A Study of Ocrelizumab in Participants With Relapsing Remitting Multiple Sclerosis (RRMS) Who Have Had a Suboptimal Response to an Adequate Course of Disease-Modifying Treatment (DMT)

Study Overview
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Brief Summary
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The purpose of this prospective, multicenter, open-label, efficacy, and safety study is to assess the efficacy and safety of ocrelizumab in participants with Relapsing Remitting Multiple Sclerosis (RRMS) who have had a suboptimal response to an adequate course of a Disease-Modifying Treatment (DMT). The study will consist of a Screening period (up to 4 weeks), an Open-label treatment period (96 weeks; with last dose administered at Week 72), and a Follow-up period of at least 2 years.

Official Title
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An Open-Label Study To Evaluate the Efficacy and Safety of Ocrelizumab in Patients With Relapsing Multiple Sclerosis Who Have A Suboptimal Response to an Adequate Course of Disease-Modifying Treatment

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Biological: Ocrelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a definite diagnosis of RRMS, confirmed as per the revised McDonald 2010 criteria Have a length of disease duration, from first symptom, of less than (<) 10 years Have received no more than two prior DMTs, and the discontinuation of the most recent DMT was due to lack of efficacy Suboptimal disease control while on a DMT Expanded Disability Status Scale (EDSS) of 0.0 to 4.0, inclusive, at Screening For women of childbearing potential: agreement to use an acceptable birth control method during the treatment period and for at least 6 months after the last dose of study drug Exclusion Criteria: Secondary progressive multiple sclerosis (SPMS) or history of primary progressive or progressive relapsing multiple sclerosis (MS) Inability to complete an Magnetic Resonance Imaging (MRI) procedure Known presence of other neurological disorders 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 History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies History of opportunistic infections History or known presence of recurrent or chronic infection History of malignancy Congestive heart failure Known active bacterial, viral, fungal, mycobacterial infection or other infection, excluding fungal infection of nail beds

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 as two 300 mg IV infusions on Days 1 and 15 followed by one 600 mg IV infusions administered at Weeks 24, 48, and 72. | Biological: Ocrelizumab<br>* Ocrelizumab will be administered as two 300 mg IV infusions on Days 1 and 15 followed by one 600 mg IV infusions administered at Weeks 24, 48, and 72.<br>* Other names: RO4964913;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With No Evidence of Disease Activity (NEDA) as Per Protocol Defined Events During a 96-Week Period | A protocol-defined event of disease activity was defined by the occurrence of at least one of the following while on treatment with ocrelizumab: A protocol-defined relapse (PDR) 24-week CDP based on increase in EDSS while on treatment with ocrelizumab A T1 Gd-enhanced lesion after Week 8 A new and/or enlarging T2 hyperintense lesion on MRI after Week 8 compared to the Week 8 MRI scan | Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Free From a Protocol-Defined Event of Disease Activity During 24 Weeks Period | A protocol-defined event of disease activity was defined by the occurrence of at least one of the following while on treatment with ocrelizumab: A protocol-defined relapse (PDR) 24-week CDP based on increase in EDSS while on treatment with ocrelizumab A T1 Gd-enhanced lesion after Week 8 A new and/or enlarging T2 hyperintense lesion on MRI after Week 8 compared to the Week 8 MRI scan | Baseline up to 24 weeks | 
| Percentage of Participants Free From a Protocol-Defined Event of Disease Activity During 48 Weeks Period | A protocol-defined event of disease activity was defined by the occurrence of at least one of the following while on treatment with ocrelizumab: A protocol-defined relapse (PDR) 24-week CDP based on increase in EDSS while on treatment with ocrelizumab A T1 Gd-enhanced lesion after Week 8 A new and/or enlarging T2 hyperintense lesion on MRI after Week 8 compared to the Week 8 MRI scan | Baseline up to 48 weeks | 
| Time to First Protocol-Defined Event of Disease Activity | The definition of a protocol-defined event of disease activity is the occurrence of at least one of the following while on treatment with ocrelizumab: A protocol-defined relapse defined as: Symptoms must persist for >24 hours and should not be attributable to confounding clinical factors; Symptoms should be preceded by neurological stability for at least 30 days; Symptoms should be accompanied by new objective neurological worsening determined with a timely EDSS/ Functional Systems Score (FSS) assessment 24 weeks confirmed disability progression based on increases in EDSS while on treatment with ocrelizumab A T1 Gd-enhanced lesion after Week 8 A new and/or enlarging T2 hyperintense lesion on MRI after Week 8 compared to the Week 8 MRI scan. | Baseline up to 96 Weeks | 
| Change From Baseline to Week 96 in Expanded Disability Status Scale (EDSS) | The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. | Baseline, Weeks: 24, 48, 72, 96 | 
| Absolute Change From Baseline in EDSS Category at Week 96 | The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. | Up to Week 96 | 
| Percentage of Participants With a Baseline EDSS Score ≥2 With CDI at Week 96 | The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. | Week 96 | 
| Annualized Protocol-defined Relapse Rate at Week 96 |  | Week 96 | 
| Time to Onset of 24-week Confirmed Disability Progression |  | Baseline up to 96 Weeks | 
| Time to Onset of First Protocol-Defined Relapse | A protocol-defined multiple sclerosis (MS) relapse is an occurrence of new or worsening neurological symptoms attributable to MS that meets the following criteria: Symptoms must persist for >24 hours and should not be attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to medications) Symptoms should be preceded by neurological stability for at least 30 days Symptoms should be accompanied by new objective neurological worsening determined with a timely EDSS/ Functional Systems Score (FSS) assessment, consistent with an increase of at least: ≥ 0.5 points on EDSS scale or ≥ 2 points on one of the following FSS scales: pyramidal, ambulation, cerebellar, brainstem, sensory, or visual or ≥ 1 point on two or more of the following FSS scales: pyramidal, ambulation, cerebellar, brainstem, sensory, or visual | Baseline up to 96 Weeks | 
| Time to Onset of First New and/or Enlarging T2 Lesion |  | Baseline up to 96 Weeks | 
| Mean Number of T1 Gd-enhancing Lesions Per MRI Scan at Weeks 24, 48 and 96 | Mean number of T1 Gd-enhancing lesions per MRI scan: Total number of T1 Gd-enhanced lesions divided by the total number of interpretable MRI scans | Weeks: 24, 48, 96 | 
| Change From Baseline to Week 96 in Total T2 Lesion Volume Detected by Brain MRI From |  | Baseline, Week 96 | 
| Percentage Change From Baseline to Week 96 in Total T2 Lesion Volume Detected by Brain MRI |  | Baseline, Week 96 | 
| Volume of New and/or Enlarging T2 Hyperintense Lesions Volume of Lesions Per MRI Scan at Weeks 24, 48, 96 | The number of new and/or enlarging T2 lesions at week 24, 48 and 96 is calculated as the sum of the individual number of new and/or enlarging lesions at each visit. Data from other unscheduled assessments is included in this summary or analysis. | Weeks 24, 48, 96 | 
| Mean Number of New and/or Enlarging T2 Hyperintense Lesions Per MRI Scan | Mean number of new and/or enlarging T2 hyperintense lesions per MRI scan: Total number of new and/or enlarging T2 hyperintense lesions divided by the total number of interpretable MRI scans | Weeks 24, 48, 96 | 
| Change From Baseline at Week 48 and 96 in T1 Hypointense Lesion Volume |  | Weeks 48, 96 | 
| Percentage Change From Baseline at Week 48 and 96 in T1 Hypointense Lesion Volume |  | Weeks 48, 96 | 
| Adjusted Mean Change From Baseline at Week 48 and 96 in T1 Hypointense Lesion Volume |  | Weeks 48, 96 | 
| Adjusted Mean Percentage Change From Baseline in Brain Volume |  | Weeks 24, 48, 96 | 
| Adjusted Mean Percentage Change From Baseline in Cortical Grey Matter Volume |  | Weeks 48, 96 | 
| Adjusted Mean Percentage Change From Baseline in White Matter Volume |  | Weeks 48, 96 | 
| Mean Change From Baseline in Cognitive Performance (Processing Speed/Working Memory) at Week 48 and Week 96 as Measured by the Brief International Cognitive Assessment for MS - Symbol Digit Modalities Test (SDMT) Score | Brief International Cognitive Assessment for MS (BICAMS) is assessing cognitive processing speed and verbal and visual memory. Symbol Digits Modalities Test (SDMT) is assessing processing speed/working memory. The SDMT presents a series of nine symbols, each paired with a single digit in a key at the top of a standard sheet of paper. Participants are asked to voice the digit associated with each symbol as rapidly as possible for 90 sec. There is a single outcome measure - the number correct over the 90 sec time span. The higher the results, the better processing speed/working memory. | Baseline, Weeks: 48, 96 | 
| Change From Baseline in Cognitive Performance (Visuospatial Memory) at Week 48 and Week 96 as Measured by the Brief International Cognitive Assessment for MS - Brief Visuospatial Memory Test-Revised (BVMT-R) Score | Brief International Cognitive Assessment for MS (BICAMS) is assessing cognitive processing speed and verbal and visual memory. Brief Visuospatial Memory Test-Revised (BVMT-R) is assessing visuospatial memory. In this test, six abstract designs are presented for 10 sec. The display is removed from view and patients render the stimuli via pencil on paper manual responses. Each design receives from 0 to 2 points representing accuracy and location. There are three learning trials, and the outcome measure is the total number of points earned over the three learning trials, thus the scale range is 0-36. The higher the result, the better visual/spatial memory. | Baseline, Weeks 48, 96 | 
| Percentage Change From Baseline in Cognitive Performance (Processing Speed/Working Memory) at Week 48 and Week 96 as Measured by the Brief International Cognitive Assessment for MS - Symbol Digit Modalities Test (SDMT) Score | Brief International Cognitive Assessment for MS (BICAMS) is assessing cognitive processing speed and verbal and visual memory. Symbol Digits Modalities Test (SDMT) is assessing processing speed/working memory. The SDMT presents a series of nine symbols, each paired with a single digit in a key at the top of a standard sheet of paper. Participants are asked to voice the digit associated with each symbol as rapidly as possible for 90 sec. There is a single outcome measure - the number correct over the 90 sec time span. | Baseline, Weeks 48, 96 | 
| Percentage Change From Baseline in Cognitive Performance (Visuospatial Memory) at Week 48 and Week 96 as Measured by the Brief International Cognitive Assessment for MS - Brief Visuospatial Memory Test-Revised (BVMT-R) Score | Brief International Cognitive Assessment for MS (BICAMS) is assessing cognitive processing speed and verbal and visual memory. Brief Visuospatial Memory Test-Revised (BVMT-R) is assessing visuospatial memory. In this test, six abstract designs are presented for 10 sec. The display is removed from view and patients render the stimuli via pencil on paper manual responses. Each design receives from 0 to 2 points representing accuracy and location. There are three learning trials, and the outcome measure is the total number of points earned over the three learning trials, thus the scale range is 0-36. The higher the result, the better visual/spatial memory. | Baseline, Weeks: 48, 96 | 
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Baseline up to to 96 weeks after the end of the Treatment Period |