Ocrelizumab

This is a randomized, parallel group, double-blind, active-controlled, clinical pharmacology study to compare Pharmacokinetics, Pharmacodynamics and safety of PB018 versus Ocrevus in patients with Multiple Sclerosis.

Primary outcome: Area under the concentration time curve

The purpose of this study is to assess the imaging biomarkers, patient outcomes, safety, tolerability, and treatment satisfaction of ocrelizumab (OCR) combined with recombinant human hyaluronidase (rHuPH20) administered subcutaneously (SC) in participants with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS) after switching from another anti-cluster of differentiation 20 (aCD20) therapy approved for RMS (ofatumumab SC, ublituximab-xiiy intravenous \[IV\], ocrelizumab IV) or PPMS (ocrelizumab IV).

Primary outcome: Percentage of Participants With no Change or Reduction From Baseline in Number of T1 Gadolinium-enhanced (Gd+) Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) at Week 24

REDEFINE-MS is a research study for people with relapsing multiple sclerosis (MS) who are participating in the RESHAPE-MS trial. The study aims to better understand how remibrutinib affects inflammation in the brain and spinal cord by using PET imaging, MRI scans, blood samples, and cerebrospinal fluid (CSF) samples collected before treatment and again six months later. \[REDEFINE\_p...2026\_clean \| Word\] The main question the study is trying to answer is whether remibrutinib changes immune activity and inflammation in people with MS, and whether these changes can be measured using imaging and biological markers that may help predict future disease progression and treatment response.

Primary outcome: Change in Microglial Activity Measured by [11C]-DPA-713 PET

The main purpose of this study is to evaluate the pharmacokinetics (PK) of ocrelizumab administered subcutaneously (SC) in children and adolescents aged 10 to \<18 years with RRMS. The study consists of a 48-week treatment period, an Optional Ocrelizumab Extension (OOE) period of at least 48 weeks, and Safety Follow-up (SFU) for 104 weeks.

Primary outcome: Peak Concentration (Cmax) of Ocrelizumab After the First SC Injection

This is an open label, Phase 1b, multiple ascending dose, and dose-expansion study of IDP-023 administered in combination with interleukin-2 (IL-2) and ocrelizumab to evaluate the safety, tolerability, and biologic activity on autoreactive immune cells in patients with refractory progressive multiple sclerosis.

Primary outcome: Incidence of AEs and SAEs - (Part 1)

Multiple sclerosis (MS), the main central nervous system autoimmune disorder, is the first cause of non-traumatic disability in young adults and has thus significant individual consequences with elevated public health cost. It commonly starts during the third and fourth decades. Over the last twenty years, several disease-modifying therapies with variable benefit/risk profiles have been introduced leading to dramatic changes in the prognosis of MS. First, several moderately effective therapies , with good safety profile, have allowed to decrease the frequency of relapses along with a possible, albeit limited, effect on medium- and long-term disability. More recently highly effective therapies (HET), with immunosuppressive properties, have dramatically reduced clinical and MRI disease activity and significantly improved patient's prognosis. Anti-CD20 therapies (B-cells depleting therapies, given either intravenous or subcutaneous), one of the main HET, have demonstrated higher efficacy than platform therapies in several phase 3 randomized clinical trials and their use within the very first years of the disease seems to be associated with improved long-term outcomes. Taking all of this into account, the investigators hypothesize that RRMS patients who experience a de-escalation from anti-CD20 therapies to platform therapies after 40 years will not experience disease activity accrual and disability worsening.

Primary outcome: Relapse

Ocrevus Zunovo implementation, feasibility, acceptability, patient satisfaction, treatment persistence, and impact on MS disease outcomes will be analyzed in this mixed methods study. This study will incorporate clinical data and questionnaire results from MS patients who take Ocrevus Zunovo as well as qualitative interviews with MS patients, family members, and other individuals involved in Ocrevus Zunovo treatment. The purpose of this study is to synthesize implementation strategies that improve patient access to high-efficacy MS therapies in real-world settings.

Primary outcome: Patient Satisfaction and Treatment Persistence

The main purpose of this study is to assess whether hyperpolarized carbon imaging in relapsing remitting multiple sclerosis (MS) patients can be used to predict response to anti-CD20 disease modifying therapy. Study procedures will include magnetic resonance imaging (MRI) assessments with a hyperpolarized pyruvate sequence, clinical assessment as well as blood markers of disease progression. This method of imaging utilizes the Warburg effect, where innate immune cells utilize a metabolic shift to glycolysis instead of oxidative phosphorylation. In pre-clinical data, increased hyperpolarized lactate production has been found to be associated with increased microglial/macrophage infiltration in the brain. Although hyperpolarized carbon imaging in humans has been established and used in the field of oncology, this will be one of the first applications of hyperpolarized carbon the study of neuroinflammation in humans. We predict that hyperpolarized carbon imaging may have the potential to monitor and evaluate neuroinflammation in MS, and in particular the innate immune activation state that plays a role in MS progression. This imaging method may provide non-invasive monitoring of disease progression and therapy response for MS patients.

Primary outcome: To determine the percent changes in MS lesions, white matter, and whole brain HP 13C pyruvate metabolism measures between the pre-treatment scan and the scan obtained 1.5-months following treatment initiation.

This real-life study aims to describe IgG levels after switching from ocrelizumab 600 mg IV every 6 to 8 months in Patients with Multiple Sclerosis (PwMS) to ofatumumab 20 mg SC every month and showing a decreasing level of IgG during treatment by ocrelizumab in real life practice in France over 24 months of follow-up. The primary objective is therefore to determine if the downward trend of IgG observed during ocrelizumab treatment is modified after a switch to ofatumumab, in PwMS treated during at least 18 months of ocrelizumab in real life practice, over 24 months of follow-up.

Primary outcome: Slope of serum immunoglobulin G (IgG) levels during ocrelizumab treatment period (minimum 18 months)

The main purpose of this study is to assess the efficacy of RO7268489 in adults with progressive multiple sclerosis (PMS) receiving ocrelizumab. After the end of the double-blind period, an open-label (OL) extension may allow eligible participants to receive open-label RO7268489.

Primary outcome: Time From Randomization to the First Occurrence of Composite Confirmed Disability Progression (cCPD) Confirmed for at Least 12 Weeks (cCDP12)

The proposed study is a pilot study of ublituximab involving people with multiple sclerosis (MS) who are experiencing a "wearing off" phenomenon (return or worsening of MS-related symptoms) while being treated with ocrelizumab, and exploring whether switching to ublituzimab can resolve, improve or delay this phenomenon.

Primary outcome: Proportion of Patients with Wearing-Off

The goal of this observational study is to learn about consequences for the child when the mother is treated with rituximab (or other monoclonal CD-20 antibodies) before or during pregnancy. The main questions it aims to answer are: * Is the infant's immune system effected with lower levels of B-cell markers, higher rates of infections or poor vaccine response? * Are the monoclonal CD20-antibodies fully eliminated in women treated within 6 (12) months prior to conception? Participants will: * At the time of clinical routine blood sampling (at the end of each trimester) the becoming mother will give some additional blood samples for analysis of drug concentration * Within the first year postpartum the child will leave a blood sample to detect antibodies induced by vaccination or infections * Within our routine contacts with the participant (mother) will be asked about infections in both the mother and the child

Primary outcome: Effect on infant immune system

The primary outcome measure is PIRA (progression independent of relapse activity), based primarily on clinical assessment, dichotomized as present or not. For Aim 1, the cohort, patient-derived disability status (PDDS) score, and ambulation score (self-reported) will be the primary endpoints of interest. For Aim 2, the clinical trial, PIRA will be measured pre-GLP-1 start and at study end (week 72). A composite score of disability, similar to the ORATORIO13 trial will be constructed including EDSS score, 25-foot timed walk, 9-hole peg test, and SDMT score.

Primary outcome: PIRA

The main purpose of this study is to assess the bioequivalence of ocrelizumab SC test formulation to the marketed ocrelizumab SC reference formulation in participants with either relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The study consists of 2 phases: a controlled phase, where participants in each group will receive one dose of test or reference formulation and a continuation phase, where all participants in both groups will receive ocrelizumab SC test formulation.

Primary outcome: Area Under the Serum Concentration-time Curve Over the First 12 Weeks Post-dose (AUC0-12W) of Ocrelizumab

The aim of this study is to compare the efficacy, safety profile, pharmacokinetics, pharmacodynamics, and immunogenicity of BCD-281 and the reference drug in subjects with relapsing multiple sclerosis.

Primary outcome: Total number of T1 gadolinium-enhancing (Gd+) lesions up to Week 24.

This study seeks to assess the effects of long-term ocrelizumab therapy on fatigue (extreme tiredness) as well as cognition (thinking and reasoning skills, such as memory, learning and attention), in veterans with multiple sclerosis. The evaluation will involve cognitive assessment scales (to assess memory, attention and learning abilities), clinical evaluations (to assess nerve function and ability to move), and patient-reported outcome measures (in which you will answer questions about your tiredness, sleep and how you function in daily life). These assessments will occur at baseline (visit 1), 6 month (Visit-2) and 12 months (visit 3) to track changes over time.

Primary outcome: Change in global cognitive performance

The main purpose of this study is to evaluate the efficacy of ocrelizumab in participants with relapsing multiple sclerosis (RMS) and to characterize the ocrelizumab pharmacodynamic (PD) profile in Chinese participants with primary progressive multiple sclerosis (PPMS).

Primary outcome: RMS Cohort: Annualized Protocol-defined Relapse Rate

The purpose of this Phase 3b study is to assess the efficacy, safety and tolerability of remibrutinib after switching from ocrelizumab and compared to continuous ocrelizumab treatment, in patients living with relapsing multiple sclerosis (plwRMS).

Primary outcome: Annualized rate of new or enlarging T2 lesions_Core Part

The goal of this clinical trial is to learn if drug CYB704, a proposed biosimilar to Ocrevus, works to treat multiple sclerosis in the same way as the reference product Ocrevus(R). The main questions it aims to answer are: * Is CYB704 distributed in the body in the same way as the reference product (demonstration of pharmacokinetic (PK) similarity)? * Does have CYB704 the same treatment effect and side effects as the reference product? Researchers will compare CYB704 to a Ocrevus (Ocrevus-US and Ocrevus-EU). Participants will: * Take drug CYB704 or Ocrevus (Ocrevus-US and Ocrevus-EU) * Visit the clinic for at least 15 treatment visits, checkups and tests * Will undergo regular magnetic resonance imaging (MRI) examinations

Primary outcome: Area under the concentration time curve

The overall aim of the study is to gain knowledge about consequences for the child´s humoral immunosystem in mothers with multiple sclerosis and due to their immunomodulating treatments. Of special interest is when the mother is treated with monoclonal CD20-antibody like rituximab, ocrelizumab and ofatumumab shortly before (within six months prior to conception) and during pregnancy. Specific aims of the study are to: * Investigate if the humoral immunosystem is fully functioning at birth in children born to mothers with MS * Investigate if the humoral immunosystem at birth in children born to mothers with MS is influenced by the mothers immunomodulating treatment * Investigate if monoclonal CD20-antibodies are fully eliminated in women treated with monoclonal CD20-antibodies within 12 months prior to conception. * Determine if children who have been exposed to monoclonal CD20-antibody in utero have reduced markers of successful B-cell production at birth. * Investigate the response to the Rota virus vaccine, a life-vaccine that is offered 6 weeks after birth to all children born after September 2019, in children to women treated with rituximab before or during pregnancy. * Investigate the response to other vaccines (DTP, Polio, HiB, pneumococcus given at 3 and 5 months after birth) the earliest one months after vaccination. * Investigate the occurrence of infections in the first-year post-partum for the mother and child due to hypogammaglobulinemia, b-cell depletion, and exposure to monoclonal CD20-antibody. * Investigate if oral exposure to rituximab through mother´s breastmilk is resulting in B-cell reduction in the child.

Primary outcome: KREC and CD19 of B-cells in offspring to mothers with MS exposed to monoclonal anti-CD20 antibodies

The study goal is to establish the equivalence of pharmacokinetic (PK) properties, as well as the comparability of safety, immunogenicity (IG) and pharmacodynamics (PD) of the drug product RPH-035 (R-Pharm JSC, Russia) in comparison with the drug product Ocrevus® (F. Hoffmann-La Roche Ltd., Switzerland) when used in patients with multiple sclerosis (MS)

Primary outcome: The area under the concentration-time pharmacokinetic curve (AUC (14-169 days)) of ocrelizumab

B cell-depleting therapies, such as ocrelizumab, are among the most effective medications currently available for the treatment of multiple sclerosis (MS). This suggests that B cells play a very important role in MS. While B cells are rapidly eliminated from the blood of patients treated with medications like ocrelizumab, little is known about how effectively B cells are eliminated from lymph nodes, which are important sites of B cell activation. This study is being conducted to determine to what extent B cells are targeted in lymph nodes following ocrelizumab treatment, which may have important consequences for long-term MS outcomes.

Primary outcome: Lymphocyte analysis

The Main objectives of the study are to demonstrate pharmacokinetic (PK) similarity between ABP 692 and ocrelizumab (US), as well as between ABP 692 and ocrelizumab (EU).

Primary outcome: Area Under the Serum Concentration-time Curve (AUC) From Time 0 to Day15 (AUC0-d15) Following Infusion 1 ofthe Initial Dose of InvestigationalProduct (IP)

The main purpose of this study is to evaluate the safety and tolerability of the ocrelizumab subcutaneous (SC) test formulation in participants with multiple sclerosis (MS). The study consists of two treatment phases: a dose-escalation and dose-continuation phase. Participants will receive single ascending doses of ocrelizumab SC during an initial dose-escalation phase, with the option to continue treatment with the selected dose of ocrelizumab SC in the dose-continuation phase.

Primary outcome: Number of Participants With Adverse Events (AEs)

The study will evaluate the physical impact of MS from participant's perspective, provide continued access to ocrelizumab and assess the safety and tolerability of ocrelizumab. From Protocol Version 6 onwards, treatment within this study will be limited to the currently approved doses of ocrelizumab, 600 milligrams (mg), intravenous (IV) infusion or 920 mg, subcutaneous (SC) injection.

Primary outcome: Change From Baseline to End of Study in the Physical Functioning Score of the Patient-Reported Outcome Measure Information System/Quality of Life in Neurological Disorders - Physical Function Measure for Multiple Sclerosis 15a (PROMISnq PFMS-15a)

The study aims to compare the experiences, including injection-related reactions (IRRs) of patients newly receiving ofatumumab to those starting to receive ocrelizumab SC formulation

Primary outcome: Proportion of patients reported local injection-related reaction post first injection

The aim of this study was to compare the effectiveness and economic burden of ofatumumab (OMB) and ocrelizumab (OCR) treatment in multiple sclerosis (MS) patients in the United States using data from an administrative claims database.

Primary outcome: Annualized Relapse Rate (ARR) in Treatment-Naïve Patients

The main purpose of the study is to evaluate participant satisfaction after administration of ocrelizumab subcutaneously (SC) after 12 months using the therapy administration satisfaction questionnaire subcutaneous (TASQ-SC).

Primary outcome: Number of Participants by Their Level of Satisfaction With Ocrelizumab SC After 12 Months Assessed Using TASQ-SC

A multi-center pilot study to evaluate safety and efficacy of ozanimod as de-escalation therapy in clinically stable MS patients previously treated with anti-CD20 therapy.

Primary outcome: New T2 lesions count

This is a double-blind, randomized, active-controlled, parallel group, Phase 1/3 study to compare efficacy, PK, PD and overall safety of CT-P53 with Ocrevus in patients with Relapsing-remitting Multiple Sclerosis.

Primary outcome: Area under the concentration-time curve in PK group

The nature, intensity, and prevalence of this wearing-off effect remain poorly understood. To our knowledge, there is no consensus in the literature on what symptoms constitute a wearing-off effect, nor is there a single validated scale that measures wearing-off effect. The current study will explore the wearing-off effect associated with OCR and OMB, using a variety of validated scales assessing MS symptoms (i.e., fatigue, mobility, pain, depression, cognition), as well as some global questions on wearing-off. In addition, impact of worsening of MS symptoms on patients' health-related quality of life (HRQoL) and their work productivity will be assessed using relevant MS-specific validated scales

Primary outcome: Proportion of patients who experience wearing-off effect

The goal of this prospective, multi-center, non-blinded, non-randomized, non-intervention clinical trial is to compare immunologic, virologic and epigenetic factors in patients with active multiple sclerosis in standard 2.line treatment with ocrelizumab, rituximab, ofatumumab or natalizumab in Region Midt, Denmark. It aims to answer how the immunologic, virologic and epigenetic response in these patients are compared to healthy controls, and analyze their treatment effect in relation to this response. Participants will get an extra blood sample, when they have their routine blood samples taken.

Primary outcome: Changes in B cell populations

The primary objective of the study is to understand what the added value of natalizumab (Tysabri®) treatment is from a participant's perspective at a given time, based on a one-shot survey. The secondary objectives of the study also aim to characterize the participant's decision-making process to get the treatment; the burden of treatment, characterization of the study population, assessment of the quality of life (QoL), and fatigue dimension.

Primary outcome: Number of Participants who Perceived the Treatment Added Value of Natalizumab Assessed by Likert's Scale

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and the leading cause of severe non-traumatic disability in young people, affecting 110,000 people in France. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, has shown remarkable efficacy in Phase III trials on the inflammatory component of the disease, reducing the annualized relapse rate by 46% and the rate of new T2 lesions by 80% compared with interferon-β 1a. The use of anti-CD20 agents, including ocrelizumab, is associated with an infectious risk that increases with duration of exposure, part of which is due to the development of hypo-gammaglobulinemia in relation to cumulative dose. Several reports suggest a persistent effect of anti-CD20 drugs in MS, with no resumption of inflammatory activity after discontinuation: * During the development of ocrelizumab, at the end of phase 2, after having received 3 or 4 semi-annual cycles of ocrelizumab, a safety period with a therapeutic window of 18 months was planned, before re-administration in the extension study. During this therapeutic window, the annualized relapse rate remained stable, and patients showed no radiological disease activity. * Scandinavian observational studies of "off-label" use of anti-CD20 in MS provide real-life evidence of the absence of recovery of clinical and radiological activity after prolonged interruption of treatment. After 2 years of treatment, and with disease activity under control, spacing administration intervals could reduce the risk of infection without reducing treatment efficacy. This would facilitate the decision to maintain highly active immunotherapy over the long term. In addition, this therapeutic de-escalation, by reducing the frequency of infusions and associated day hospitalizations, would help to reduce treatment management costs. Our aim is to evaluate the non-inferiority of 12-monthly spacing of ocrelizumab infusions versus the conventional 6-monthly regimen, in a population of active MS patients over 18 years of age who have already received 4 or more semi-annual cycles of treatment for 2 years.

Primary outcome: Absence of radiological disease activity at 2 years

The goal of this non-interventional, observational study is to learn if cortical plexus enhancement in patients with primary progressive multiple sclerosis occurs in response to the autoimmune inflammatory process.

Primary outcome: T2 lesion volume

The goal of this non-interventional, observational study is to determine whether cortical pathology can be slowed down by use of ocrelizumab.

Primary outcome: Cortical lesion number accumulation

This study will evaluate the evolution of leptomeningeal lesions via leptomeningeal contrast enhancement (LMCE) presence/disappearance after treatment administration in patients with active progressive multiple sclerosis (MS). In addition, this study will investigate if the presence of leptomeningeal inflammation is associated with alterations of B cell repertoire and whether therapy with ocrelizumab will lead to change of B cell repertoire in LMCE-positive patients.

Primary outcome: The number of LMCE foci at the Month 24 visit compared to the number of LMCE foci at the Baseline visit in the LMCE-positive group

The MRI scan is one of the most important tools for diagnosing multiple sclerosis (MS) and for monitoring disease progression and medication effects. Increasingly strong MRI magnets (higher field strength) enable us to see abnormalities in the brain in greater detail. On the other hand, it poses challenges because these higher field strength MRIs are more sensitive to disturbances, for example due to motion, including physiological motion such as breathing and swallowing. In current practice, field strengths of up to 3 Tesla are common. The aim of this study is to compare scanning at field strengths of 3 Tesla in 10 MS patients at two different moments (baseline and 6 months) with scanning at field strengths that are higher, namely 7 and 9.4 Tesla, in order to identify the advantages and disadvantages. With the further development of this technique, the investigators may be able to make a better diagnosis in the future and detect subtle changes in the course of the disease more quickly in order to optimize treatments.

Primary outcome: Detected white- and grey-matter lesions

Several prospective monocentric cohorts of between 250 and 1000 patients have been set up in order to characterize more precisely the evolution of the disease. Nevertheless, due to an initial recruitment carried out in the years 2000-2010, they do not constitute a faithful representation of the patients followed in clinical routine, in particular in terms of distribution of treatments. Indeed, the introduction, about 10 years ago, of high efficacy treatments (HET) has changed the management of the disease and a significant proportion of patients not controlled by medium efficacy treatments (MET) of the disease are now stable on HET. Nevertheless, if their short-term efficacy has been clearly demonstrated, it remains important to be able to confirm the superiority of HET over MET with the help of prospective cohorts (thus ensuring a retention of patients \> 90% over the long term) analyzing all clinical and imaging biomarkers, imaging and biological data. The measurement of cerebral atrophy and its progression is probably one of the most interesting and most easily used biomarkers that can be used clinically to assess this silent progression in these groups of patients. The progression of brain atrophy is also dependent on many other non-modifiable but also modifiable factors outside of MS that need to be better evaluated and eventually managed. Nevertheless, the existence of various neurological comorbidities (sleep disorders, headaches) on this atrophy has not been specifically analyzed to date. The functional assessments used in routine follow-up are most often performed in a care facility and have many limitations: lack of reproducibility, inter/intra operator variability, poor correlation with functional and quality of life scales, etc. It is therefore extremely important to be able to identify new clinical biomarkers of disease progression of the disease by evaluating the physical capacities of the patients as precisely as possible. This study is a single-center, prospective cohort study of a population of 400 patients with relapsing remitting MS (RRMS). The main objective of this study is to compare, on morphological imaging criteria (T1 volumetry), the progression of brain atrophy (biomarker of disease progression) at 3 years in RRMS patients according to treatment line (MET vs HET).

Primary outcome: Total brain atrophy

The goal of this randomized clinical trial is to compare relapse remitting multiple sclerosis (RRMS) patients treated by ocrelizumab or by rituximab followed for 2 years. The main question it aims to answer is : • to demonstrate the non-inferiority of rituximab versus ocrelizumab in active relapsing MS patients on the % of patients without disease activity at 2 years. During the 2 years, the study includes 6 follow-up visits and the completion of various health and quality of life questionnaires. The protocol visits follow the usual schedule of treatment infusions for the disease (at initiation of treatment, 15 days after, and then every 6 months). Two comparison groups: Researchers will compare rituximab treated patients versus ocrelizumab treated patients to see the % of patients without disease activity at 2 years.

Primary outcome: To demonstrate the non-inferiority of rituximab versus ocrelizumab in active relapsing MS patients on the percentage of patients without disease activity at 2 years.

Multiple Sclerosis is a chronic autoimmune disease associated with inflammatory response harmful for the Central Nervous System. Immunological imbalance is involved with Th1 and Th17 cells in correlation with a disturbance of regulators mechanisms as Treg cells. Despite years of research, the mechanisms involved remain unclear. Serotonin (5-HT) seems to be play an essential role in developing CNS inflammatory diseases and in particular in MS. Indeed, several studies have shown the anti-inflammatory potential of this neurotransmitter and also its vulnerability in inflammatory context. Moreover, a recent study has shown that 5-HT can reduced CD4 T cells proliferation and pro-inflammatory cytokines released in vitro. Interestingly, treatment, treatment with SSRIs (selective serotonin reuptake inhibitor) in an animal model of MS, on Experimental Autoimmune Encephalomyelitis, was shown to improve the clinical score and promote remission of the disease. Among serotonin receptors, the 5-HT7 receptor, can be considered as an interesting target to treat neurological disorders associated with inflammatory context. Present in humans and mice, this receptor is expressed on the surface of a large number of cells, such as T-lymphocytes, macrophages, dendritic cells as well as on cells of CNS such as neurons, astrocytes and microglia. Given the importance of the positive cells for 5-HT7 receptor, in the inflammatory context observed in multiple sclerosis, the investigators propose to study the receptor expression in blood samples from multiple sclerosis patient.

Primary outcome: 5-HT7 receptor expression on circulating cells

This study is a prospective, multi-center, randomized, double blinded, placebo-controlled study of OCR treatment-discontinuation in patients with early RMS. All eligible participants will be initiated on OCR using the standard approved administration schedule of two 300 mg infusions separated by 14 days (i.e., Days 0 and 14) for a total of 600 mg, followed by 600 mg infusions at Month 6,12, 18, and 24. At Month 24, participants will be randomized (2:1) to one of two Arms with randomized treatment beginning at Month 30: Arm 1: placebo infusions every 6 months; or Arm 2: OCR infusions every 6 months. The treatment period will be for a total of 48 months.

Primary outcome: Absence of clinical relapse

To study whether highly effective therapies can halt disease progression in people with multiple sclerosis by modulating the peripheral myeloid landscape.

Primary outcome: Number of fading/disappearing paramagnetic rim lesions (PRLs)

This is a retrospective and prospective, observational mixed-methods (quantitative and qualitative) cohort study of patients who are treated with either Ofatumumab or Ocrelizumab that will be recruited and followed up for one year to collect their profiles across the Gulf countries.

Primary outcome: Expanded Disability Status Scale (EDSS)

This double-blind, double-dummy study will evaluate the safety and efficacy of ocrelizumab compared with fingolimod in children and adolescents with RRMS aged between 10 and \< 18 years over a flexible duration. The double-blind period will last until after the last participant randomized has completed 24 weeks.

Primary outcome: Protocol-defined Annualized Relapse Rate (ARR)

This study will evaluate the pharmacokinetics, pharmacodynamics, safety, immunogenicity, and radiological and clinical effects of subcutaneous (SC) administration of ocrelizumab compared with the intravenous (IV) infusion of ocrelizumab in patients with either relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS).

Primary outcome: Serum Ocrelizumab Area Under the Concentration-Time Curve Over the First 12 Weeks (AUCW1-12) After SC Administration

This is a Phase IIIb, single-arm, multicenter, OLE study. Participants receiving ocrelizumab as an investigational medicinal product (IMP) in a Roche sponsored Parent study who continue to receive ocrelizumab or are in safety follow-up at the time of the closure of their respective Parent study (WA21092, WA21093 or WA25046) are eligible for enrollment in this extension study. Participants who will continue ocrelizumab treatment will receive IMP based on the dosage and administration received at the time of rollover from the Parent study.

Primary outcome: Incidence and severity of adverse events, with severity determined according to the NCI CTCAE v5.0

Rationale: B-cell depleting therapies like ocrelizumab are very effective in the treatment of relapsing remitting multiple sclerosis (RRMS). As B cell repopulation varies extensively between individuals (ranging from 27-175 weeks), using a treatment scheme with a fixed infusion interval may be suboptimal. So far personalized adapted treatment of ocrelizumab in RRMS has not been studied in a prospective setting. Objective: Evaluating the efficacy, safety and cost-effectiveness of ocrelizumab when administered in personalized B cell tailored intervals in RRMS patients. Study design: This is a national multicenter randomized controlled trial with 96 week follow-up. Study population: The study population consists of 296 adult RRMS patients who have received ocrelizumab treatment for a minimum of 12 months (2x 300 mg infusion and 1x 600mg infusion). Intervention: Patients will be randomized into the standard interval group (600 mg infusions every 24 weeks) or the personalized interval group in which the infusions will be extended as long as the serum CD19 B cell count is below 10 CD19 cells/µL, determined every 4 weeks. Main study parameters: To conclude non-inferiority of personalized B cell tailored ocrelizumab there will be two co-primary endpoints: 1. the difference of percentage of confirmed relapse-free patients between the two groups after 96 weeks and 2. the difference of percentage of patients free from new/enlarging T2 lesions on MRI between the two groups after 96 weeks. Secondary study parameters are number of confirmed relapses, annualized relapse rate, number of new T2 lesions and brain atrophy on MRI, disability progression, no evidence of disease activity (NEDA), MS disease biomarkers (serum neurofilament light), quality of life, burden of treatment, immunoglobulin levels and (serious) adverse events including occurrence of infections and COVID-19. Furthermore, various immune cell subsets will be studied in relation to ocrelizumab concentration in a subgroup. Nature and extent of the burden and risks: All patients will be subjected to visits every 24 weeks including clinical scoring and questionnaires. Blood samples and MRI scans will be taken and performed every 48 weeks. Continuous assessment of key stroke dynamics on the patients smartphone and monthly digital cognitive test and walk test will be performed in most patients. As CD19 B cells are kept near complete depletion, the estimated risk of recurrence of disease activity is very low.

Primary outcome: Confirmed relapse-free patients

This study will evaluate the potential placental transfer of ocrelizumab in pregnant women with clinically isolated syndrome (CIS) or multiple sclerosis (MS) \[in line with the locally approved indications\] whose last dose of ocrelizumab was administered any time from 6 months before the last menstrual period (LMP) through to the first trimester (up to gestational week 13) of pregnancy, and the corresponding pharmacodynamic effects (B cell levels) in the infant.

Primary outcome: Percentage of Infants With B Cell Levels (Cluster of Differentiation 19 [CD19+] Cells) Below the Lower Limit of Normal (LLN)

The study duration of 4 years was considered to be sufficient to show a reliable and relevant effect of ocrelizumab on disability progression in the main study (CONSONANCE). However, given the potential long-term use of ocrelizumab in patients with progressive MS, it is critical that additional effectiveness and safety data are accrued in this patient population. In particular, understanding how ocrelizumab can prevent or delay time to major disability milestones such as the need to use an assisting device (Expanded Disability Status Scale \[EDSS\] 6.0) or a wheelchair (EDSS ≥7.0) is of significant relevance, given that progression to such milestones is associated with a significant reduction in patients' quality of life and an increase in cost of treatment (Kobelt et al. 2017). In the ORATORIO trial, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 by 46% (hazard ratio \[HR\]: 0.54, 95% CI 0.31-0.92; p = 0.022) in patients with primary progressive multiple sclerosis (PPMS). To further characterize the potential long-term impact of ocrelizumab treatment on time to 24-week confirmed EDSS ≥7.0, an analysis was used to extrapolate the observed data into the future, estimating the time at which 50% of patients were expected to have reached EDSS ≥7.0. Extrapolated median time to confirmed EDSS ≥7.0 was 12.1 years for placebo, which was similar to the actual median time observed in MSBase (12.4 years), and 19.2 years for ocrelizumab, representing a 7.1-year delay (95% CI: -4.3 to 18.4) \[Butzkueven et al 2021\]. A recent MSBase analysis also showed that in a cohort of patients with secondary progressive MS (SPMS), 17.9% reached a confirmed EDSS score of 7.0 from the diagnosis of SPMS, over a period of approximately 12 years (Lizak et al. 2020). Therefore, following patients who complete CONSONANCE beyond the 4-year study period is justified, to better assess the impact of ocrelizumab on these long-term disability milestones. Another important therapeutic clinical goal in patients with progressive MS is preserving upper limb function. Patients with progressive MS with high EDSS scores, including those who are wheelchair-restricted, experience a devastating reduction in quality of life if they lose any residual function in their arms and/or hands, as this affects the level of independence and significantly limits the ability to perform activities of daily living (Kraft et al. 2014). The Nine-Hole Peg Test (9-HPT) has become one of the most frequently used measures of upper extremity function in MS (Earhart et al. 2011). A 20% worsening in test time is commonly used to define clinically meaningful worsening, as it corresponds to predefined clinically significant changes of established clinician- and patient-reported measures (Feys et al. 2017). Progression rates are lower for 9-HPT compared to EDSS or the Timed 25-Foot Walk Test (25FWT; Goldman et al. 2019). Therefore, following patients who complete CONSONANCE beyond the 4 year study period is justified, to better assess the long-term impact of ocrelizumab on preserving upper limb function. Patients with MS who have completed the CONSONANCE study, and have a favorable benefit risk ratio, as determined by the treating neurologist, can be included in this study if they meet the inclusion and exclusion criteria. 1.1. Study design This is a 4-year, single-arm, open-label, multicenter study for patients who have completed 192 weeks of treatment with ocrelizumab in the CONSONANCE study (NCT03523858), and enrolled under the protocol version 1 of CONSONANCE. It is estimated that the study will enroll approximately 90 patients with progressive MS. The study will consist of the following periods: 1. Screening period: The screening visit should be scheduled up to two weeks before the first infusion of ocrelizumab, and always after the last visit of CONSONANCE at Week 192. This period should not be exceeded. 2. Treatment period: The first visit of the treatment period (first infusion of ocrelizumab) will occur at the baseline visit, which should be 24 weeks (+14 days) after the last infusion of ocrelizumab in CONSONANCE. Ocrelizumab will be administered every 24 weeks up to Week 168 of this study. The last visit in the treatment period will be conducted 24 weeks after the last dose of ocrelizumab (i.e., at Week 192).

Primary outcome: Proportion of patients with upper limb disability progression

Coronavirus (Covid-19) has affected millions of people worldwide. Vaccines to prevent Covid-19 infection have been offered to reduce the risk of infection. While these vaccines have been offered to people with multiple sclerosis (MS), they have not been tested in these individuals. It is uncertain whether people with MS will develop protective antibodies after a Covid-19 vaccination and how long these antibodies will last. The investigators are planning to study the immune response to the full course of Covid-19 vaccine in people with MS (study group) and compare this to people without MS or immune suppression (control group).

Primary outcome: Blood titres of Anti-SARS-CoV-2 S1/S2/N IgG antibody Roche in MS patients compared with healthy volunteers 12 months from date of first dose of Covid-19 vaccine

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).

Primary outcome: Time to Development of First New Radiologic or Clinical Evidence of MS

The primary aim of this project is to determine whether there are differences in access to, efficacy and tolerability of Ocrelizumab in men and women of different racial and ethnic origins and socio-economic backgrounds with RRMS and PPMS in two large academic MS Centers with a high volume of patients on Ocrelizumab. The study is a retrospective analysis of multiple sclerosis patients cared for at Brigham and Women's Hospital and Boston Medical Center who were treated with Ocrelizumab during the 4 year study period.

Primary outcome: Time to treatment initiation

This is a 24-month, prospective, exploratory, observational study to investigate immune phenotypes in patients with MS following treatment with ocrelizumab.

Primary outcome: Change from baseline in T cell capacity achieved by eliminating B cells as measured by flow cytometry.

To assess the efficacy of Mayzent on microglia pathology in patients with active SPMS, as compared to the active control group of MS patients treated with the Ocrevus, as measured by changes in microglial activation in the lesional and non-lesional NAWM and NAGM and in the peri-plaque area of chronic lesions in the brain.

Primary outcome: Change From Baseline in PET Activation at 12 Months

In this study, researchers will learn more about the effects of diroximel fumarate (DRF), also known as VUMERITY®, when taken during pregnancy in people with multiple sclerosis, also known as MS. In MS, the immune system attacks the nerves in the brain and spinal cord. The affected areas are called lesions. The damage makes it difficult for the brain and spinal cord to function and send messages throughout the body. MS can be a progressive disease, which means it may get worse over time. In relapsing forms of MS (RMS), new symptoms may happen, and existing symptoms may get better or worse over time. DRF is an approved drug that is used to treat people with RMS. This is known as an "observational" study, which collects health information about study participants without changing their medical care. The main goal of this study is to collect birth and health information from 3 groups of participants and their babies. These groups are: * Those who took DRF during their pregnancy * Those who took disease-modifying therapies (DMTs) for RMS during their pregnancy, but not DRF. DMTs are drugs that slow how the disease develops over time, not just relieve symptoms. * Those who did not take any drugs for RMS during their pregnancy The main question researchers want to learn about in this study is: • How many participants' babies were born with major congenital malformations (MCMs)? MCMs are problems with how a baby's body forms before birth. In this study, researchers will measure how often the following outcomes happen and compare them between groups: * Loss of pregnancy before 20 weeks * Loss of pregnancy at or after 20 weeks (stillbirth) * Babies born early (before 37 weeks) * Babies who are smaller than expected for the stage of pregnancy * Live births This study will be done as follows: * The study includes data in adult women with multiple sclerosis on pregnancies happening between October 29th, 2019 and July 31st, 2030. Information will start being collected when the participant decides to join the study. * Medical records and clinical notes will be reviewed at the end of the study. * The study will include information from pregnancy through delivery, and for babies up to 1 year after birth. * The study is planned to end by 30th April 2031.

Primary outcome: Number of Major Congenital Malformations (MCMs)

This study will evaluate the pharmacokinetics of ocrelizumab in the breastmilk of lactating women with clinically isolated syndrome (CIS) or multiple sclerosis (MS) \[in line with the locally approved indications\] treated with ocrelizumab, by assessing the concentration of ocrelizumab in mature breastmilk, as well as the corresponding exposure and pharmacodynamic effects (blood B cell levels) in the infants.

Primary outcome: Percentage of Infants With B Cell Levels (Cluster of Differentiation 19 [CD19+] Cells) Below the Lower Limit of Normal (LLN) Measured at Day 30 After the Mother's First Ocrelizumab Postpartum Infusion

The primary goal of this study is to assess the impact of the two major disease modifying therapy (DMT) classes (B cell therapies and S1P modulators) on humoral and cell-mediated immunity to SARS- CoV-2 vaccination compared to non-MS controls. We have chosen to compare DMT-treated MS patients to non-MS controls because the pivotal vaccine studies were conducted in non-MS healthy control groups in which there is significant clinical data and validated assays for antibody responses.

Primary outcome: Primary endpoint

The purpose of this research study is to investigate the effectiveness of MS Disease modifying medications on cognitive fatigue in persons with relapsing remitting multiple sclerosis (RRMS). Cognitive fatigue is the kind of fatigue that occurs after intense mental concentration as after a session of problem solving.

Primary outcome: Brain activation (BOLD signal)

The DanNORMS study is a phase 3, non-inferiority clinical trial examining whether treatment of active multiple sclerosis with rituximab is non-inferior to ocrelizumab regarding efficacy and safety.

Primary outcome: Percentage of patients without new or enlarging T2 white matter lesions on brain MRI scans

ROS-MS is a clinical pharmacological substudy to the OVERLORD-MS study (NCT04578639), designed to examine the possibilities of personalized treatment with rituximab and ocrelizumab in patients with relapsing-remitting multiple sclerosis.

Primary outcome: Serum drug concentration measured using liquid chromatography tandem mass spectrometry (LC-MS/MS)

The purpose of this study is to test if people with relapsing multiple sclerosis (RMS) can improve ambulatory functions after one-year treatment with Ocrevus in comparison with other Disease Modifying Treatments (DMT). Sixty qualified individuals with RMS will be evenly assigned into two groups: Ocrevus and other DMT. Each group will receive the respective treatment following the FDA regulations over the one-year course. Their ambulatory functions will be assessed five times three months apart. In addition, they will receive brain MRI scans three times six months apart. Their ambulatory functions and MRI measurements will be compared between groups over time to fulfill the purposes of this study.

Primary outcome: Dynamic Gait Stability

Using magnetic resonance-PET (MR-PET) imaging with \[11C\]PBR28, a second-generation 18kDa translocator protein (TSPO) radiotracer, we have previously demonstrated abnormally high TSPO expression, indicative of microglia activation, across different brain tissue compartments of multiple sclerosis (MS) patients1. In this study, we propose to study the efficacy of ocrelizumab, a humanized monoclonal antibody that has been shown to decrease neuroinflammation in relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis (MS) patients. We will test these effects by studying a cohort of 24 MS patients (12 RRMS, 12 progressive MS). Participants will be studied before (within 3 months prior to initiating treatment) and after treatment with ocrelizumab (\~12 month follow up), a therapeutic drug that will be part of their standard medical care. We will use \[11C\]PBR28 to help determine changes in neuroinflammation. The purpose of this study is to determine the effects of ocrelizumab treatment on neuroinflammation by analyzing the uptake and distribution of \[11C\]PBR28 in individuals with multiple sclerosis. The specific aims of the current study are: 1. To assess whether treatment with ocrelizumab in subjects with either relapsing-remitting MS or progressive MS is associated with decreased \[11C\]PBR28 binding in the cortex and white matter (lesions and normal appearing white matter), suggesting reduced neuroinflammation. 2. To assess whether changes in neuroinflammation under ocrelizumab treatment, as measured by \[11C\]PBR28 uptake at 12-month follow up relative to baseline, are associated with changes in structural MR metrics of brain tissue damage including white matter lesion load, cortical atrophy, and demyelination in the cortex and in the normal-appearing white matter as measured by magnetization transfer ratio (MTR). 3. To explore whether changes in functional and structural imaging metrics under ocrelizumab are associated with changes in clinical outcome measures.

Primary outcome: 11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR)

This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and PK of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks (Q24W) in participants with PPMS, in comparison to the approved 600 milligrams (mg) dose of ocrelizumab.

Primary outcome: Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12)

This is a randomized, double-blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and PK of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks (Q24W) in participants with RMS, in comparison to the approved 600 milligrams (mg) dose of ocrelizumab.

Primary outcome: Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12)

This is a multicenter non-inferiority study, designed to establish non-inferiority of the study treatment rituximab compared with the comparator ocrelizumab for consecutively included patients (male or female) with active relapsing-remitting multiple sclerosis aged 18-60 years.

Primary outcome: Proportion without new MRI activity

A study to evaluate the efficacy and safety of fenebrutinib on disability progression in adult participants with Primary Progressive Multiple Sclerosis (PPMS). All eligible participants will be randomized 1:1 to either daily oral fenebrutinib (and placebo) or intravenous (IV) ocrelizumab (and placebo) in a blinded fashion through an interactive voice or web-based response system (IxRS). 985 participants were enrolled and recruited globally. Participants who discontinue study medication early or discontinue from the study will not be replaced. The Open-Label Extension (OLE) phase is contingent on a positive benefit-risk result in the Primary Analysis of the study.

Primary outcome: Time to Onset of Composite 12-week Confirmed Disability Progression (cCDP12)

A single arm study evaluating the continued efficacy, safety and tolerability of ofatumumab in patients with relapsing multiple sclerosis who are transitioning from aCD20 mAb therapy

Primary outcome: Percentage of Participants With no Change or a Reduction From Baseline in the Number of Gadolinium Enhancing (GdE) Lesions at Month 12 Using Non-responder Imputation

Newly diagnosed relapsing multiple sclerosis (MS) and high risk clinically isolated syndrome (CIS) patients will be treated with ocrelizumab at disease onset to see if treatment favorably alters CSF markers of chronic inflammation.

Primary outcome: Comparison of intrathecal synthesis of gammaglobulins in treatment-naïve relapsing MS and clinically isolated syndrome participants before and after treatment with ocrelizumab

B-cells have an important role in the pathogenesis of multiple sclerosis (MS). Ocrelizumab, a medication that targets B-cells have been found to be highly effective in stopping the disease activity in relapsing-remitting MS. The efficacy of ocrelizumab might be related to the specific pattern of B-cell tolerance defect in patients with MS and the potential of its normalization with treatment with ocrelizumab. By analyzing the reactivity of recombinant antibodies expressed from single B-cells, the investigators' collaborators have demonstrated that the pattern of B-cell tolerance defect is different in people with MS who only display an impaired removal of developing autoreactive B-cells in the periphery while central B-cell tolerance in the bone marrow is functional in most patients. In contrast, patients with rheumatoid arthritis (RA), type-1 diabetes (T1D) or Sjögren's syndrome (SS) show defective central and peripheral B-cell tolerance checkpoints. As a consequence, while anti-B-cell therapy does not correct defective early B-cell tolerance checkpoints in T1D and only temporarily slows down autoimmune processes before newly generated autoreactive B-cells likely induce patient relapse, the investigators postulate that the efficacy of ocrelizumab in MS may be linked to normal central B-cell tolerance and the production of a normal B-cell and T-cell compartment after ocrelizumab therapy. In an open-label study, 10 patients with relapsing MS will be treated with two courses of ocrelizumab and will be followed clinically and radiologically for at least two and a half years. Assessment of T and B-cell phenotypes and function at baseline and 18-24 months post-B-cell depletion will be the primary outcome of the study.

Primary outcome: Change in Peripheral B-cell Tolerance Checkpoints in People With MS Before and After Ocrelizumab Therapy.

Open-label, prospective, single-arm, multi-center study to assess disease activity and biomarker of neuronal damage in minority patients (self-identified Black or African American (AA) and Hispanic/Latino (HA) patients with relapsing multiple sclerosis (RMS) receiving treatment with Ocrelizumab. The study plans to enroll approximately 150 participants (75 AA and 75 HA) with 50 participants enrolled in a CSF sub-study.

Primary outcome: Proportion of Participants Free of Any Protocol-defined Events During a 48-week Period on Treatment

The purpose of this study is to investigate the immune cell and other factor changes with Ocrevus in Multiple Sclerosis (MS) patients. Researchers will recruit 35 participants for this study. Patients will be enrolled from the Multiple Sclerosis Center at the University of Michigan Health System in Ann Arbor. The goal of the study is to understand the role of regulatory B cell, T cell and other factors in mediating the therapeutic effects of Ocrevus.

Primary outcome: Change in frequency of regulatory B cells

This pilot study will establish a proof of concept for using a systems biology approach to characterize the dynamics of MS disease processes. The primary objective of the study is to identify multi-omic (genetic, proteomic, biochemical and/or microbial) factors that correlate with clinical and subclinical MS disease activity. Identification of such biomarkers could have an immediate clinical utility in identification of MS patients prone to more aggressive disease earlier in their disease course, thus affording the opportunity to better individualize therapy. In addition, insights from better understanding of the complex interplay of various systems biology factors should improve our understanding of MS in general. The study will recruit 14 patients with relapsing MS who are initiating treatment with ocrelizumab, and follow them for 30 months.

Primary outcome: Proportion of relapse free patients

This 6-month randomized controlled pilot study will determine whether there is some evidence that cetirizine is better tolerated than diphenhydramine without an increase in Infusion-Related Reactions (IRRs) in subjects receiving ocrelizumab(OCR) for multiple sclerosis (MS).

Primary outcome: Proportion of Participants With Infusion-related Reaction (IRR) on Day 0

This 2-year study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic (PD) effects of ocrelizumab in children and adolescents ages ≥ 10 to ≤ 18 years with relapsing-remitting multiple sclerosis (RRMS). The data from this study will serve to determine the dosing regimen of ocrelizumab to be further investigated in the subsequent Phase III study in children and adolescents.

Primary outcome: Dose Exploration Period: Area Under the Concentration Versus Time Curve of Ocrelizumab

This is a multi-center prospective rater-masked (blinded) randomized controlled trial of 156 participants, comparing the treatment strategy of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1 to 1 (1:1) ratio. All participants will be followed for 72 months after randomization (Day 0, Visit 0).

Primary outcome: Multiple Sclerosis (MS) Relapse-Free Survival

This study will evaluate the efficacy and safety of ocrelizumab (Ocrevus®) compared with placebo in participants with primary progressive multiple sclerosis (PPMS), including participants later in their disease course. This study will consist of the following phases: screening, double-blind treatment, an optional post-double-progression ocrelizumab (PDP OCR) treatment, follow-up 1 (FU1), an optional open-label extension (OLE), and follow-up 2 (FU2).

Primary outcome: Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12) in FAS

This study will evaluate the pharmacokinetics, safety and tolerability, and immunogenicity of ocrelizumab administered subcutaneously to participants with multiple sclerosis (MS).

Primary outcome: Area Under the Serum Concentration-Time Curve (AUC) of Ocrelizumab following subcutaneous (SC) administration

In this observational study, the investigators aim to recruit 50 patients over an 10-12 month period. The investigators will recruit patients with relapsing-remitting MS (based on 2017 McDonald Criteria) beginning treatment with ocrelizumab and fulfilling study inclusion and exclusion criteria. Participants recruited in this study will be participants in the Johns Hopkins MS Precision Medicine Center of Excellence bio-banking protocol which requires collection of serum and plasma at 6-monthly intervals and hence will have blood collection performed prior to Ocrevus start and then at 6, 12, 18 and 24 months following ocrelizumab initiation as part of the bio-banking protocol. All recruited participants will provide written informed consent. The investigators will collect demographic and clinical characteristics at baseline and update these at follow-up visits. These will include disease duration, co-morbidities, relapses, treatment status and history. The investigators will also collect physiological variables - height and weight at each visit. All recruited patients will return for follow up visits at 6,12, 18 and 24 months post-ocrelizumab initiation. At each visit patients will undergo the following evaluations - EDSS, MSFC, SDMT, fatigue scale (MFIS), quality of life measure (MS-QOL), depression scale (Beck depression inventory, 2nd version) and Block Food Frequency Questionnaire. The investigators will then utilize plasma collected at the various time points to perform global metabolomics analysis. This will yield measures of various metabolites in the circulation, including amino acids and metabolites of the amino acids. The investigators will utilize this data to determine the change in the circulating metabolome produced by treatment with ocrelizumab. Following this the investigators will assess changes in the various clinical measures collected - disability (EDSS, MSFC), cognition (SDMT), mood (BDI-II), fatigue (MFIS) and quality of life (MS-QOL) with Ocrelizumab treatment and correlate these with the changes noted in the metabolome. This approach will allow us to determine whether the metabolic changes are associated with/ could underlie the changes noted in clinical measures.

Primary outcome: Change in Global metabolomic profile

Several disease-modifying therapies (DMTs) have been shown to be effective in reducing the disease activity in patients with relapsing forms of multiple sclerosis (MS) but these treatments, often need to be used continuously for an unknown duration, rendering the long-term use extremely expensive. In addition, chronic administration of DMTs is often associated with undesirable side effects. Among these medications, B-cell depleting monoclonal antibodies might have the properties of an ideal group of medications: i) B-cell depleting antibodies have proven to be extremely potent in reducing or stopping the disease activity in relapsing MS, ii) B-cell depleting antibodies are very safe if used for a short period and use for a short duration may stop the inflammatory disease activity over long term, although current clinical practice and protocols are based on continuing B-cell depletion for an unknown period of time. Indeed, early phase clinical trials of rituximab and ocrelizumab suggested that a short course treatment with B-cell depleting antibodies can have long term effects and disease activity will not return even long after B-cell repopulation in the blood. This long-term effect might be related to the specific pattern of B-cell tolerance defect in patients with MS and the potential of its normalization with B-cell depleting antibodies. By analyzing the reactivity of recombinant antibodies expressed from single B-cells, the investigators' collaborators have demonstrated that the pattern of B-cell tolerance defect is different in people with MS who only display an impaired removal of developing autoreactive B-cells in the periphery while central B-cell tolerance in the bone marrow is functional in most patients. In contrast, patients with rheumatoid arthritis (RA), type-1 diabetes (T1D) or Sjögren's syndrome (SS) show defective central and peripheral B-cell tolerance checkpoints. As a consequence, while anti-B-cell therapy does not correct defective early B-cell tolerance checkpoints in T1D and only temporarily slows down autoimmune processes before newly generated autoreactive B-cells likely induce patient relapse, the investigators postulate that the efficacy of B-cell depleting antibodies in MS may be linked to the B-cell depleting antibodies' normal central B-cell tolerance and the production of a normal B-cell and T-cell compartment after anti-B-cell therapy. The investigators' goal is to provide proof-of-concept that a short duration of treatment with B-cell depleting antibodies can correct B-cell tolerance defects in MS and allow for medication-free prolonged freedom from disease activity, at least in a proportion of subjects with relapsing MS. In an open label study, 10 patients with active relapsing MS will be treated with two courses of ocrelizumab and will be followed clinically and radiologically for at least two and a half years. Time to the return of disease activity (defined as clinical relapses or new or enhancing lesions on the MRI) will be the primary outcome of the study. The investigators will harvest B-cells before starting the treatment and after B-cell repopulation and assess the central and peripheral tolerance defects. The investigators hypothesize that in most participants, the disease activity will not come back, and this prolonged response to anti cluster of differentiation 20 (CD-20) therapy is associated with normalization of B-cell tolerance defect in these patients. Considering the safety of this approach, it can be adopted widely among people with MS. Hence, the proposed B-cell analyses before and after B-cell depletion in people with MS will provide novel insights regarding the mechanisms underlying the beneficial effect of B-cell depleting antibodies and the potential long-term suppression of disease activity. This strategy can therefore improve the approach to treatment of many people with relapsing MS.

Primary outcome: Number of Patients With a Return of Disease Activity After the Third Month Post-first-infusion

The DELIVER-MS study seeks to answer the question: Does early treatment with highly effective DMT improve the prognosis for people with MS? This is an area of significant controversy and no data currently exist to guide treatment choices for patients and clinicians. The study results will help guide overall treatment philosophy and will be applicable not only to a wide range of existing therapies but also to new therapies, meeting a significant unmet need in patient decision making and aiding the decision for medication approval by third parties.

Primary outcome: Brain volume loss, baseline to month 36

CLUE is a prospective study to assess structural and functional changes of the brain, spinal cord, and optic nerve, as well as the inflammatory environment in patients with neuroinflammatory and demyelinating diseases. Participants will receive magnetic resonance (MR) techniques including DIR, DKI, QSM, Rs-fMRI, conventional sequences (T1WI/T2WI/FLAIR), and the MR metabolic SPICE sequence, and will be followed up for one year using 3T MRI. In addition, participants will receive a one-time baseline examination including T1WI, T2WI, FLAIR, and SWI sequences on 7T MRI, as well as PET-MRI.

Primary outcome: The brain structural change over time between the baseline MRI and the follow-up MRIs

This is a multicentre non-interventional study aimed at evaluating the real-world effectiveness and safety of ocrelizumab treatment in participants with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS), who have been prescribed ocrelizumab as per routine practice. This study will use a comprehensive combination of participant reported outcomes and conventional multiple sclerosis (MS) endpoints that measure clinical domains commonly affected by MS (e.g. fatigue, hand function, gait, cognition), and their impact on employment, activities of daily living, quality of life and healthcare resource utilization. The incidence, type, and pattern of serious adverse events (SAEs), and of adverse events (AEs) leading to treatment discontinuation will also be determined.

Primary outcome: Changes in the overall SymptoMScreen score in participants with RMS

Multiple Sclerosis (MS) is an autoimmune disorder of the central nervous system. In MS, inflammation is known to attack areas of the brain, spinal cord, and optic nerves; resulting in disability. Current MRI technology provides an adequate view of the impact of MS on the "white matter" of the brain, which contains many of the connections between neurons. Quantification of lesions in the white matter due to MS are a standard part of clinical trials and clinical care in MS. However, it has long been known that MS not only can affect the white matter, but also the "gray matter," which contains the majority of the nerve cells in the brain and can cause inflammation in the meninges (the protective tissue that surrounds the brain and spinal cord). Autopsy studies have shown that the inflammation seen in the meninges is driven by a B-cells, a subset of white blood cells and that meningeal inflammation may be responsible for damage to the gray matter of the brain. Ocrelizumab is a new treatment for multiple sclerosis. This medication works by targeting and destroying circulating B-cells. It is thought that this may reduce the level of meningeal inflammation in patients with multiple sclerosis. By reducing meningeal inflammation, this medication may result in less damage to the gray matter and subsequently less disability in MS patients. In this study, the investigators will evaluate the use of a method on 7 tesla (7T) MRI to identify inflammation in the meninges as a potential predictor of response to ocrelizumab treatment for multiple sclerosis. Further, the investigators will evaluate if this MRI technique can be used to monitor the long-term effect of the medication on meningeal inflammation and the development of damage to the gray matter of the brain.

Primary outcome: Change in the Number of Enhancing Leptomeningeal Foci on 1 Year Follow up Compared to Baseline in MS Patients Treated With Ocrelizumab.

The investigators are measuring the effectiveness of Ocrevus™ in helping patients with hand or arm weakness, especially if posed by a more advanced MS patient than those included in the clinical trials.

Primary outcome: Stabilization of Scores Using the Test d'Evaluation de la Performance Des Membres Supérieurs Des Personnes Agées (TEMPA) -Translasted in English to Mean "Performance Evaluation Test for the Elderly"

This extension study will evaluate the effectiveness and safety of ocrelizumab in multiple sclerosis (MS) participants who were previously enrolled in a F. Hoffmann-La Roche (Roche) sponsored ocrelizumab phase IIIb/IV trial (i.e. the Parent, P-trial).

Primary outcome: Time to onset of CDP sustained for at least 24 weeks and for at least 48 weeks

This study is a prospective, multicenter, open-label, single-arm effectiveness and safety study in participants with progressive multiple sclerosis (PMS).

Primary outcome: Proportion of Participants with No Evidence of Progression (NEP)

FDA-approved multiple sclerosis (MS) disease-modifying therapies (DMTs) target the relapsing phase of MS but have minimal impact once the progressive phase has begun. It is unclear if, in the relapsing phase, there is an advantage of early aggressive therapy with respect to preventing long-term disability. The infectious risks and other complications associated with higher-efficacy treatments highlight the need to quantify their effectiveness in preventing disability. The TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial is a pragmatic, randomized controlled trial that has two primary aims: 1) to evaluate, jointly and independently among patients deemed at higher risk vs. lower risk for disability accumulation, whether an "early aggressive" therapy approach, versus starting with a traditional, first-line therapy, influences the intermediate-term risk of disability, and 2) to evaluate if, among patients deemed at lower risk for disability who start on first-line MS therapies but experience breakthrough disease, those who switch to a higher-efficacy versus a new first-line therapy have different intermediate-term risk of disability.

Primary outcome: Time to sustained disability progression

This study is a randomized multicentre, multinational, treatment interventional study of RRMS patients with breakthrough inflammatory disease activity in spite of ongoing standard immunomodulatory medication. The study has two treatment arms; arm A: HSCT (hematopoietic stem cell transplantation) and arm B: alemtuzumab, cladribine or ocrelizumab. A pre-planned 3-year follow-up extension period will be performed depending on future funding. The aim of the study is to assess the effectiveness and side effects of a new treatment intervention in RRMS; HSCT, and, thereby, the value of HSCT in clinical practice. Data from recently published patient series indicate that HSCT may have a significantly higher treatment effect than currently registered RRMS immunomodulatory treatments. This study will determine the relative role of HSCT versus alemtuzumab, cladribine or ocrelizumab.

Primary outcome: Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol).

Ocrelizumab is FDA approved for therapy of multiple sclerosis (MS). It depletes B cells and stops MS inflammation.

Primary outcome: Number of Participants With Complete Depletion of B Cells

The primary objective of this study is to assess the efficacy of Ocrelizumab (OCR) in Relapsing Multiple Sclerosis patients who have been previously treated with natalizumab (NTZ) by evaluating relapse rate, progression on MRI and disability progression.

Primary outcome: Relapse Free Survival at Month 12

This is a prospective, multicenter, open-label, single-arm, phase 3b study which evaluates effectiveness and safety of ocrelizumab in participants with early stage RRMS. The study will consist of an open-label treatment period of 192 weeks and follow-up period of at least 48 weeks. The optional shorter infusion substudy will evaluate the safety of a shorter infusion of ocrelizumab in a subgroup of participants with early stage RRMS enrolled in the main MA30143 study. Approximately 700 patients will be enrolled in the substudy, and will receive additional 600 mg ocrelizumab administered in a shorter time frame.

Primary outcome: Time to Onset of Confirmed Disability Progression (CDP) Sustained for at Least 24 Weeks and 48 Weeks as Measured Using Expanded Disability Status Scale (EDSS)

The specific aims of the study are: Primary: To determine the presence and regional distribution of microglial activation, as assessed by Fluorine-18 (18F) labeled "Peripheral Benzodiazepine Receptor 06" (PBR06) -PET, in subjects with active Relapsing Remitting Multiple Sclerosis (RRMS), Secondary Progressive Multiple Sclerosis (SPMS), and Alzheimer's Disease (AD) as compared to healthy controls Secondary: 1. To assess the relationship between microglial activation and clinical variables including disease severity and comorbidities (such as pain, fatigue and/or depression), as well as clinical MRI findings (such as lesions and atrophy) 2. A pilot substudy aims to establish the non-inferiority of \[F-18\]PBR06 as compared with Carbon-11 \[C-11\] labeled "Peripheral Benzodiazepine Receptor 28" (PBR28) PET in patients with RRMS. Hypothesis: The working hypothesis is that there is microglial activation in multiple sclerosis and Alzheimer's disease as compared to healthy controls and that the pattern/ regional distribution of microglial activation is different in Multiple Sclerosis (MS) versus AD and correlates with disease severity and comorbidities. In addition, the investigators hypothesize that \[F-18\]PBR06-PET scans will be at least as good as \[C-11\]PBR28-PET scans, the current gold standard.

Primary outcome: Standardized uptake values (SUV)/Standardized uptake value ratios (SUVR)

This is an open-label, multicenter, biomarker study designed to be hypothesis-generating in order to better understand the mechanism of action of ocrelizumab and B-cell biology in RMS or PPMS. The study will be conducted in two cohorts i.e. RMS cohort (4 arm group) and PPMS cohort (one arm group). RMS cohort: Ocrelizumab will be administered as two intravenous (IV) infusions of 300 milligrams (mg) on Days 1 and 15. Subsequent doses will be given as single 600-mg infusions at Weeks 24 and 48. Participants will be randomized in 1:1:1 ratio to receive lumbar puncture (LP) post-treatment at Week 12, 24, or 52 following the first dose of ocrelizumab in three arm groups. A fourth RMS arm with delayed treatment start (Arm 4 \[control group\]) will not be a part of the randomization and will be recruited separately, wherein treatment with ocrelizumab will be delayed for 12 weeks from pre-treatment baseline. PPMS cohort: Ocrelizumab 600 mg will be administered as two 300-mg IV infusions separated by 14 days at a scheduled interval of every 24 weeks. Participants will receive a LP at the start of the study before dosing with ocrelizumab and second LP at Week 52 following the first dose of ocrelizumab. A long-term extension will be conducted for participants that complete the study and continue to receive ocrelizumab. Treatment with ocrelizumab in the entire study will continue for approximately 4.5 years after the first infusion.

Primary outcome: Change in Levels of NfL (Neurofilament Light) in CSF From Treatment Baseline to Post-Treatment With Ocrelizumab

This multicenter, randomized, open-label study will evaluate the immune response to vaccines (tetanus toxoid \[TT\]-containing adsorbed vaccine, 23-valent pneumococcal polysaccharide vaccine \[23-PPV\] either unboosted or boosted with 13-valent pneumococcal conjugate vaccine \[13-PCV\], influenza vaccine, keyhole limpet hemocyanin \[KLH\]) after administration of a dose of ocrelizumab (OCR) in participants with relapsing multiple sclerosis (RMS).

Primary outcome: Percentage of Participants With Positive Response to TT Vaccine Measured 8 Weeks After TT Vaccine

This randomized, double-blind, double-dummy, parallel-group study will evaluate the efficacy and safety of ocrelizumab in comparison with interferon beta-1a (Rebif) in participants with relapsing multiple sclerosis. Participants will be randomized to receive either ocrelizumab 600 mg or matching placebo intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week; or interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).

Primary outcome: Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks In Double Blind Period

This randomized, double-blind, double-dummy, parallel-group study will evaluate the efficacy and safety of ocrelizumab in comparison with interferon beta-1a (Rebif) in participants with relapsing multiple sclerosis. Participants will be randomized to receive either ocrelizumab 600 mg or matching placebo intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week; or interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks). Planned duration of double-blind treatment is 96 weeks. Participants who complete the 96-week double-blind treatment will have an option to enter a single-group, active-treatment, open-label extension period, providing they fulfill the eligibility criteria.

Primary outcome: Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks

This randomized, parallel group, double-blind, placebo controlled study will evaluate the efficacy and safety of ocrelizumab in participants with primary progressive multiple sclerosis. Eligible participants will be randomized 2 : 1 to receive either ocrelizumab or placebo.

Primary outcome: Time to Onset of Clinical Disability Progression (CDP) Sustained for at Least 12 Weeks During the Double-Blind Treatment Period

This is a phase II, multicenter, randomized, parallel-group, partially blinded, placebo and Avonex (interferon beta-1a) controlled dose finding study to evaluate the efficacy as measured by brain MRI lesions, and safety of 2 dose regimens of ocrelizumab in participants with Relapsing Remitting Multiple Sclerosis (RRMS).

Primary outcome: Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic Resonance Imaging (MRI) Scans of the Brain

The goal of our research is to find out how safe and effective the drugs used to treat multiple sclerosis (MS) are when used in the everyday, real world. To achieve these study goals, we have two main study Themes. The first Theme focuses on how effective the MS drugs are. We will examine whether the MS drugs can extend life expectancy or prolong a person's ability to stay mobile and walk. We will also look at whether the MS drugs have a beneficial effect on reducing the number of times a person with MS is admitted to a hospital or visits a physician. The second Theme focuses on side effects, including whether the MS drugs are associated with harmful effects, such as cancer, stroke or depression. We will be able to compare the different MS drugs to each other. Also, we will see if men and women or people of different ages and with other illnesses (such as having both MS and diabetes) respond to the MS drugs differently. Our findings will help people with MS and their physicians when trying to make decisions as to which MS drug might be best for them.

Primary outcome: Study 1: All-cause hospitalizations