| Eligibility |
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-ß-1a (Avonex, Rebif), IFN-ß-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 ß-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
|
