A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis

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).

The screening phase will last up to 24 weeks. In the double-blind treatment phase, participants will undergo at least 144 weeks of study treatment. Study drug (ocrelizumab or placebo) will be administered every 24 weeks. All participants who discontinue prematurely from the double-blind treatment phase will enter the FU1 phase, including participants receiving other immunomodulatory or immunosuppressive treatment(s) for MS, commercial ocrelizumab, or no treatment. The FU1 phase will run in parallel with the double-blind treatment phase for 144 weeks or until the primary analysis is performed, whichever occurs first. An optional OLE phase is planned for eligible participants who either have either completed 144 weeks of the double-blind treatment phase or are ongoing in the double-blind treatment phase at the time of the primary analysis and, in the opinion of the investigator, could benefit from ocrelizumab treatment. The following participants will move into the FU2 phase: participants who are ongoing in the FU1 at 144 weeks from randomization or at the time of the primary analysis; participants who have either completed 144 weeks of the double-blind treatment phase or are ongoing in the double-blind treatment phase at the time of the primary analysis and will not enter the OLE phase; participants who have completed or withdrawn from the OLE phase or from PDP OCR treatment phase.

Inclusion Criteria: * EDSS score at screening and baseline \>= 3.0 to 8.0, inclusive * Disease duration from the onset of MS symptoms relative to randomization date: Less than 20 years in participants with an EDSS score at screening 7.0 - 8.0 Less than 15 years in participants with an EDSS at screening 5.5 - 6.5 Less than 10 years in participants with an EDSS at screening \<= 5.0 * Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen: Elevated immunoglobulin G (IgG) index or one or more IgG oligoclonal bands detected by isoelectric focusing * Screening and baseline 9-HPT completed in \> 25 seconds (average of the two hands) * Neurological stability for ≥ 30 days prior to baseline * Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline * Neurological stability for \>/= 30 days prior to baseline * Participants previously treated with immunosuppressants, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required. * For female participants without reproductive potential: Women may be enrolled if surgically sterile (i.e hysterectomy, complete bilateral oophorectomy) or post-menopausal unless the participant is receiving a hormonal therapy for her menopause or if surgically sterile Exclusion Criteria: * History of relapsing-remitting or secondary progressive MS at screening * Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease * Participants who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML) * Known active malignancy or are being actively monitored for recurrence of malignancy * Immunocompromised state * Receipt of a live-attenuated vaccine within 6 weeks prior to randomization * Inability to complete an MRI or contraindication to Gd administration. * Participants requiring symptomatic treatment of MS and/or physiotherapy who are not on a stable regimen. Participants must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization. * Contraindications to mandatory premedications for infusion-related reactions, including: uncontrolled psychosis for corticosteroids and closed-angle glaucoma for antihistamines * Known presence of other neurologic disorders * Pregnant or breastfeeding, or intending to become pregnant during the study and for 6 or 12 months after last infusion of the study drug * Lack of peripheral venous access * Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude participant from participating in the study * Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study * History of alcohol or other drug abuse * History of primary or secondary immunodeficiency * Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS * Previous treatment with B-cell targeting therapies * Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation * Any previous history of transplantation or anti-rejection therapy * Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization * Systemic corticosteroid therapy within 4 weeks prior to screening * Positive serum human chorionic gonadotropin (hCG) measured at screening or positive urine β-hCG at baseline * Positive screening tests for hepatitis B * Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above * Lack of MRI activity at screening/baseline if more than 650 participants without MRI activity have already been enrolled, as defined by T1 Gd+ lesion(s) and/or new and/or enlarged T2 lesion(s) in the screening, to ensure that at least 350 participants with MRI activity will be randomized Eligibility Criteria for OLE Phase: * Completed the 144 weeks of double-blind treatment phase of the trial or are ongoing in the double blind treatment phase at the time of the primary analysis, and who, in the opinion of the investigator, may benefit from treatment with Ocrelizumab. Participants who withdrew from study treatment and received another DMT or commercial ocrelizumab will not be allowed to enter in the OLE phase. * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required. * For female participants without reproductive potential: Women may be enrolled if surgically sterile (i.e. hysterectomy, complete bilateral oophorectomy) or post-menopausal unless the participant is receiving a hormonal therapy for her menopause or if surgically sterile