Effect of Ocrelizumab on Brain Innate Immune Microglial Cells Activation in MS Using PET-MRI With 18F-DPA714

1. Inability to complete an MRI (contraindications for MRI include but are not restricted to weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, contraindication to gadoteric acid etc.).

2. Impossibility to complete a PET scan: pregnancy, nuclear medicine irradiation in the year preceding baseline visit for clinical research and one year after the end of their participation in the study, lactation.

3. Known presence of other neurological disorders, including but not limited to, the following:

1. History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or ischemia of the spinal cord

2. History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma)

3. History or known presence of potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)

4. History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-lymphotropic virus 1 (HTLV-1), herpes zoster myelopathy)

5. History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis; MELAS \[mitochondrial myopathy, encephalopathy, lactic acidosis, stroke\] syndrome)

6. Neuromyelitis optica

7. History or known presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sjogren's syndrome, Behçet's disease)

8. History or known presence of sarcoidosis

9. History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression) - General Health:

1\. Pregnancy or lactation 2. Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressant drugs during the course of the study 3. History or currently active primary or secondary immunodeficiency 4. Lack of peripheral venous access 5. Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal or any other significant disease that may preclude patient from participating in the study 6. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies 7. Congestive heart failure (New York Heart Association \[NYHA\] III or IV functional severity) 8. Known active bacterial, viral, fungal, mycobacterial infection or other infection \[including tuberculosis \[TB\] or atypical mycobacterial disease (but excluding fungal infection of nail beds)\] or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to baseline visit; Note: Active infections should be treated and effectively controlled before possible inclusion in the study 9. History or known presence of recurrent or chronic infection 10. History of malignancy, including solid tumors and hematological malignancies, except basal cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix of the uterus that have been previously completely excised with documented, clear margins 11. History of alcohol or drug abuse within 24 weeks prior to baseline 12. History or laboratory evidence of coagulation disorders 13. History of major opportunistic infections (i.e. cryptococcosis, Pneumocystis pneumonia, progressive multifocal leukoencephalopathy \[PML\]) 14. History of recurrent aspiration pneumonia requiring antibiotic therapy 15. Hypersensitivity to the active substance or to any of the excipients (Sodium Acetate Trihydrate, Glacial Acetic Acid, Trehalose Dihydrate, Polysorbate 20, Water for Injection)

Laboratory Findings:

1. TSPO polymorphism indicating a low affinity profile.

2. Positive serum β human chorionic gonadotropin (hCG) measured at screening and before each PET-Scan procedure

3. Positive screening tests for hepatitis B (hepatitis B surface antigen \[HBsAg\] positive, or positive hepatitis B core antibody \[total HBcAb\] confirmed by a positive viral DNA polymerase chain reaction \[PCR\]) or hepatitis C (HepCAb)

4. Lymphocyte count below lower limit of normal (LLN)

5. CD4 count \<300/μL.

6. Absolute neutrophil count \<1.0 × 103/µL

Medications:

1. Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the baseline visit. In rare cases when patient requires vaccination with a live vaccine, the screening period may be extended but cannot exceed 8 weeks

2. Treatment with any investigational agent within 24 weeks of screening 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)

3. Treatment with Flumitrazepam, triazolam, diazepam

Treatment of Multiple Sclerosis:

1. Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab)

2. Systemic corticosteroid therapy within 4 weeks prior to screeningii

3. Treatment with IV immunoglobulin (Ig) within 12 weeks prior to baseline

4. Any previous treatment with alemtuzumab, daclizumab, anti-CD4, total body irradiation or bone marrow transplantation

5. Any previous treatment with biotin in the last month prior to screening

6. Previous treatment with mitoxantrone, cyclosporine or cladribine in the last 96 weeks

7. Previous treatment with azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate, or laquinimod in the last 24 weeks

8. Previous treatment with teriflunomide, unless an accelerated elimination procedure is implemented before screening visit. Accelerated elimination procedure after stopping treatment with teriflunomide:

1. cholestyramine 8g is administered 3 times daily for a period of 11 days, or cholestyramine 4g three times a day can be used, if cholestyramine 8g three times a day is not well tolerated,

2. alternatively, 50g of activated powdered charcoal is administered every 12 hours for a period of 11 days

9. Previous treatment with natalizumab in the last 12 weeks

10. Previous treatment with fingolimod or dimethyl fumarate if at baseline the lymphocyte count is below lower limit of normality (LLN). Apart from the lymphocytes count within normal ranges, 12 weeks of a washout period of fingolimod or dimethylfumarate would be required before the start of ocrelizumab administration

11. History of recurrent aspiration pneumonia requiring antibiotic therapy

12. Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stable dose for ≥ 30 days prior to screening. Wherever possible, patients should remain on stable doses throughout the 96-week treatment period

13. Treatment with β interferons, glatiramer acetate, plasmapheresis, or other immunomodulatory therapies within 4 weeks prior to baselinei

Healthy volunteers:

1. Inability to complete an MRI (contraindications for MRI include but are not restricted to weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, contraindication to acid gadoteric etc.)

2. Impossibility to complete a PET scan: pregnancy, nuclear medicine irradiation in the year preceding baseline visit for clinical research

3. Known presence of any neurological disorders

4. Pregnancy or lactation

5. Lack of peripheral venous access

6. Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal infectious, neoplasic or any other significant disease that may preclude patient from participating in the study

7. History of alcohol or drug abuse within 24 weeks prior to baseline

8. TSPO polymorphism indicating a low affinity profile.

9. Treatment with Flumitrazepam, triazolam, diazepam

What this study is about