A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis

INTERVENTION: Trade Name: Ocrevus Product Name: Ocrelizumab Product Code: RO4964913/F07‐01 Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Ocrelizumab CAS Number: 637334‐45‐3 Current Sponsor code: RO4964913 Other descriptive name: OCRELIZUMAB Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 30‐ Pharmaceutical form of the placebo: Concentrate for solution for infusion Route of administration of the placebo: Intravenous use CONDITION: Primary Progressive Multiple Sclerosis (MS) ; MedDRA version: 21.1 Level: PT Classification code 10063401 Term: Primary progressive multiple sclerosis System Organ Class: 10029205 ‐ Nervous system disorders ; MedDRA version: 20.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 ‐ Nervous system disorders ; MedDRA version: 20.1 Level: LLT Classification code 10039720 Term: Sclerosis multiple System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: • To demonstrate the superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab as assessed by risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks Primary end point(s): 1. Reduction in cCDP sustained for at least 12 weeks Secondary Objective: • To demonstrate superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab on the basis of time to onset of 24 week cCDP (cCDP24), CDP12, CDP24, time to >= 20% increase in 12 and 24 week confirmed timed 25 foot walk test (T25FWT) and 9 hole peg test (9 HPT), change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29), percent change in total brain volume, Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT); • To evaluate the safety profile of a higher dose of ocrelizumab compared with the approved dose of ocrelizumab as well as the overall safety profile and safety profile by treatment arm over time; • To assess the exposure to ocrelizumab in serum in all patients in both study arms; • To characterize the ocrelizumab PD profile; • To evaluate the immune response to ocrelizumab; • To identify biomarkers that are predictive of response to a higher dose of ocrelizumab; Timepoint(s) of evaluation of this end point: 1. Up to Week 120 (Double blind treatment [DBT]) and Week 96 (Open label extension [OLE]) SECONDARY OUTCOME: Secondary end point(s): 1. Time to onset of 24 week cCDP (cCDP24); 2. Time to onset of 12‐week CDP (CDP12); 3. Time to onset of 24‐week CDP (CDP24); 4. Time to >= 20% increase in 12 week confirmed T25FWT; 5. Time to >= 20% increase in 24 week confirmed T25FWT; 6. Time to >= 20% increase in 12 week confirmed 9 HPT; 7. Time to >= 20% increase in 24 week confirmed 9 HPT ; 8. Change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29) physical scale at Week 120; 9. Percent change in total brain volume from Week 24 to Week 120; 10. Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT); 11. Presence, frequency, timing, outcome and severity of AEs, serious adverse events (SAE) and AEs leading to study treatment withdrawal; 12. Proportion of patients with AEs and SAEs; 13. Incidence and severity of adverse events, with severity determined according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0; 14. Change from baseline in clinical laboratory test results (including hematology, chemistry, Ig levels); 15. Change from baseline in vital signs (including systolic and diastolic blood pressure, pulse rate) following study treatment administration; 16. Serum concentration of ocrelizumab at specified timepoints; 17. B cell levels in blood as the pharmacodynamic marker of ocrelizumab (including comparing the degree of B‐cell depletion between the doses); 18. Proportion of patients achieving 5 or less B‐cells per microliter of blood; 19. Proportion of patients achieving 5 or less B‐cells per microliter of blood in patients with the high versus low affinity Fcgamma Receptor 3A (FcgR3A) genotype per arm; 20. Prevalence of anti‐drug antibodies (ADAs) at baseline and incidence of ADAs during the study; 21. Levels of soluble biomarkers ; 22. Levels of blood B‐cells based on a highly sensitive assay that can accurately measure below 5 B‐cells per microliter in blood; 23. Levels of B or T cell subsets in blood; 24. DNA genotype of patients; Timepoint(s) of evaluation of this end point: 1‐7. Up to Week 120 (DBT) and Week 96 (OLE); 8. Baseline to Week 120; 9. Week 24 to Week 120; 10. Up to Week 120 (DBT) and Week 96 (OLE); 11‐13. Up to Week 120 (DBT) and Week 96 (OLE); 14‐15. Baseline to Week 120 (DBT) and Week 96 (OLE); 16‐19. Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96; 20. Week 0, 24, 48, 72, 96; 21‐24. DBT: Week 0, 2, 12, 24, 48, 72, 96; OLE: Week 0, 48, 96; INCLUSION CRITERIA: • Ages 18‐55 years at time of signing ICF • Ability to comply with the study protocol • Diagnosis of PPMS in accordance with the revised McDonald Criteria 2017 • Expanded disability status scale (EDSS) score at screening and baseline >=3‐ 6.5, inclusive • Score of >=2.0 on the Functional Systems (FS) scale for the pyramidal system that was due to lower extremity findings • Patients requiring symptomatic treatment for MS (e.g., fampridine, cannabis) and/or physiotherapy must be treated at a stable dose during the screening period prior to the initiation of study drug on Day 1 and must have a plan to remain at a stable dose for the duration of study treatment • Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments • Disease duration from the onset of MS symptoms: o Less than 15 years in patients with an EDSS score at screening >5.0 o Less than 10 years in patients with an EDSS scor