chest pain, or hypoxia 
E. Acetaminophen – pain, fever, and headaches 
F. Methylprednisolone – hives, itching, shortness of breath, or anaphylaxis 
 
Suggested Management of IRRs 
 
All CD20+ depleting agents administered via the intravenous route, including OCR, 
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, dyspnea, 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. 
 
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. 
 
Severe IRRs 
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 re-started 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. 
 
Mild-Moderate IRRs 
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 

 
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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. 
 
See Section 5.1, Assessment of Safety, for complete details of the safety evaluation for 
this study. 
3.5 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current ICH GCP Guidelines and the 
Code of Federal Regulations for clinical research, applicable national and local health 
authorities, and IRB requirements. Any amendment to the study protocol must be 
approved by Providence IRB before implementation. AEs and protocol deviations must 
be reported according to the guideline of the IRB.  
4.0 
MATERIALS AND METHODS 
4.1 
PATIENTS 
 
4.1.1 Patient Selection 
Patient selection will be based on meeting all of the required inclusion and 
exclusion criteria to be eligible to participate in the trial. 
 
4.1.2 Inclusion Criteria 
1. Male or female patient with relapsing or progressive forms of MS, age 18 to 70 
inclusive at the time of consent. 
2. Able to understand the purpose, responsibilities and risks of the study and 
provide signed informed consent. 
3. Naïve to OCR and will receive OCR as part of standard of care for MS 
treatment. 
4. No evidence, in the opinion of the investigators of significant cognitive limitation 
or psychiatric disorder that would interfere with the conduct of the study.  
5. Estimated EDSS of ≤ 6.5 at screening.  
6. Female patients of childbearing potential must practice effective contraception 
and continue contraception during the study.  
4.1.3 Exclusion Criteria 
1. Any mental condition of such that patient is unable to understand the nature, 
scope, and possible consequences of the study.  
2. Evidence of active hepatitis B infection at screening. 
3. Patients with untreated hepatitis C, or tuberculosis. Patients who have history of 
PML or known to be HIV positive, per standard care. 
4. Any persistent or severe infection. 

 
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5. Pregnancy or lactation. 
6. Significant, uncontrolled somatic disease or severe depression in the last year.  
7. Current use of immunosuppressive medication, lymphocyte-depleting agents, or 
lymphocyte-trafficking blockers. 
8. Patients with any significant comorbidity that in the opinion of the investigator, 
would interfere with participation in the study.  
9. Any known allergy or inability to tolerate diphenhydramine or cetirizine.  
 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
Randomization will be based on a computer-generated sequence using a permuted 
block design with block size equal to four. Participants will be allocated in a 1:1 ratio of 
oral diphenhydramine to oral cetirizine. All patients on this study will receive OCR as 
part of their standard care.  
 
4.3. 
STUDY TREATMENT  
Patients will be enrolled and randomized to either the diphenhydramine or the cetirizine 
arm to be administered before their OCR doses, after informed consent and screening 
assessment have been completed. The premedication and OCR will be paid for by the 
patient or by the patient’s insurance. Patients may receive any generic products of 
cetirizine or diphenhydramine that are available at their infusion center and do not 
require the same brand of the premedication for their subsequent infusions.  The same 
brand does not need to be used at each OCR infusion, per patient. 
 
4.3.1 Packaging, Preparation, Storage, Handling, Dosage, and Administration  
Packaging, Preparation, Storage and Handling 
The study team is not responsible for collecting or reviewing data on how the 
premedications or OCR were packaged, prepared, stored, or handled for the purposes 
of this trial.  
 
The treating physician will refer to the specific prescribing information provided by the 
drug manufactures for detailed instructions on packaging, preparation, storage, and 
handling for both the premedications and OCR4. The standard of care process is to be 
followed.  
 
Dosage and Administration 
1. Patients will be randomized to either diphenhydramine 25mg orally or cetirizine 
10mg orally. The patients randomized to diphenhydramine will receive 
diphenhydramine 25mg orally 30-60 minutes prior to each OCR infusion. The 
patients randomized to cetirizine will receive cetirizine 10mg orally 30-60 minutes 
prior to each OCR infusion. 
 
The treating physician will refer to the specific prescribing information provided by 
the drug manufactures for detailed instructions on administration of the 
premedications. The standard of care process is to be followed.  
 

 
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2. OCR 300mg IV will be given on Day 0 and repeated with the same dose on Day 
14±2. Patients will then receive OCR 600mg IV at 24 weeks.  
 
Although OCR may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator. OCR infusions 
should always be administered in a hospital or clinic environment under close 
supervision of the investigator or a medically qualified staff member. 
 
The treating physician will refer to the OCR prescribing information for detailed 
instructions on administration4. The standard of care process is to be followed. 
 
4.3.2 Dosage Modification 
Dose modifications of diphenhydramine or cetirizine are not permitted. See section 3.4 
for dose modifications of OCR in the case of IRRs.  
4.4 
CONCOMITANT AND EXCLUDED THERAPY 
All concomitant medications are allowed except immunosuppressants, lymphocyte-
depleting agents, or lymphocyte-trafficking blockers while patients are receiving OCR. 
All medications including over-the-counter medication and supplements will be recorded 
at each clinical visit. At screening, all medications taken 4 weeks prior to screening will 
be reviewed and recorded, as well as all prior lifetime MS disease modifying therapies 
taken by the patient.  
4.5 
STUDY ASSESSMENTS 
Informed consent must be obtained before proceeding with the study assessments. See 
section 6.2 for the detailed description of the informed consent process.  
 
4.5.1 Assessments during Treatment 
Visit 1 or Screening Visit (-28 to -1 days prior to Baseline) 
• 
Informed consent 
• 
Eligibility review 
• 
Demographic information 
• 
Review of disease and medical history 
• 
Review of prior and concomitant medications, including lifetime MS disease 
modifying therapy history 
• 
Reason(s) for switching to OCR 
• 
Vital signs (blood pressure, heart rate, oral temperature, weight, and height) 
• 
Neurological exam (may be historical exam if completed within 28 days prior to 
consent) 
• 
Confirmation of estimated EDSS of 0 to 6.5, inclusive  
• 
Laboratory assessments:  
o Urine or serum pregnancy test (females of childbearing potential only) 
o CBC and LFTs (may be historical laboratories if completed within 28 
days prior to consent) 
o Hepatitis B testing (may be historical laboratories if completed within 6 
months prior to consent) 

 
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o Serum immunoglobulins, quantitative (may be historical laboratories if 
completed within 28 days prior to consent) 
• 
SSS  
• 
VAS-F  
• 
MFIS 
• 
MSIS-29 
• 
Adverse events 
 
Visit 2 or Baseline Visit (Day 0) 
• 
Concomitant medications and adverse events  
• 
Eligibility review (can be done day -7 to day 0) 
• 
Randomization for premedication arm (can be done day -7 to day 0) 
• 
Administration of premedication and OCR (300mg) 
• 
Infusion reaction assessment 
• 
TSMQ (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
SSS (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
VAS-F (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
Phone Call (next business day) to assess infusion reactions and any other AEs 
Visit 3 (Day 14 +/- 2 days from baseline) 
• 
Concomitant medications and adverse events 
• 
Administration of premedication and OCR (300mg) 
• 
Infusion reaction assessment 
• 
TSMQ (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
SSS (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
VAS-F (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
Phone Call (next business day) to assess infusion reactions and any other AEs 
Visit 4 (24 weeks +/- 14 days from baseline) 
• 
Vital signs (blood pressure, heart rate, oral temperature, and weight) 
• 
Neurological exam (must be completed pre-OCR infusion) 
• 
Estimated EDSS (must be completed pre-OCR infusion) 
• 
Concomitant medications and adverse events (AE reporting period continues 30 
days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. Reassess AEs via phone call at 
30 days +7 from time of last dose or study termination.) 
• 
Laboratory assessments:  
o Urine pregnancy test (females of childbearing potential only, if positive, 
confirm by serum pregnancy test) 
o CBC and LFTs  
o Serum immunoglobulins, quantitative 
• 
Administration of premedication and OCR (600mg) 
• 
Infusion reaction assessment 

 
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• 
TSMQ (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
SSS (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
VAS-F (Administered within 2 hours after OCR infusion, may be completed via 
phone) 
• 
MFIS  
• 
MSIS-29  
• 
Phone call (next business day) to assess infusion reactions and any other AEs 
Premature Termination Visit 
If OCR or the premedication is withdrawn and the patient is unwilling to continue in the 
trial for observation, complete a premature termination visit as soon as possible. If the 
patient discontinues from the study for any other reason noted in the patient 
discontinuation criteria, a premature termination visit must be performed as soon as 
possible. Patients who were withdrawn from the study for any reason will not be 
replaced. The following clinical and laboratory evaluations will be performed: 
• 
Vital signs (blood pressure, heart rate, oral temperature, and weight) 
• 
Neurological exam 
• 
Estimated EDSS 
• 
MFIS 
• 
MSIS-29 
• 
Concomitant medications and adverse events (AE reporting period continues 30 
days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. Reassess AEs via phone call at 
30 days +7 from time of last dose or study termination.) 
• 
Laboratory assessments:  
o CBC and LFTs  
o Serum immunoglobulins, quantitative  
• 
Primary reason for discontinuation 
Lost to Follow-up 
If a patient is lost to follow-up, she/he will be withdrawn from the study. Appropriate 
means of contact to consider lost to follow-up are 3 documented phone attempts and 1 
certified letter.  
 
4.6 
DISCONTINUATION OF THERAPY 
1. Diphenhydramine or cetirizine must be discontinued for any of the following reasons: 
• 
Life-threatening or serious hypersensitivity reaction 
• 
Patient discontinues OCR therapy 
• 
Patient election to discontinue therapy (for any reason) 
 
2. OCR therapy must be discontinued for any of the following reasons: 
• 
Life-threatening IRR or serious hypersensitivity reaction 
• 
Active hepatitis B infection 
• 
PML 
• 
Active TB, either new onset or reactivation 
• 
HIV 

 
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• 
Patient becomes pregnant 
• 
Unacceptable toxicity 
• 
Multiple serious infections 
• 
Patient election to discontinue therapy (for any reason) 
 
4.7 
PATIENT DISCONTINUATION 
Patients may be withdrawn from the study for any of the following reasons: 
• 
Patient withdraws consent 
• 
Patient is unwilling or unable to comply with the protocol 
• 
Physician’s discretion 
 
4.8 
STUDY DISCONTINUATION 
Genentech, Inc. and the Principal Investigator have the right to terminate this study at 
any time. Reasons for terminating the study may include the following: 
• 
Patient enrollment is unsatisfactory 
• 
Data recording are inaccurate or incomplete 
• 
Study protocol not followed 
 
4.9 
STATISTICAL METHODS 
4.9.1 Analysis of the Conduct of the Study 
For the primary, non-inferiority endpoint, analysis will be on both the intention-to-treat 
and per-protocol populations (two-sample proportion non-inferiority test). Analysis for 
secondary endpoints will be on the intention-to-treat population. The intention-to-treat 
population is defined as all randomized patients, and the per-protocol population will be 
those who completed the study as per protocol specification. 
 
If the study is terminated before planned enrollment is reached, only descriptive 
analysis will be performed.  
 
4.9.2 Analysis of Treatment Group Comparability 
Baseline characteristics will be reported by arm. Categorical variables will be 
summarized as frequency and proportion and continuous variables by mean and 
standard deviation or median and 25th and 75th percentiles, as appropriate based on 
normality.  
 
4.9.3 Efficacy Analysis 
a. Primary Endpoint 
The proportion of patients with IRRs during or after the first infusion on day 0 will be 
reported for each arm. Cetirizine will be considered non-inferior to diphenhydramine if 
the lower limit of the two-sided, 90% confidence interval for the difference in proportions 
(diphenhydramine-cetirizine) is greater than the non-inferiority margin of -0.305.  
 

 
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b. Secondary Endpoints 
The proportion of patients with IRRs during or after infusion will be compared using 
Fisher’s exact tests at day 14 and week 24, as we expect the proportion of IRRs to be 
small at these time points based on OPERA I and II. Additionally, the proportion of IRRs 
after each infusion will be plotted overall and by severity for the two arms. At day 0, day 
14, and week 24, TSQM scores will be compared between arms using Wilcoxon Rank 
Sum or two-sample t-tests, as appropriate based on normality, and SSS and VAS-F 
scores will be compared using Wilcoxon rank sum tests. MFIS, physical MSIS-29, and 
psychological MSIS-29 will be compared at week 24 using multiple linear regression 
with analysis of covariance (ANCOVA), adjusting for the screening score. 
 
4.9.4 Safety Analysis 
Information on the timing, severity, relationship to premedication, relationship to OCR 
therapy, effect on therapy, and degree of seriousness of adverse events will be 
collected from and summarized for all patients.  
 
4.9.5 Missing Data 
Baseline characteristics and outcomes for patients who followed protocol and 
completed the study, violated protocol, and discontinued the study will be reported 
separately. The reasons for discontinuing or violating protocol will be reported and any 
influence on the trial results will be discussed. Any other irregularities that result in 
missing data will be fully identified and discussed.  
For the primary endpoint using the intention-to-treat population, the missing data 
mechanism will be examined and multiple imputation or best/worst imputation will be 
used, assuming missing at random. For the primary endpoint, assessed at day 0, we 
expect missing data will be limited.  
 
4.9.6 Determination of Sample Size 
Based on the results of the OPERA I and II trials, we assume that 25% of patients in the 
diphenhydramine arm and 25% of patients in the cetirizine arm will experience mild to 
severe IRRs during or after receiving the first infusion on day 0. Assuming that a 30% 
absolute difference (i.e. margin = - 0.30) in the proportion of patients with IRRs between 
premedication groups is the maximum relevant difference when holding that cetirizine is 
not inferior to diphenhydramine, 26 patients per arm are needed to achieve 80% power 
with a one-sided significance level of 0.05. As this is a pilot study, we allow a large 
margin to establish some evidence of non-inferiority. The two-sample proportion test for 
non-inferiority in the R package Trial Size was used for the calculation.  
 
4.10 
DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of standard 
practices and procedures.  
 
5. 
REPORTING OF ADVERSE EVENTS  
At the time of consenting, each patient will be given the names and telephone numbers 
of the study personnel for reporting AE’s. The investigator must conduct thorough 

 
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assessment to determine the severity of the AE and the relationship to the 
premedication and OCR. The investigator must review the laboratory findings for 
significance (all out of range values must be assessed as clinically significant or not 
clinically significant) and sign and date the laboratory report. All clinically significant 
laboratory findings must be reported as adverse events. MS related symptoms are not 
to be reported as AEs unless, in the opinion of the investigator, the symptoms are 
unusually serious and relevant. Any AE of severity moderate or higher, requires follow 
up until resolution or stabilization by the treating investigator beyond the final study 
contact as part of standard care. 
 
All AEs should be recorded in the patient’s AE case report form regardless of severity 
or relationship to the premedication or OCR.  
 
Infusion-Related Reactions (IRRs) 
Adverse events that occur during or within 24 hours after OCR administration and are 
judged to be related to OCR 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 OCR, 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. 
 
Investigators should consider a local IRR for any symptoms affecting the skin and 
localized to only one place. Any other IRR should be considered systemic. 
 
Severity 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  The below table should be used for assessing 
severity for adverse events that are not specifically listed in the NCI CTCAE. 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 

 
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Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. 
Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using 
the toilet, and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a “significant medical event,” it must be reported as a serious adverse event.  
d. 
Grade 4 and 5 events must be reported as serious adverse events.  
 
Relationship to Premedication and OCR 
The relationship or association of the AE to the premedication and OCR will be 
characterized as follows: 
 
Not related 
Any event that does not follow a reasonable temporal sequence from 
administration of drug AND that is likely to have been produced by the 
patient’s clinical state or other modes of therapy administered to the 
patient. 
 
Unlikely 
Any event that does not follow a reasonable temporal sequence from 
administration of drug OR that is likely to have been produced by the 
patient’s clinical state or other modes of therapy administered to the 
patient. 
 
Possibly 
Any reaction that follows a reasonable temporal sequence from 
administration of drug OR that follows a known response pattern to the 
suspected drug AND that could not be reasonably explained by the 
known characteristics of the patient’s clinical state or other modes of 
therapy administered to the patient. 
 
Related 
Any reaction that follows a reasonable temporal sequence from 
administration of drug AND that follows a known response pattern to the 
suspected drug AND that recurs with re-challenge, AND/OR is improved 
by stopping the drug or reducing the dose. 
 

 
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5.1  
ASSESSMENT OF SAFETY 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) that are considered related to the premedication or 
OCR, per protocol. This includes all events of death, and any study specific issue of 
concern. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of the premedication, OCR, or other protocol-imposed 
intervention, whether or not there is a causal relationship with OCR or the 
premedication. 
 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period. 
 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., 
procedures such as OCR infusions). 
 
 
• 
If applicable, AEs that occur after signing consent, prior to assignment of study 
treatment associated with medication washout, no treatment run-in, or other protocol-
mandated intervention. 
 
• 
Preexisting medical conditions (other than the condition being studied) judged by 
the investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period. 
 
Serious Adverse Events 
An AE should be classified as an SAE if any of the following criteria are met: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the 
patient at immediate risk of death. It does not include an AE that, had it occurred 
in a more severe form, might have caused death.). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the premedication and/or OCR. 
• 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
 
 
5.2  
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES 
 

 
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The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, are collected and reported to the FDA (as applicable), 
appropriate IRB(s) (as applicable), and Genentech, Inc., in accordance with CFR 
312.32 (IND Safety Reports). 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained and ends 30 days following the last administration of 
study treatment or study discontinuation/termination, whichever is earlier. After this 
period, investigators should only report SAEs that are attributed to prior study 
treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel 
during questioning, or detected through examination, laboratory test, or other means 
will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to OCR (see above guidance) and premedication, and actions 
taken. 
 
Expected versus unexpected is to be evaluated for SAEs.  
 
Expected adverse events are those adverse events that are listed or characterized in 
the current prescribing information4.  
 
Unexpected adverse events are those not listed in the prescribing information4 or not 
identified. This includes adverse events for which the specificity or severity is not 
consistent with the description in the prescribing information. For example, under this 
definition, hepatic necrosis would be unexpected if the prescribing information only 
referred to elevated hepatic enzymes or hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
 
5.3  
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all patient evaluation time points should be 
adopted. Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new/changed health problems since you were last here?”  
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 

 
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symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.1.2), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the single medical concept. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, report “Unexplained Death”. 
c. 
Preexisting Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only 
if the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”). 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a patient is hospitalized to undergo a medical 
or surgical procedure as a result of an AE, the event responsible for the procedure, not 
the procedure itself, should be reported as the SAE. For example, if a patient is 
hospitalized to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
e. 
Pregnancy 
Female patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if they become pregnant during the study or within 6 
months after the last dose of OCR.  If a pregnancy occurs during this time period for a 
female patient, a report should be completed and submitted to Genentech, Inc. Follow-
up to obtain the outcome of the pregnancy should also occur, whenever possible, 
based upon due diligence taken to obtain the follow-up information. Abortion, whether 
accidental, therapeutic, or spontaneous, should always be classified as serious, and 
expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a 
child born to a female patient exposed to the premedications and/or OCR should be 
reported as an SAE. 
 
Additional information on any ocrelizumab-exposed pregnancy and infant will be 
requested by Genentech/Roche Drug Safety at specific time points (i.e. after having 

 
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received the initial report, at the end of the second trimester, 2 weeks after the expected 
date of delivery, and at 3, 6, and 12 months of the infant’s life). 
 
Pregnancies will not be reported to the premedication manufacture. 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has 
completed or discontinued study participation if attributed to prior OCR exposure. If the 
investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female patient who participated in 
the study, this should be reported as an SAE. 
 
SAEs will not be reported to the premedication manufacture after the end of the 
patient’s study participation.  
 
g.       Case Transmission Verification of Single Case Reports 
The Sponsor agrees to conduct the Case Transmission Verification to ensure that all 
single case reports have been adequately received by Genentech, Inc. via Providence 
Brain and Spine Institute emailing Genentech, Inc. a quarterly line-listing documenting 
single case reports sent by Providence Brain and Spine Institute to Genentech, Inc. in 
the preceding time period.  
 
The periodic line-listing will be exchanged within seven (7) calendar days of the end of 
the agreed time period. Confirmation of receipt should be received within the time 
period mutually agreed upon. 
                    
If discrepancies are identified, the Sponsor and Genentech, Inc. will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall handle the 
matter on a case-by-case basis until satisfactory resolution.  The sponsor shall receive 
reconciliation guidance documents within the ‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been 
received by Genentech, Inc. shall be forwarded by Providence Brain and Spine 
Institute to Genentech, Inc. within five (5) calendar days from request by Genentech, 
Inc. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be 
sent to Genentech, Inc.  
 
Case Transmission Verification will not be completed for the premedication 
manufactures.  
 
h.  
AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result 
of safety monitoring of OCR. AESIs are not being reported for the premedications.  
 
There are no ocrelizumab Events of Special Interest.
 
 
 Adverse events of special interest for this study include the following: 

 
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• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law: 
• 
Treatment-emergent ALT or AST  3  ULN in combination with total 
bilirubin  2  ULN 
• 
Treatment-emergent ALT or AST > 3 x ULN in combination with clinical 
jaundice 
• Data related to a suspected transmission of an infectious agent by the 
study drug (STIAMP), as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible spongiform encephalopathy), pathogenic or 
non-pathogenic, is considered an infectious agent.  A transmission of 
an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a 
medicinal product.  This term applies only when a contamination of the 
study drug is suspected. 
i. 
Exchange of Single Case Reports  
Providence Brain and Spine Institute will be responsible for collecting all protocol-
defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports), 
and Product Complaints (with or without an AE) originating from the Study.  
 
Investigators must report all of the above mentioned single case reports adequately to 
Genentech, Inc., Providence Health & Services, and the premedication manufactures (if 
applicable) within the timelines described below. The completed applicable report form 
should be submitted immediately upon completion to: 
 
Genentech, Inc. Drug Safety:  
Email: usds_aereporting-d@gene.com 
OR 
Fax: (650) 238-6067  
 
Providence Health & Services Regional Research Regulatory Office:  
Email: Regulatory Associate noted on Sponsor Contact List and CC 
tiffany.gervasi-follmar@providence.org (Study Manager) 
 
OR 
Fax: (503) 215-6547 (Regulatory) and (503) 216-1039 (Study Manager) 
 
Cetirizine manufacturer: 
Follow manufacture guidance to report drug safety information.  
 
Diphenhydramine manufacturer:  
Follow manufacture guidance to report drug safety information.  
 
Genentech, Inc. Investigational Medicinal Product Complaints (without an 
AE): 
Communicate details on form verbally to the Product Complaint Hotline, 
document communication in subject source. 

 
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Phone: (800) 334-0290 (M-F, 5am to 5pm PST)  
 
Relevant follow-up information should be submitted to each applicable party as soon as 
it becomes available for each type of report, if applicable [SAEs, AESIs, and Other 
Special Situations (including pregnancy)]. 
 
• 
Serious Adverse Drug Reactions (SADRs) 
Serious AE reports that are related to OCR shall be transmitted to 
Genentech, Inc. Drug Safety within fifteen (15) calendar days of the 
awareness date.  
 
Serious AE reports that are related to the premedication shall be transmitted to 
the manufacture within fifteen (15) calendar days of the awareness date.  
 
All SADR reports should be transmitted to the Providence Health & Services 
Regional Research Office within 24 hours of knowledge of the event.  
 
Use the MedWatch 3500A form for reporting all SASRs. Include the Safety 
Reporting Cover Sheet (Appendix B) for all transmissions. 
 
• 
Other SAEs 
Serious AE reports that are unrelated to OCR shall be transmitted to 
Genentech, Inc. Drug Safety within thirty (30) calendar days of the 
awareness date.  
 
Serious AE reports that are unrelated to the premedication will not be reported 
to the premedication manufacture.  
 
All other SAE reports should be transmitted to the Providence Health & Services 
Regional Research Office within 24 hours of knowledge of the event.  
 
Use the MedWatch 3500A form for reporting all other SAEs. Include the Safety 
Reporting Cover Sheet (Appendix B) for all transmissions. 
 
• 
AESIs 
AESIs shall be transmitted to Genentech, Inc. Drug Safety within fifteen (15) 
calendar days of the awareness date.  
 
All AESI reports should be transmitted to the Providence Health & Services 
Regional Research Office within fifteen (15) calendar days of the awareness 
date.  
 
Use the MedWatch 3500A form for reporting all AESIs. Include the Safety 
Reporting Cover Sheet (Appendix B) for all transmissions. 
 
AESIs will not be reported to the premedication manufactures.  
 
• 
Special Situation Reports 
Pregnancy Reports 
Pregnancy in a female patient shall be transmitted to Genentech, Inc. Drug 
Safety within thirty (30) calendar days of the awareness date.  
 

 
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All pregnancy reports should be transmitted to the Providence Health & Services 
Regional Research Office within thirty (30) calendar days of the awareness 
date.  
 
Use the Clinical Trial Pregnancy Reporting (Appendix C) for reporting all 
pregnancies.  
 
Pregnancies will not be reported to the premedication manufacture. 
 
• 
Other Special Situation Reports 
In addition to SAEs, AESIs, and pregnancy reports, the following Other Special 
Situations Reports should be collected and transmitted to Genentech, Inc. Drug 
Safety, even in the absence of an AE, within thirty (30) calendar days: 
• Data related to OCR usage during pregnancy or breastfeeding 
• Data related to overdose, abuse, misuse, inadvertent/erroneous 
administration, medication error or occupational exposure of OCR, with or 
without association with an AE/SAE unless otherwise specified in the 
protocol 
• Data related to a suspected transmission of an infectious agent via a 
medicinal product (STIAMP) 
All Other Special Situation Reports should be transmitted to the Providence 
Health & Services Regional Research Office within thirty (30) calendar days of 
the awareness date.  
 
Use the MedWatch 3500A form for reporting all Other Special Situation 
Reports. Include the Safety Reporting Cover Sheet (Appendix B) for all 
transmissions. 
 
Other Special Situation Reports are not being transmitted to the premedication 
manufactures.  
 
In addition, reasonable attempts should made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population. 
• 
Product Complaints  
A Product Complaint is defined as any written or oral information received from 
a complainant that alleges deficiencies related to identity, quality, safety, 
strength, purity, reliability, durability, effectiveness, or performance of a product 
after it has been released and distributed to the commercial market or clinical 
trial.  
 
All OCR Product Complaints with an AE should be transmitted to Genentech, 
Inc. Drug Safety within fifteen (15) calendar days of the awareness date.  
 
All OCR Product Complaints without an AE should be transmitted to Genentech, 
Inc. Investigational Medicinal Product Complaints within fifteen (15) calendar 
days of the awareness date.  
 

 
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All OCR Product Complaints with or without an AE should be transmitted to the 
Providence Health & Services Regional Research Office within thirty (15) 
calendar days of the awareness date.  
 
Use the MedWatch 3500A form for reporting all OCR Product Complaints. 
Include the Safety Reporting Cover Sheet (Appendix B) for all transmissions. 
 
Product Complaints are not being transmitted to the premedication 
manufactures.  
 
j. 
Aggregate Reports 
Providence Brain and Spine Institute will forward a copy of the Final Study Report to 
Genentech, Inc. upon completion of the Study.  
 
Providence Brain and Spine Institute will forward a copy of the manuscript to 
Genentech, Inc. before the manuscript is submitted for publication.  
 
5.4  
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic (Section A) and suspect 
medication information (Section C&D), the report should include the following 
information within the Event Description (section B.5) of the MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Investigator’s assessment of the relationship of the adverse event to the 
premedication and OCR 
• 
Expected versus unexpected event 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• 
Summarizing new information and submitting it with a cover letter including patient 
identifiers (i.e. D.O.B. initials, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (the patient identifiers are important so that the new 
information is added to the correct initial report) 
 
Occasionally, Genentech, Inc., Providence Health & Services, or the premedication 
manufactures may contact the reporter for additional information, clarification, or current 
status of the patient for whom an adverse event was reported.  
 
The MedWatch 3500A (Mandatory Reporting) form is available at: 
https://www.fda.gov/media/69876/download 
 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 

 
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Genentech, Inc. as the Marketing Authorization Holder will be responsible for the 
reporting of individual case safety reports from the study to the regulatory authority in 
compliance with applicable regulations. 
Providence Brain and Spine Institute will be responsible for the distribution of safety 
information to its own investigators, where relevant. 
 
Providence Brain and Spine Institute will be responsible for the distribution of safety 
information to the IRB of record: 
 
 
Providence Health & Services Institutional Review Board 
5251 NE Glisan St. 
Portland, OR 97213 
Tel: (503) 215-6512 
Fax: (503) 215-6632 
 
For questions related to safety reporting, please contact the following parties: 
Genentech, Inc. Drug Safety: 
Phone: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
Providence Health & Services:  
Phone: Regulatory Associate noted on Sponsor Contact List or (503) 216-1023 
(Study Manager) 
Email: Regulatory Associate noted on Sponsor Contact List or tiffany.gervasi-
follmar@providence.org (Study Manager) 
 
Cetirizine manufacturer: 
Follow the manufacture’s guidelines for drug safety reporting questions.  
 
Diphenhydramine manufacturer:  
Follow the manufacture’s guidelines for drug safety reporting questions.  
 
5.5  
STUDY CLOSE-OUT 
 
Any literature articles that are a result of the study should be sent to Genentech, 
Inc./Roche. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
Email: Ocrelizumab-iis-d@gene.com 
 
And to Genentech Inc. Drug Safety CTV oversight mail box at:  
 
Email: ctvist_drugsafety@gene.com 
 
5.6  
QUERIES 
 
Queries related to the Study will be answered by Providence Brain and Spine Institute. 
However, responses to all safety queries from regulatory authorities or for publications 
will be discussed and coordinated between the Parties. The Parties agree that 
Genentech Inc./Roche shall have the final say and control over safety queries relating to 
OCR. Providence Brain and Spine Institute agrees that it shall not answer such queries 
from regulatory authorities and other sources relating to OCR independently, but shall 

 
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redirect such queries to Genentech Inc./Roche. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to 
urgent requests for information or review of data are met. The Parties will clearly indicate 
on the request the reason for urgency and the date by which a response is required. 
 
5.7 
SIGNAL MANAGEMENT AND RISK MANAGEMENT 
 
Genentech is responsible for safety signal management (signal detection and/or 
evaluation) for their own Product. However, it is agreed that the Sponsor of the Study 
will be primarily responsible for assessment of the benefit-risk balance of the Study.  
If the sponsor issues a safety communication relevant for Genentech (i.e., a safety 
issue that notably impacts the benefit-risk balance of the Study and/or triggers any 
changes to the Study) this will be sent to Roche within five (5) business days of its 
internal approval.  
As needed, Genentech will reasonably assist the sponsor with signal and risk 
management activities related to the Product within the Study.  
Genentech will also provide the sponsor with any new relevant information that may 
modify or supplement known data regarding the Product (e.g., relevant Dear 
Investigator Letter). 
 
5.8 
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT/ AUDIT 
 
The Parties shall follow their own procedures for adherence to AE reporting timelines.  
Each Party shall monitor and, as applicable, request feedback from the other Party 
regarding AE report timeliness in accordance with its own procedures. The Parties 
agree to provide written responses in a timely manner to inquiries from the other Party 
regarding AE reports received outside the agreed upon Agreement timelines.  
If there is any detection of trends of increasing or persistent non-compliance to 
transmission timelines stipulated in this Agreement, both Parties agree to conduct ad 
hoc or institute a regular joint meeting to address the issue.  
In case of concerns related to non-compliance of processes, other than exchange 
timelines, with this Agreement, the Parties will jointly discuss and collaborate on 
clarifying and resolving the issues causing non-compliance. Every effort will be made by 
the non-compliant Party to solve the non-compliance issues and inform the other Party 
of the corrective and preventative actions taken.  
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, 
an audit under the provisions of this Agreement can be requested by either Party. The 
Parties will then discuss and agree in good faith upon the audit scope, agenda and 
execution of the audit. The requesting Party will bear the cost of the audit. 

 
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6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with Genentech 
Inc. or a Genentech Inc. representative: 
• 
Current curriculum vitae of the Principal Investigator 
• 
Written documentation of IRB approval of protocol and informed consent 
document 
• 
A copy of the IRB-approved informed consent document 
• 
A signed Clinical Research Agreement 
6.2 
INFORMED CONSENT 
The investigator or designated research staff will obtain informed consent from each 
patient after explaining the purpose of the study and the potential risks and benefits 
known, or can be reasonably expected. The case history for each patient shall 
document that informed consent was obtained prior to participation in the study. The 
IRB approved informed consent will be signed by the patient before any screening 
assessments or procedures are performed. A copy of the informed consent document 
must be provided to the patient. If applicable, it will be provided in a certified translation 
of the local language. Signed consent forms must remain in each patient’s study file 
and must be available for verification at any time. 
6.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL 
This protocol, the informed consent document, and relevant supporting information 
must be submitted to the IRB for review and must be approved before the study is 
initiated.  
The Principal Investigator is responsible for keeping the IRB apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate, but in any 
case the IRB must be updated at least once a year. The Principal Investigator must also 
keep the IRB informed of any significant adverse events that meet reporting criteria. 
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected. This generally refers to serious 
adverse events that are not already identified in the prescribing information and that are 
considered possibly or probably related to the molecule or study drug (premedications) 
by the investigator. Some IRBs may have other specific adverse event requirements 
that investigators are expected to adhere. Investigators must immediately forward to 
their IRB any written safety report or update provided by Genentech, Inc. (e.g., safety 
amendments and updates, etc.) that meet the IRB reporting requirements. 
 
6.4 
STUDY MONITORING REQUIREMENTS 
A study specific monitoring plan will be developed according to the Providence Internal 
Monitoring of Study Data SOP to verify the approved protocol is being followed, study 
data are accurately recorded, and regulatory documents are properly maintained.  
 

 
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6.5 
DATA COLLECTION 
A secure, password-protected clinical trials management system will be used to collect 
patient information and study data. The completeness of data and whether the data 
values are in appropriate ranges will be checked periodically according to the 
monitoring plan. Investigators or designated personnel will be asked to complete data 
clarification requests for confirmation of missing data or questionable information.    
 
6.6 
STUDY MEDICATION ACCOUNTABILITY (IF APPLICABLE) 
Not applicable. 
 
6.7 
DISCLOSURE AND PUBLICATION OF DATA 
Patient medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, Genentech Inc., 
and the IRB for each study site, if appropriate. 
The results of this study may be published or presented at scientific meetings. The 
Sponsor will comply with the requirements for the publication of study results.  
Additionally, Section 801 of the Food and Drug Administration Amendments Act 
(FDAAA 801) (PDF) requires Responsible Parties to register and submit summary 
results of clinical trials with ClinicalTrials.gov. The law applies to certain clinical trials of 
drugs (including biological products) and medical devices (refer to FDAAA 801 
Requirements to learn about Responsible Party, Applicable Clinical Trials, and 
deadlines for registration and results submission). 
 
6.8 
RETENTION OF RECORDS 
The records and documents pertaining to the conduct of this study must be retained by 
the principal investigator for a minimum period of ten (10) years after the study is 
terminated or completed at all sites. HIPPA and other appropriate legal guidelines 
regarding privacy and retention of records must also be followed. 

 
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APPENDIX A: STUDY FLOWCHART 
Procedure/Visit 
Visit 1  
Screening 
(day -28 to -1) 
Visit 2  
Baseline  
(day 0) 
Visit 3  
(day 14±2 days) 
Visit 4  
(week 24±14 
days) 
Premature 
Termination Visit 
Informed consent 
X 
 
 
 
 
Eligibility review (INC/EXC) 
X 
XI 
 
 
 
Randomization 
 
XI 
 
 
 
Demographics 
X 
 
 
 
 
VitalsD 
X 
 
 
X 
X 
Disease & medical history 
X 
 
 
 
 
Reason(s) for switching to OCR 
X 
 
 
 
 
Neurological exam  
XE 
 
 
XK 
X 
EDSS (estimated) 
X 
 
 
XK 
X 
CBC & LFTs 
XE 
 
 
X 
X 
Serum immunoglobulins, quantitative 
XE 
 
 
X 
X 
Urine or serum pregnancy test F 
X 
 
 
X 
 
Hepatitis B testing 
XG 
 
 
 
 
Premedication 
 
X 
X 
X 
 
OCR infusionH 
 
X  
X 
X 
 
Infusion reaction assessment 
 
X 
X 
X 
 
Phone call 
 
XB 
XB 
XB, J 
XJ 
TSMQ  
 
XA 
XA 
XA 
 
MFIS & MSIS-29 
X 
 
 
X 
X 
VAS-F 
X 
XA 
XA 
XA 
 
SSS 
X 
XA 
XA 
XA 
 
AEs 
X 
X 
X 
X 
X 
Con meds 
XC 
X 
X 
X 
X 
Primary reason for discontinuation 
 
 
 
 
X 
A: Administered within 2 hours post OCR infusion, may be completed via phone.  
B: On next business day after OCR infusion to assess infusion reactions and any other AEs.  
C: Prior & concomitant medications, including lifetime MS disease modifying therapy history.  
D: To include heart rate, blood pressure, oral temperature, and weight. At screening only, also collect height.  
E: May be historical if completed within 28 days prior to consent.  
F: Females of childbearing potential only. Urine or serum test at screening. Urine test at week 24. If positive urine test, confirm by serum pregnancy test.   
G: May be historical if completed within 6 months prior to consent.  
H: 300mg IV at Visits 2 and 3, 600mg IV at Visit 4.  
I: Can be done day -7 to day 0.  
J: AE reporting period continues 30 days following the last administration of study treatment or study discontinuation/termination, whichever is earlier. 
Reassess AEs via phone call at 30 days +7 from time of last dose or study termination.  
K: Must be completed pre-OCR infusion.  

 
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APPENDIX B: SAFETY REPORTING COVER SHEET 
 
 
 
SAFETY REPORTING COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: (650) 238-6067 
AE / SAE EMAIL: usds_aereporting-d@gene.com 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
______ / ______/ ______ (DD/MMM/YY) 
Follow-up Report Date 
______ / ______/ ______ (DD/MMM/YY) 
 
Patient Initials 
(Enter a dash if patient has no 
middle name) 
____ - ____ - ____ 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 
 
 
 
 
 
 

 
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APPENDIX C: CLINICAL TRIAL PREGNANCY REPORTING FORM 
 
CLINICAL TRIAL PREGNANCY REPORTING FORM 
 
 
Instructions: 
Complete all Essential Elements (fields marked with   and  *). All fields marked with  * are minimal data elements and, if missing, 
the Pregnancy form will be considered invalid. 
• This form is to be used to report pregnancy information and any events associated with the fetus/baby 
• Complete in English, writing clearly in block capitals using black ink, or complete the form electronically and print 
• For dates spell out the first three letters of the month, dd/MMM/yyyy e.g., 07 Apr 2010 
• For multiple births complete one form per infant 
• All sections of this form (other than the AER Number and Company Received Date) must be completed by the 
Investigator/Designee 
• Follow up information can be provided at any time until the outcome of the pregnancy is known 
 
 
♦ Protocol No: 
Site No: 
♦* Screening No: 
♦ Subject No  
(Randomization or Enrolment or CRF No): 
      
      
      
      
For Internal Use 
Only 
AER No: 
      
Company 
Received Date 
      
 
1. 
SERIOUS ADVERSE EVENTS PREVIOUSLY REPORTED FOR CLINICAL TRIAL SUBJECT 
 Yes   
 No 
If yes, Provide: 
♦* Study Drug Name: 
      
Event(s): 
      
 
2. 
PERSONAL DATA for Clinical Trial Subject 
Consider local laws regarding data privacy when completing this section 
♦*Birth Date 
dd/MMM/yyyy 
♦*Sex   
 Male   
 Female 
Height (Select unit): 
      
 cm 
 inch 
Weight (Select unit): 
      
 kg  
  lb 
Race: 
   Caucasian    
 Black      
  Asian      
 Other    Specify:       
If Clinical Trial Subject is male, has the female partner consented to pregnancy follow up? 
 Yes   
 No 
♦*Personal Data for Female Partner:  
(Only complete this section for a pregnancy of a partner of a male subject)  
Consider local laws regarding data privacy when completing this section. 
♦*Birth Date 
dd/MMM/yyyy 
Height (Select unit): 
      
 cm 
 inch 
Weight (Select unit): 
      
 kg  
  lb 
Race: 
   Caucasian    
 Black      
  Asian      
 Other     Specify:       
 
3. 
PREGNANCY INFORMATION  
for Clinical Trial Subject or Female Partner 
Last menstrual period Date (dd/MMM/yyyy): 
      
 estimated* 
*check if the documented date is 
estimated 
Conception Date (dd/MMM/yyyy): 
      
 estimated* 
Estimated Delivery Date (dd/MMM/yyyy): 
      

 
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♦* Pregnancy Outcome  
Mark current status of pregnancy including date where appropriate 
Pregnancy ongoing  
     
Unknown   
 
Lost to follow up   
      
Therapeutic Abortion   
     
Spontaneous/Missed Abortion  
    Ectopic Pregnancy   
 
Live Birth    
 
Elective Birth    
 
Still Birth  
 (complete date of death in section 4) 
Date of Abortion/Live Birth 
(dd/MMM/yyyy):: 
      
4. 
♦* BIRTH OUTCOME 
Check to indicate the current status of the fetus/baby. Where applicable specify the details  
Unknown 
 
(go to section 6) 
Not reported 
 
(go to section 6) 
Normal  
 If yes: 
 Vaginal delivery  
 C-Section  
(go to section 5) 
Abnormal  
 If yes: 
 Vaginal delivery  
 C-Section  
(Birth defects/congenital abnormalities and other events 
experienced by the fetus/baby) 
Specify abnormality: 
      
Death   
 
(e.g., intrauterine death, still birth, post-delivery death) 
Specify cause of Death: 
      
Date of Death 
(dd/MMM/yyyy):: 
      
♦ Event Seriousness 
Was the event (i.e., 
birth outcome) serious? 
 Yes   
 No 
If Yes, check all that apply: 
 Results in death 
 Requires prolongation of existing hospitalization 
 Life-threatening 
 Persistent or significant disability / incapacity 
 Requires in-patient hospitalization 
 Congenital anomaly / birth defect 
OR   only when no 
other criteria applies 
 Medically Significant 
♦ Possible Causes of the Event (i.e., birth outcome)  
 Study Treatment (Includes the Investigational Product, Comparator or Placebo i.e., excipients) 
 Yes   
 No 
Specify study drug(s):  
      
This option indicates that there is a reasonable possibility of a causal relationship between the study drug(s) and the event 
Other suspect causes (select all that apply): 
 None (only applicable if study treatment is related)   
 Disease under study  
Specify: 
      
 Medical history or concurrent illness 
Specify: 
      
 Concomitant medication 
Specify: 
      
 Protocol related procedure 
Specify: 
      
 Other  
(e.g., accident, erroneous administration, 
intercurrent/unrelated illness): 
Specify: 
      
 
5. 
INFANT INFORMATION 
Gestational 
week at birth: 
      
If multiple birth (e.g., twins) 
indicate number: 
      
Sex: 
 Male 
 Female 
 Unknown 
Length: 
      
 cm 
 inch 
Weight 
      
 kg  
  lb 
Head Circumference: 
      
 cm 
 inch 
Apgar Score (0-10) (at 10 minutes) 
      
 
6. 
RELEVANT DRUG INFORMATION OF CLINICAL TRIAL SUBJECT 
Please complete drug section for all relevant medications taken before pregnancy by clinical trial subject including study 

 
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Page 31 of 33  
drug. If study design is blinded enter Study Drug/Comparator in name field 
Reported Drug 
Name 
(generic or trade 
name) 
Indication 
Time of 
Exposure 
(Pre-conception, 1st, 
2nd, 3rd trimester) 
Route 
Dosing 
Regimen 
and 
Frequency 
Start Date 
(dd/MMM/yyyy) 
End Date 
(dd/MMM/yyyy) 
Ongoing 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
7. 
RELEVANT DRUG INFORMATION OF MOTHER (Only complete this section for a pregnancy of a partner of a male 
subject) 
Please complete drug section for all relevant medications taken before and during pregnancy by the female partner if not the 
clinical trial subject 
Reported Drug 
Name 
(generic or trade name) 
Indication 
Time of 
Exposure  
(Pre-conception, 1st, 
2nd, 3rd trimester) 
Route 
Dosing 
Regimen 
and 
Frequency 
Start Date 
(dd/MMM/yyyy) 
End Date 
(dd/MMM/yyyy) Ongoing 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
 
8. 
RELEVANT MEDICAL HISTORY OF MOTHER 
Contraception 
(If known enter the method used at time of 
conception; may choose more than one) 
Number of Previous 
Pregnancies 
(Not including current pregnancy) 
Risk Factors 
(Enter all known relevant risk 
factors) 
 Unknown 
 Infertility (male) 
 Unknown 
 Unknown 
 None 
 Infertility (female) 
 None 
 Alcohol 
 Rhythm 
 Surgical Sterilization 
Pregnancies: 
      
 Diabetes 
 Condom 
 Contraceptive  Medication 
Abortions: 
      
 Infection 
 Diaphragm 
 Withdrawal 
Spontaneous / Missed 
abortions 
      
 Smoking 
 IUD 
 Abstinence 
Stillbirths: 
      
 Drug abuse 
 Spermicide 
 
Deliveries 
      
 None 
 
Child born with defects: 
      
 Other Specify:       
 
9. 
RELEVANT LAB TESTS AND PROCEDURES CARRIED OUT ON MOTHER 
Enter what tests were performed, e.g., ultrasound, amniocentesis; name and results of each one, plus units and normal 
ranges if applicable. If you need more space, continue in section 10 
Lab Test/ Procedure 
Date of Test 
(dd/MMM/yyyy) 
Result 
      
      
      

 
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10. ADDITIONAL DETAILS OF PREGNANCY, FETUS AND/OR BABY 
Enter any information which could not be entered in the other sections of the form. Please identify the section to which the 
information applies. 
      
 
 

 
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REFERENCES 
 
1. 
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus Interferon Beta-
1a in Relapsing Multiple Sclerosis. The New England journal of medicine. 
Jan 19 2017;376(3):221-234. 
2. 
Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus Placebo in 
Primary Progressive Multiple Sclerosis. The New England journal of 
medicine. Jan 19 2017;376(3):209-220. 
3. 
National Cancer Institute. Common Terminology Criteria for Adverse 
Events (CTCAE).  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.ht
m. Accessed 02/13/19, 2019. 
4. 
Genentech Inc. Ocrevus: Highlights of Prescribing Information. 2020; 
https://www.gene.com/download/pdf/ocrevus_prescribing.pdf. Accessed 
03/18/2021. 
5. 
US Food and Drug Administration. Non-Inferiority Clinical Trials to 
Establish Effectiveness: Guidance for Industry. 2016.