Study to Evaluate the Effectiveness and Safety of Ocrelizumab in Participants With Early Stage Relapsing Remitting Multiple Sclerosis (RRMS)

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label, Single-Arm Study to Evaluate the Effectiveness and Safety of Ocrelizumab in Patients With Early Stage Relapsing Remitting Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Ocrelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a definite diagnosis of RRMS, as per the revised McDonald 2010 criteria Have a length of disease duration, from first documented clinical attack consistent with MS disease of less than or equal to (</=) 3 years Within the last 12 months one or more clinically reported relapse(s) or one or more signs of MRI activity EDSS of 0.0 to 3.5 inclusive, at screening An agreement to use an acceptable birth control method for women of childbearing potential, during the treatment period and for at least 6 months or longer after the last dose of study drug Exclusion Criteria: Secondary progressive multiple sclerosis or history of primary progressive or progressive relapsing MS Inability to complete an MRI Known presence of other neurological disorders Exclusions Related to General Health: Pregnancy or lactation Participants intending to become pregnant during the study or within 6 months after the last dose of the study drug Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study History or currently active primary or secondary immunodeficiency Lack of peripheral venous access History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies Significant or uncontrolled somatic disease or any other significant disease that may preclude participant from participating in the study Congestive heart failure (New York Heart Association III or IV functional severity) Known active bacterial, viral, fungal, mycobacterial infection or other infection, (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks prior to screening or oral antibiotics 2 weeks prior to screening History of malignancy, major opportunistic infections, alcohol or drug abuse, recurrent or chronic infection, and/or coagulation disorders Exclusions Related to Medications: Received any prior approved disease modifying treatment (DMT) with a label for MS, for example, interferons, glatiramer acetate, natalizumab, alemtuzumab, daclizumab, fingolimod, teiflunomide and dimethylfumarate Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the baseline visit Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab) Any previous treatment with immunosuppressants/ immunomodulators/ antineoplastic therapies (cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, cladribine, mitoxantrone, laquinimod, total body irradiation, or bone marrow transplantation) Treatment with investigational DMT Treatment with fampridine/dalfamipridine unless on stable dose for >/=30 days prior to screening Exclusion related to Shorter Infusion Substudy: - Any previous serious IRRs experienced with ocrelizumab treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ocrelizumab<br>Ocrelizumab will be administered intravenously (IV) as two 300-milligram (mg) infusions (infusion length=2.5 hours) on Days 1 and 15, followed by one 600-mg infusion dose every 24 weeks (+/- 14 days) for a maximum of 8 doses throughout the 192 weeks treatment period. | Drug: Ocrelizumab<br>* Ocrelizumab will be administered via IV infusion as specified throughout the treatment period.<br>|
| Active Comparator: Substudy Group 1<br>At week 24 of the main study, eligible participants will be randomized to receive 600 mg ocrelizumab infused over approximately 3.5 hours every 24 weeks for the remainder of the study duration | Drug: Ocrelizumab<br>* Ocrelizumab will be administered via IV infusion as specified throughout the treatment period.<br>|
| Experimental: Substudy Group 2<br>At week 24 of the main study, eligible participants will be randomized to receive 600 mg ocrelizumab infused over approximately 2 hours followed by sodium chloride given as a slow infusion over the remaining 1.5 hours to mimic the standard-length infusion (3.5 hour) every 24 weeks for the remainder of the study duration | Drug: Ocrelizumab<br>* Ocrelizumab will be administered via IV infusion as specified throughout the treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of Confirmed Disability Progression (CDP) Sustained for at Least 24 and 48 Weeks, As Measured Using Expanded Disability Status Scale (EDSS) |  | Baseline up to 4 years | 
| Percentage of Participants With Confirmed Disability Improvement (CDI) at Year 1, As Measured Using EDSS |  | Year 1 | 
| Percentage of Participants With CDP Sustained for At Least 24 and 48 Weeks at Year 1, As Measured Using EDSS |  | Year 1 | 
| Percentage of Participants With CDI at Year 2, As Measured Using EDSS |  | Year 2 | 
| Percentage of Participants With CDP Sustained for At Least 24 and 48 Weeks at Year 2, As Measured Using EDSS |  | Year 2 | 
| Percentage of Participants With CDI at Year 4, As Measured Using EDSS |  | Year 4 | 
| Percentage of Participants With CDP Sustained for At Least 24 and 48 Weeks at Year 4, As Measured Using EDSS |  | Year 4 | 
| Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 1, As Measured Using EDSS |  | Year 1 | 
| Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 2, As Measured Using EDSS |  | Year 2 | 
| Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 3, As Measured Using EDSS |  | Year 3 | 
| Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 4, As Measured Using EDSS |  | Year 4 | 
| Mean Change From Baseline in EDSS Score at Week 24 |  | Baseline, Week 24 | 
| Mean Change From Baseline in EDSS Score at Week 48 |  | Baseline, Week 48 | 
| Mean Change From Baseline in EDSS Score at Week 72 |  | Baseline, Week 72 | 
| Mean Change From Baseline in EDSS Score at Week 96 |  | Baseline, Week 96 | 
| Mean Change From Baseline in EDSS Score at Week 120 |  | Baseline, Week 120 | 
| Mean Change From Baseline in EDSS Score at Week 144 |  | Baseline, Week 144 | 
| Mean Change From Baseline in EDSS Score at Week 168 |  | Baseline, Week 168 | 
| Mean Change From Baseline in EDSS Score at Week 192 |  | Baseline, Week 192 | 
| Time to First Protocol-Defined Event of Disease Activity | Protocol-defined event of disease activity is defined as having at least one of the following: (1). protocol defined relapse (occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis [MS], as determined using EDSS/Functional Systems Score [FSS] assessment). (2). CDP, as determined using EDSS. (3). a T1 Gd-enhanced lesion after Week 8 (4). a new and/or enlarging T2 hyperintense lesion on magnetic resonance imaging (MRI) after Week 8 compared to the Week 8 MRI scan. | Baseline up to 4 years | 
| Time to First Relapse | Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. | Baseline up to 4 years | 
| Annualized Relapse Rate | Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. | Baseline up to 4 years | 
| Proportion of Participants with Infusion Related Reactions (IRRs) Occurring During or Within 24 Hours Following the First Infusion After Randomization to the Shorter Infusion Substudy |  | From Week 24 through Week 192 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Are Relapse Free | Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. | Weeks 48, 96, 144, 192 | 
| Percentage of Participants With No Evidence of Protocol Defined Disease Activity | Protocol-defined disease activity is defined as having at least one of the following: (1). protocol defined relapse (occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis [MS], as determined using EDSS/Functional Systems Score [FSS] assessment). (2). CDP, as determined using EDSS. (3). a T1 Gd-enhanced lesion after Week 8. (4). a new and/or enlarging T2 hyperintense lesion on magnetic resonance imaging (MRI) after Week 8 compared to the Week 8 MRI scan. | Weeks 96, 144, 192 | 
| Percentage of Participants With no Evidence of Progression (NEP) | NEP is defined as no progression sustained for at least 24 weeks on all of the following three components (CDP; 20 percent [%] increase from baseline in timed 25 Foot Walk Test [T25FWT]; 20% increase from baseline in timed 9 hole peg test [9HPT]). CDP will be assessed using EDSS. | Weeks 96, 192 | 
| Percentage of Participants With no Evidence of Progression Sustained for At Least 24 Weeks and no Active Disease (NEPAD) | NEPAD is defined as no progression on all of the three components of NEP (CDP, T25FWT, 9HPT), no new relapse and no enlarging or new T2 or T1 Gd-enhancing lesion. CDP will be assessed using EDSS. Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. | Weeks 96, 192 | 
| Change from Baseline in Multiple Sclerosis Functional Composite (MSFC) Total Score |  | Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192 | 
| Change from Baseline in MSFC Composite Timed 25 Foot Walk Test (T25FW) Score |  | Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192 | 
| Change from Baseline in MSFC Composite 9 Hole Peg Test (9HPT) Score |  | Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192 | 
| Change from Baseline in MSFC Composite (Paced Auditory Serial Addition Test [PASAT]) Score |  | Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192 | 
| Change from baseline in cognitive performance as measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) |  | Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192 | 
| Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI |  | Baseline, Weeks 8, 24, 48, 96, 144, 192 | 
| Total Number of New and/or Enlarging T2 Lesion as Detected by Brain MRI |  | Baseline, Weeks 8, 24, 48, 96, 144, 192 | 
| Change from baseline in total T1 hypointense lesion volume as Detected by Brain MRI |  | Baseline, Weeks 8, 24, 48, 96, 144, 192 | 
| Total Number of Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI |  | Baseline, Weeks 8, 24, 48, 96, 144, 192 | 
| Change From Baseline in Brain Volume as Detected by Brain MRI |  | Baseline, Weeks 8, 24, 48, 96, 144, 192 | 
| Time to Treatment Discontinuation |  | Baseline up to 4 years | 
| Employment Status: Work Productivity and Activity Impairment Questionnaire (WAPI) Score |  | Baseline, Weeks 24, 48, 96, 120, 144, 192 | 
| SymptoMScreen Composite Score |  | Baseline, Weeks 24, 48, 96, 120, 144, 192 | 
| Quality of Life: Multiple Sclerosis Impact Scale (MSIS)-29 Questionnaire Score |  | Baseline, Weeks 24, 48, 96, 120, 144, 192 | 
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Short term safety related to the infusion (infusion-related reactions [IRRs], during infusion and up to 24h after) the overall safety is measured continuously at clinical visits and including every 8 week telephone visits up to 48 weeks post study. | Baseline up to 4 years | 
| Proportion of Participants with IRR (overall) in the Shorter Infusion Substudy |  | From Week 24 through Week 192 | 
| Proportion of Participants with IRR By Dose at Randomization in the Shorter Infusion Substudy |  | From Week 24 through Week 192 | 
| Proportion of Participants with IRRs Leading to Treatment Discontinuation in the Shorter Infusion Substudy |  | From Week 24 through Week 192 |