AN OPEN-LABEL, SINGLE-ARM 4-YEAR STUDY TO EVALUATE EFFECTIVENESS AND SAFETY OF OCRELIZUMAB TREATMENT IN PATIENTS WITH PROGRESSIVE MULTIPLE SCLEROSIS

- Able to comply with the study protocol, in the investigator's judgement
- Age 18-65 years, inclusive
- Have a definite diagnosis of PMS (as per the revised McDonald 2010 criteria
for PPMS or Lublin et al. 2014 criteria for PMS)
- Expanded Disability Status Scale (EDSS) <=6.5 at screening
- Have documented evidence of disability progression independent of relapse
activity at any point over the 2 years prior to the screening visit. In case
relapse(s) have occurred in the last 2 years, disability progression will have
to be considered as independent of relapse activity as per treating physician*s
judgment
- Fulfill at least one of the 21 criteria assessing the evidence of disability
progression independent of relapse activity in the last 2 years using the
pre-baseline disability progression rating system checklist
- Have experience of having used a smartphone and connecting a smartphone to
Wi-Fi network providers
-

- Relapsing-remitting multiple sclerosis (RRMS) at screening.
- Inability to complete an MRI
- Gadolinium (Gd) intolerance
- Known presence of other neurological disorders, including but not limited to,
the following:
History of ischemic or hemorrhagic disorders of the brain or the spinal cord.
History or known presence of Central nervous system (CNS) or spinal cord tumor.
History or known presence of potential metabolic causes of myelopathy.
History or known presence of infectious causes of myelopathy.
History of genetically inherited progressive CNS degenerative disorder.
Neuromyelitis optica.
History or known presence of systemic autoimmune disorders potentially causing
progressive neurologic disease.
History of severe, clinically significant brain or spinal cord trauma.
Exclusions Related to General Health
- Pregnancy
- Lactation
- Any concomitant disease that may require chronic treatment with systemic
corticosteroids or immunosuppressant*s during the course of the study
- History of or currently active primary or secondary immunodeficiency.
- Lack of peripheral venous access.
- Significant or uncontrolled somatic disease or any other significant disease
that may preclude patient from participating in the study.
- Active infections must be treated and resolved prior to the first infusion of
ocrelizumab
- Patients in a severely immunocompromised state until the condition resolves
- Patients with known active malignancies or being actively monitored for
recurrence of malignancy
- Patients who have or have had confirmed progressive multifocal
leukoencephalopathy (PML)

Exclusions Related to Laboratory Findings
Any abnormal screening laboratory value that is clinically relevant should be
retested only once in order to rule out any progressive or uncontrolled
underlying condition. The last value before randomisation must meet study
criteria.
• Positive screening tests for hepatitis B: All patients must be tested for
hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (total
HBcAb).
o If HBsAg is positive, the patient is not eligible
o If HBsAg is negative and HBcAb is positive, hepatitis B virus (HBV) DNA must
be measured by polymerase chain reaction (PCR)
* If HBV DNA is positive, the patient is not eligible
* If HBV DNA is negative, the patient is eligible and HBV DNA (by PCR) must be
repeated every 24 weeks.
o If HBsAg and HBcAb are both negative, the patient is eligible.
Note: Hepatitis B virus serologies measured using biotin-based immunoassays
should be interpreted with caution in MS patients using high-dose biotin, as
false positives have been reported in these patients. A biotin-free immunoassay
is recommended in these patients; if unavailable, an appropriate correction
technique should be applied.
• CD4 count <250 cells/µL
• Absolute neutrophil count (ANC) <1.0 × 103/µL
• Aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase
(SGOT) or alanine aminotransferase (ALT) /serum glutamic pyruvic transaminase
(SGPT)>=3.0 × the upper limit of normal (ULN)
Please note: based on local Ethics Committees or National Competent Authority
requirements, additional diagnostic testing may be required for selected
patients or selected centres to exclude tuberculosis, Lyme disease, HTLV-1
associated myelopathy (HAM), acquire immunodeficiency syndrome (AIDS),
hepatitis C virus infection (HCV), SARS-CoV-2, hereditary disorders, connective
tissue disorders, or sarcoidosis. Other specific diagnostic tests may be
requested when deemed necessary by the Investigator.

Exclusions Related to Medications
Absolute exclusions:
- Previous treatment with Ocrelizumab
• Hypersensitivity to ocrelizumab or to any of its excipients.
• Previous treatment with B-cell targeted therapies (i.e. atacicept, tabalumab,
belimumab, ofatumumab, or obinutizumab). Note: previous treatment with
rituximab is allowed as long as the last dose was administered more than 6
months before the ocrelizumab infusion AND if discontinuation was due to
adverse events or immunogenicity AND if B-cell levels are above the lower limit
of normal (LLN) prior to screening.
• Any previous treatment with alemtuzumab (Campath/Mabcampath/Lemtrada), total
body irradiation, or bone marrow transplantation.
• Previous treatment with natalizumab where PML has not been excluded according
to specific algorithm in the protocol.
• Contraindications to or intolerance of oral or intravenous (IV)
corticosteroids, including methylprednisolone administered IV, according to the
country label, including:
a) Psychosis not yet controlled by a treatment.
b) Hypersensitivity to any of the constituents.
Relative exclusions:
2 weeks prior to screening: previous treatment with siponimod.
4 to 8 weeks prior to screening:
• Systemic corticosteroid therapy within 4 weeks prior to screening
• All vaccines should be given at least 6 weeks before the first infusion of
ocrelizumab unless the local regulations allow for a shorter interval .
Live/live attenuated vaccines should be avoided during treatment and safety
follow-up period until B cells are peripherally repleted.
• Previous treatment with daclizumab in the last 8 weeks.
• Treatment with fampridine/dalfampridine (Fampyra®)/Ampyra®) or other
symptomatic MS treatment unless on stable dose for >=30 days prior to screening.
Wherever possible, patients should remain on stable doses throughout the
treatment period.
• Previous treatment with fingolimod or ozanimod in the last 8 weeks prior to
screening (a different wash-out period when
switching from fingolimod or ozanimod to ocrelizumab can be used).
12 weeks prior to screening:
• Previous treatment with natalizumab in the last 12 weeks prior to screening.
(A different wash-out period when switching from natalizumab to ocrelizumab can
be used. An assessment should be made to balance risk of return of MS disease
activity with possible additive immunosuppressive effects of each drug.)
• Previous treatment with azathioprine, cyclophosphamide, mycophenolate mofetil
or methotrexate in the last 12 weeks prior to screening.
• Treatment with teriflunomide in the last 12 weeks. This washout period can be
shortened if an accelerated elimination procedure
is implemented before screening visit.
24 weeks prior to screening:
• Treatment with any investigational agent within 24 weeks of screening (Visit
1) or five half-lives of the investigational drug (whichever is longer) or
treatment with any experimental procedures for MS (e.g., treatment for chronic
cerebrospinal venous
insufficiency) within 24 weeks of screening (Visit 1).
96 weeks prior to screening:
• Previous treatment with mitoxantrone, cyclosporine or cladribine in the last
96 weeks.

Exclusions for Subjects participating in the OCT assessments
• Patients with clinically relevant ocular pathologies, potentially interfering
with clinical and instrumental evaluations.

Exclusions for Subjects participating in the measurement of Motor Evoked
Potentials (MEP)
• History of seizures
• Prior craniotomy or skull fracture
• Movable metallic implant in the head (patients with jaw- or bone-fixed metal
implants can be included)
• Implanted stimulators (e.g. cochlear implant or cardiac pacemaker, deep brain
stimulator)
• Known history of high intracranial pressure.