Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease.

A Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy of Ocrelizumab in Patients With Radiologically Isolated Syndrome

This is a multicenter, randomized, double-blind, placebo-controlled, Phase 4 study in which eligible patients with RADIOLOGICALLY ISOLATED SYNDROME (RIS) (as defined by meeting 2017 McDonald criteria for DIS) will be randomized 1:1 to receive ocrelizumab treatment or placebo (standard of care).

This study is designed to investigate the treatment effect of ocrelizumab compared with placebo on clinical and radiological outcomes in patients with RIS (i.e., asymptomatic CNS lesions fulfilling the 2017 McDonald criteria for DIS), as well as neuroimaging, serologic, immunologic and other exploratory biomarkers of MS disease biology in order to improve the understanding of B cell biology in early disease pathophysiology, characterize the emergence of CNS autoimmunity, and the mechanism of action of ocrelizumab in this population.

Inclusion Criteria

Pre-Screening of First-Degree Family Members

Family members must meet the following inclusion criteria for pre-screening:

Signed informed consent form First-degree family member of an individual with clinically definite MS Age 18-55 years No prior exposure to DMT or long-term immunomodulatory medications Willingness to participate in full study protocol, if RIS is discovered

Screening

Patients must meet the following inclusion criteria for screening:

Signed informed consent form

One of the following:

First degree family member of an individual with clinically definite MS who was identified to have CNS lesions meeting McDonald 2017 criteria for DIS during a pre-screening MRI.

Established RIS diagnosis (i.e. CNS lesions consistent with MS, meeting McDonald 2017 criteria for DIS), either diagnosed within the last 5 years or known to have had accumulation of CNS lesions within the last 5 years.

Age 18-55 years No prior exposure to DMT or long-term immunomodulatory medications Willingness to participate in full study protocol

Randomization

Patients must meet the following criteria for study entry and randomization:

Signed Informed Consent Form Aged 18-55 years at time of signing Informed Consent Form Ability to provide written informed consent and be compliant with the study protocol CNS lesions consistent with MS, meeting McDonald 2017 criteria for DIS RIS diagnosis established within last 5 years OR with known accumulation of CNS lesions within last 5 years No alternative diagnosis established during serologic workup for MS mimics Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use one method of contraception with a failure rate of <1% per year or a barrier method supplemented with spermicide. Contraception must continue for the duration of study treatment and for at least 24 weeks after the last dose of study treatment.

• A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause of other than menopause), and has not undergone surgical sterilization (removal of the ovaries and/or uterus)
• Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, established hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception.
• Examples of barrier methods supplemented with the use of spermicide include male or female condom, cap, diaphragm, or sponge.

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from pre-screening, screening and randomization:

Intolerance to gadolinium-based contrast agent Contraindications to MRI 5 years of radiologic stability since first known abnormal MRI, for patients previously diagnosed with RIS History of remitting clinical symptoms consistent with MS lasting 24 hours prior to CNS imaging revealing anomalies suggestive of MS CNS MRI anomalies are better accounted for by another disease process, for patients previously diagnosed with RIS Infection Related Known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis) 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 treatment phase and 6 months after the last infusion of study drug Women of childbearing potential must have a negative serum or urine 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 associated with systemic symptoms (e.g., 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, high dose corticosteroid therapy within 4 weeks prior to screening 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 Prior exposure to immunomodulatory medications and/or DMT Prior treatment with any disease modifying therapy for MS including but not limited to: interferon (IFN-β-1a (Avonex, Rebif), IFN-β-1b (Betaseron/Betaferon), glatiramer acetate, dimethyl fumarate (DMF; Tecfidera), diroximel fumarate (Vumerity) fingolimod (Gilenya) or siponimod (Mayzent), ozanimod (Zeposia®) natalizumab (Tysabri), alemtuzimab (Lemtrada), cladribine (Mavenclad), rituximab (Rituxan), and other anti-CD20 agents 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 or live-attenuated vaccine or an inactivated/non-live vaccine within 6 weeks prior to enrollment

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]) AST or ALT less than or equal to 3.0, upper limit of normal Total white blood cell count, including differential counts, below lower limit of normal Absolute lymphocyte count below lower level of normal Absolute neutrophil count below lower limit of normal Platelet count below lower limit of normal