• This research study is testing a drug called ocrelizumab in patients that have relapsing multiple sclerosis (RMS). 
• Ocrelizumab is a type of drug called a monoclonal antibody.  Ocrelizumab has been shown to slow disability progression in multiple sclerosis (MS).  Monoclonal antibodies act like the body’s immune system and attach to certain cells that attack germs and other illnesses in the body.  Ocrelizumab attaches to certain types of white blood cells (B cells) that are thought to play a role in MS.
• The purpose of this study is to investigate the impact of ocrelizumab on RMS in Blacks or African Americans with multiple sclerosis (AAwMS) and Hispanic/Latino Americans with multiple sclerosis (HAwMS).  This study will also investigate the impact of ocrelizumab on certain biomarkers of RMS in Blacks or African American (AA) and Hispanic/Latino American (HA) minority patients with RMS.  A biomarker is a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease.
• Ocrelizumab is already approved for the treatment of MS in several countries including, the United States of America, Australia, Canada, the European Union, and others.  It was approved by the FDA March 28, 2017.  The purpose of this study is to specifically study the efficacy and safety of the ocrelizumab in Blacks or AA and HA patients with RMS, and to gain in-depth understanding of the underlying disease process.
• The purpose of this study is to find out what effects, good or bad, ocrelizumab has on RMS.  This study will also look at the way ocrelizumab may change certain biomarkers related to RMS in the body.
• A CSF sub-study will be optional and conducted at selected sites. 50 patients (~25 Blacks/AAwMS and ~25 HAwMS) will be optionally enrolled in the CSF sub-study. There will be a separate consent form for the CSF sub-study
• About 150 people aged 18-65 years with a diagnosis of RMS will take part in this study, including 75 self-identified Blacks or AAwMS and 75 self-identified HAwMS.
• This non-randomized open label study
• The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 5 years.

TITLE: AN OPEN-LABEL, MULTICENTER STUDY TO ASSESS DISEASE ACTIVITY AND BIOMARKERS OF NEURONAL DAMAGE IN MINORITY PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS RECEIVING TREATMENT WITH OCRELIZUMAB

PROTOCOL NUMBER: ML42071

VERSION NUMBER: 2

EUDRACT NUMBER: 2015-004616-37

IND NUMBER: 100,593

NCT NUMBER: NCT04377555

TEST PRODUCT: Ocrelizumab (RO4964913) (OCREVUS®)

PHASE: IV

INDICATION: Multiple Sclerosis

SPONSOR: Genentech, Inc.

Objectives and Endpoints

Primary Objective

• The primary objective of this study is to assess disease activity during treatment with ocrelizumab over 48 weeks in minorities represented by Black or African Americans with RMS (AAwMS) and Hispanic/Latinos with RMS (HAwMS).

Secondary Objectives

• The secondary objectives of this study are to evaluate other clinical measures of effectiveness, and biomarkers of disease activity and neuronal damage in serum, before and during treatment with ocrelizumab.

Exploratory Objectives

• The exploratory objectives of this study are to evaluate additional immune, ancestral, genomic, and other exploratory markers of disease and their correlations with disease severity and progression, including patient reported outcomes (PROs), before and during treatment with ocrelizumab.

Safety Objectives

The safety objectives of this study are the following:

• Nature, frequency, severity, and timing of adverse events
• Adverse events related to biomarker sample collection (sub-study only)
• Vital signs, physical findings, and clinical laboratory results during and following ocrelizumab administration

Study Design

Description of Study

This is an open-label, multicenter, Phase IV study that will be conducted at centers in the US including Puerto Rico and Ex US sites (i.e., Kenya). Self-identified Blacks or AA and HA patients, aged 18−65 years of age, with a diagnosis of relapsing multiple sclerosis (RMS) in accordance with the 2017 revised McDonald criteria and an EDSS score of 0−5.5 points, at screening may be enrolled. Their treating neurologist must make an independent medical assessment and decision to initiate ocrelizumab treatment per label (USPI) as the most appropriate standard of care treatment for the patient.

Patients will be evaluated at baseline, monitored, and followed for a 1-year period. Patients

may continue in the study for a second year of treatment and follow-up (second year extension).

Patients could be treatment naïve, or may be switching following treatment with up to two disease modifying therapies (DMT) (either interferon, glatiramer acetate, fingolimod, dimethyl fumarate (DMF), diroximel fumarate, teriflunomide, ozinamod, siponimod, and natalizumab).

For patients switching over from fingolimod, DMF, diroximel fumarate, ozinamod, or siponimod, a minimum treatment-free period of 1 month is required before the baseline screening may be carried out. For patients switching from teriflunomide, an accelerated elimination procedure (per the product label) should be performed. Switch from natalizumab will require at least 4 months from last dose and a treatment duration of less than 1 year.

Consistent with the USPI, ocrelizumab will be administered at a dose of 600 mg every

24 weeks. The first dose of ocrelizumab will be administered as two 300 mg IV infusions given

14 days apart. For the subsequent dose, ocrelizumab will be administered as a single 600 mg

IV infusion after 24 weeks. A minimum interval of 22 weeks must be maintained between each

600 mg dose of ocrelizumab.

An alternative shorter infusion of subsequent 600 mg ocrelizumab doses in patients who did not

experience a serious infusion-related reaction (IRR) with any previous ocrelizumab infusion is described

in Section 4.3.2.1.

Treatment may be stopped at any time due to lack of clinical benefit, unacceptable toxicity, withdrawal of consent, patient or physician decision to discontinue treatment, death, or if the sponsor decides to close the trial, whichever occurs first.

Assessments will include clinical, PROs, MRI, and peripheral blood draws, as detailed in the

SOA. MRIs will be conducted at baseline, at Week 24, and at Week 48. MRIs will be read by a central reader. In case of MS relapse or worsening, the patient should have an unscheduled visit and a full assessment, as detailed in the SOA.

All patients may continue for a second year extension. During the optional second year extension, patients will receive: 2 additional doses of ocrelizumab (at Weeks 48 and 72); clinical, PRO, and peripheral blood evaluations at Weeks 72 and 96; and one MRI at Week 96.

All patients will be evaluated for safety throughout the study. In the case of early termination, the patient will be asked to return for an early termination visit.

Patients who do not meet the criteria for participation in this study (screen failure) may qualify for two additional re-screening opportunities (for a total of three screenings per participant) at the investigator's discretion.

Number of Patients

Approximately 150 patients will be enrolled including 75 self-identified AAwMS and 75 selfidentified HAwMS.

Target Population

Inclusion Criteria

Patients must meet the following criteria for study entry:

• Ability to provide written informed consent and be compliant with the study protocol
• The treating neurologist’s independent medical assessment and decision to initiate the patient on ocrelizumab treatment as most appropriate standard of care for the patient
• Age 18-65 years inclusive at the time of signing Informed Consent Form
• Diagnosis of RMS in accordance with the revised 2017 McDonald Criteria (Thompson et al 2018) EDSS 0-5.5 inclusive at enrollment.
• Patients who self-identify as Black or African American or Hispanic/Latino American.
• Treatment-naïve patients, or initiating first or second switch from receiving treatment with any of the following classes of disease-modifying therapies (including FDA approved generic versions):

Class 1

• Interferons: (IFN)-β-1a (Avonex, Rebif), IFN-β-1b(Betaseron/Betaferon), Peg-Interferon Beta-1a (Plegridy) or
• Glatiramer acetate (Copaxone), including generic glatiramer acetate

Class 2

• Fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia)
• Dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity)
• Teriflunomide (Aubagio)

Class 3

• Natalizumab (Tysabri)

For patients switching over from any of the Class 2 agents, at least 1-month of treatment free period between the last dose of the DMT and the initiation of screening Additionally, for patients switching from teriflunomide (Aubagio), an accelerated elimination procedure is required during the treatment free period (as per teriflunomide USPI, see below).

▪ After discontinuation of teriflunomide, elimination can be accelerated by either one of the following procedures:

Administration of cholestyramine 8 g every 8 hours for 11 days. If

cholestyramine 8 g three times a day is not well tolerated,

cholestyramine 4 g three times a day can be used

Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.

If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly

Note: Use of the accelerated elimination procedure may potentially

result in return of disease activity if the patient had been

responding to teriflunomide treatment

 For patients switching over from Natalizumab, at least 4 months from last infusion and less than

1 year of total treatment duration

· Disease duration from the onset of MS symptoms: any duration of the disease except for

those patients with EDSS >5 where disease duration should be <15 years.

· At least one documented clinical attack (for naïve patients) or suboptimal response, or poor

adherence, or intolerance to prior DMT (for switch patients) in the past year, 2 documented clinical relapses within the last 2 years or 1 documented clinical relapse within 12 months of screening (but not within 30 days prior to screening) and/or at least one T1 Gd-enhancing lesion in the past year and/or at least one new or expanding T2 lesion in the past year at the time of enrollment. For active SPMS, documented evidence of disability progression independent of clinical relapse over the past 12 months from screening and at least one documented clinical relapse within the previous 2 years before screening or at least 1 T1 Gd enhancing lesion on MRI at screening if no clinical relapses within the previous 2 years.

· For women of childbearing potential: agreement to remain abstinent (refrain from

heterosexual intercourse) or use acceptable contraceptive methods during the treatment

period and for 6 months after the final dose of ocrelizumab.

A woman is considered to be of childbearing potential if she is postmenarchal, has not

reached a postmenopausal state (12 continuous months of amenorrhea with no

identified cause other than menopause), and has not undergone surgical sterilization

(removal of ovaries and/or uterus). The definition of childbearing potential may be

adapted for alignment with local guidelines or requirements.

– The following are acceptable contraceptive methods (as defined by the guidelines):

progesterone-only hormonal contraception, where inhibition of ovulation is not the

primary mode of action; male or female condom with or without spermicide; and cap,

diaphragm, or sponge with spermicide. More effective contraceptive methods

(e.g., bilateral tubal ligation; male sterilization; copper intrauterine devices) may be

used, but are not required.

· Neurologically stable for at least 30 days prior to randomization and baseline assessments

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from study entry:

· MS Related

– Diagnosis of secondary progressive MS without relapses for at least 1 year (nonactive or inactive SPMS)

– PPMS

· Patients with contraindication to gadolinium based contrast agent for MRI and patients who cannot tolerate MRI procedure

· Infection Related

– Known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis,

HPV)

– History of recurrent aspiration pneumonia requiring antibiotic therapy

– History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy)

– Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with

IV antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to baseline visit

· Cancer Related

– History of cancer, including solid tumors and hematological malignancies (except basal cell, in situ squamous cell carcinomas of the skin, and in situ carcinoma of the cervix or the uterus that have been excised and resolved with documented clean margins on pathology)

· Pregnant or lactating, or intending to become pregnant during the study

– Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study drug.

· Other Medical Conditions

– History of or currently active primary or secondary immunodeficiency

– History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies

– History of alcohol or other drug abuse within 24 weeks prior to enrollment

– History or known presence of systemic autoimmune disorders, potentially causing progressive neurologic disease (e.g., rheumatoid arthritis, lupus, anti-phospholipid antibody syndrome, Sjögren’s syndrome, Behçet’s disease)

– Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study

– Significant, uncontrolled disease, as defined by AMA guidelines or similar, such as cardiovascular (including congestive heart failure – NYHA grade 3 or 4, cardiac arrhythmia), uncontrolled hypertension, pulmonary (including chronic obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), gastrointestinal, or any other significant disease

· Known presence or history of other neurologic disorders, including but not limited to, the

following:

– Progressive multifocal leukoencephalopathy, CNS or spinal cord tumor, potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)

– History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes

[MELAS])

– Neuromyelitis optica spectrum disorders (NMOSD)

– Ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or ischemia

of the spinal cord

– Severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal

cord compression)

– Psychosis not yet controlled by a treatment

· Drug Related

– Systemic corticosteroid therapy within 4 weeks prior to baseline

– Contraindications for, or intolerance to, oral or IV corticosteroids, including IV

methylprednisolone, according to the country label, including hypersensitivity to any of

the treatment drug constituents

– Previous treatment with any other immunomodulatory or immunosuppressive medication not

already listed above without appropriate washout as described in the applicable local label

– If the washout requirements are not described in the applicable local label, then the washout

period must be 5 times the half-life of the medication. The pharmacodynamic effects of the

previous medication must also be considered when determining the required time for washout.

· Prior DMT for MS

– Previous treatment with natalizumab for more than 1-year and within 4 months of baseline

visit.

– Previous treatment with alemtuzumab or cladribine

– Previous treatment with any anti-CD20 therapy

– Previous treatment with cyclophosphamide, mitoxantrone, azathioprine, mycophenolate

mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow

transplantation

– Previous or concurrent treatment with any investigational agent or treatment with any

experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous

insufficiency)

· Vaccinations:

– Receipt of a live vaccine, or attenuated, or inactivated / component vaccine within

6 weeks prior to first administration of ocrelizumab

· Laboratory: Certain laboratory abnormalities or findings at screening, including the

following:

– Positive serum β-hCG

– Positive for hepatitis B (hepatitis B surface antigen [HBsAg] positive or hepatitis B core

antibody [total HBcAb] confirmed by positive viral DNA polymerase chain reaction

[PCR])

– Positive screening test for hepatitis C (positive hepatitis C antibodies)

– AST or ALT ³2.0 ´upper limit of normal

– Platelet count below lower limit of normal (LLN)

– Absolute neutrophil count below LLN

– Lymphocyte count below LLN

– Serum IgG and/or IgM levels below LLN

– Absolute CD4+ and CD8+ T Cell counts below LLN

· Any previous use of IV immunoglobulins or plasmapheresis 3 months prior to baseline visit.

End of Study

The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis whichever occurs later. The end of the study is expected to occur 12 months after the last patient is enrolled for the main study.

Note: Patients may opt into one additional year of treatment and evaluation as part of the second year extension.

In addition, the Sponsor may decide to terminate the study at any time.

Length of Study

The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 5 years.

Investigational Medicinal Products

Test Product (Investigational Drug)

The investigational medicinal product (IMP) for this study is ocrelizumab.

The ocrelizumab dose administered will be 600 mg every 24 weeks. The first dose of

ocrelizumab will be administered as two 300 mg IV infusions given 14 days apart (Weeks 0 and

2). For the subsequent doses, ocrelizumab will be administered as a single 600-mg IV infusion every 24 weeks (Weeks 24, 48, and 72). A minimum interval of 22 weeks must be maintained

between each dose of ocrelizumab. This dosing regimen is consistent with the dosing regimen

used in the ocrelizumab USPI.

Non-Investigational Medicinal Products

In this study, non-investigational medicinal products will include premedication to the

ocrelizumab infusion. The following premedication will be used:

· Mandatory methylprednisolone (or an equivalent)

· Mandatory antihistaminic drug (e.g., diphenhydramine)

· Recommended oral analgesic/antipyretic (e.g., acetaminophen 1 g)

Statistical Methods

Primary Analysis

In this study, the analyses will be mostly descriptive and hypothesis-generating. Unless otherwise specified, statistical tests will be two sided and the statistical significance level will be

5%. Corresponding 95% confidence intervals will be presented as appropriate. No corrections

for multiple testing will be applied to the primary, secondary, exploratory endpoint analyses.

The statistical summaries will be descriptive if not otherwise specified. For continuous variables, the mean, median, standard deviation, 25th and 75th percentiles, minimum and maximum will be provided. For categorical variables, number and percentage in each category will be displayed. Full details of all statistical issues and planned statistical analyses will be specified in a separate Statistical Analysis Plan (SAP), which will be finalized prior to the locking of the study database.

The spearman’s rank-correlation coefficient will be used to evaluate the relationship among the levels of biomarkers or between levels of biomarkers and clinical outcomes.

Determination of Sample Size

Based on CHORDS study, MN30035, it is estimated that the proportion of AAwMS patients who will be free of protocol defined events during 48 weeks is 38%. Assuming the same expected proportion for HAwMS patients, this study is planned to enroll total 150 patients (75 in each patient cohort). This sample size can provide 95% confidence intervals of proportion of patient who will be free of protocol defined events in each patient cohort to be (27.0%, 49.9%) using the exact Clopper-Pearson method.

Interim Analyses

Approximately three interim analyses may be performed during the course of the study,

according to patient enrollment and availability of data of interest. Interim analyses may be

used for internal decision making, hypothesis generation, abstract/publication for major MS

conferences, or other purposes, as applicable. Details on the timing and scope of interim analyses will be described in the SAP.

For the CSF sub-study, interim analyses may be performed when:

· After approximately 50% patients in both the AAwMS and HAwMS cohort have undergone baseline CSF assessments

· After approximately 100% patients in both the AAwMS and HAwMS cohort have undergone baseline CSF assessments

· After approximately 50% of patients in each cohort (AAwMS and HAwMS) complete Week 48