A Study to Evaluate Ocrelizumab Treatment in Participants With Progressive Multiple Sclerosis

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

Official Title
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An Open-Label, Single-Arm 4-Year Study to Evaluate Effectiveness and Safety of Ocrelizumab Treatment in Patients With Progressive Multiple Sclerosis

Conditions
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Progressive Multiple Sclerosis (PMS)

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 PMS (as per the revised McDonald 2010 criteria for PPMS or Lublin et al. 2014 criteria for PMS) EDSS (Expanded Disability Status Scale) </ =6.5 at screening Have a documented evidence of disability progression independent of relapse at any point over the 2 years prior to the screening visit. In case relapse(s) have occurred in the last 2 years, disability progression will have to be considered as independent of relapse activity as per treating physician's judgment Fulfill at least one of the 21 criteria assessing the evidence of disability progression independent of relapse activity in the last 2 years using the pre-baseline disability progression rating system checklist Have experience of having used a smartphone and connecting a smartphone to Wi-Fi network providers For women of childbearing potential: agreement to remain abstinent or use acceptable contraceptive methods during the treatment period and for at least 6 months, or longer if the local label is more stringent after the last dose of study drug Exclusion Criteria: Relapsing-remitting multiple sclerosis (RRMS) at screening Inability to complete an MRI Gadolinium (Gd) intolerance Known presence of other neurological disorders Exclusions Related to General Health: Pregnancy confirmed by positive serum β human chorionic gonadotropin (hCG) measured at screening Lactation Any concomitant disease that may require chronic treatment of systemic corticosteroids or immunosuppressants during the course of the study History or currently active primary or secondary immunodeficiency Lack of peripheral venous access Significant or uncontrolled somatic disease or any other significant disease that may preclude participant from participating in the study. Active infections must be treated and resolved prior to the first infusion of ocrelizumab Participants in a severely immunocompromised state until the condition resolves Participants with known active malignancies or being actively monitored for recurrence of malignancy Participants who have or have had confirmed progressive multifocal leukoencephalopathy (PML) Exclusions Related to Laboratory Findings: Positive screening tests for hepatitis B CD4 count <250/μL ANC <1.0 × 103/μL AST/SGOT or ALT/SGPT ≥3.0 × ULN in combination with either an elevated total bilirubin (>2 X ULN) or clinical jaundice Exclusions Related to Medications: Hypersensitivity to ocrelizumab or to any of its excipients Previous treatment with ocrelizumab Previous treatment with B-cell targeted therapies (i.e., atacicept, tabalumab, belimumab, ofatumumab, or obinutuzumab). Note: previous treatment with rituximab is allowed as long as the last dose was administered more than 6 months before the ocrelizumab infusion AND if discontinuation was due to adverse events or immunogenicity AND if Bcell levels are above the lower limit of normal (LLN) prior to screening. Any previous treatment with alemtuzumab (Campath/Mabcampath/Lemtrada), total body irradiation, or bone marrow transplantation Previous treatment with natalizumab where PML has not been excluded according to specific algorithm Contraindications to or intolerance of oral or intravenous (IV) corticosteroids, including methylprednisolone administered IV, according to the country label Systemic corticosteroid therapy within 4 weeks prior to screening All vaccines should be given at least 6 weeks before the first infusion of ocrelizumab, unless the local regulations allow for a shorter interval. Live/live attenuated vaccines should be avoided during treatment and safety follow-up period until B cells are peripherally repleted Previous treatment with daclizumab, ozanimod or figolimod in the last 8 weeks Previous treatment with siponimod in the last 2 weeks Treatment with fampridine/dalfampridine (Fampyra)/Ampyra) or other symptomatic MS treatment unless on stable dose for ≥30 days prior to screening Previous treatment with natalizumab in the last 12 weeks. Previous treatment with teriflunomide in the last 12 weeks. This washout period can be shortened if an accelerated elimination procedure is implemented before screening visit. One of the following elimination procedures can be used: Cholestyramine 8 g administered 3 times daily for a period of at least 7 days (cholestyramine 4 g three times a day can be used, if cholestyramine 8 g three times a day is not well tolerated) Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for a period of at least 7 days. Previous treatment with azathioprine, cyclophosphamide, mycophenolate mofetil or methotrexate in the last 12 weeks Treatment with any investigational agent within 24 weeks of screening (Visit 1) or five half-lives of the investigational drug (whichever is longer) or treatment with any experimental procedures for MS Previous treatment with mitoxantrone, cyclosporine or cladribine in the last 96 weeks Participants previously treated with teriflunomide within the last two years, unless measured plasma concentrations are less than 0.02 mg/l. If above or not known, an accelerated elimination procedure should be implemented before screening visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 via intravenous (IV) infusion. | Drug: Ocrelizumab<br>* Ocrelizumab will be administered via intravenous (IV) infusion at an initial dose of two 300-mg infusions separated by 14 days (on Days 1 and 15), and then 600 mg at every subsequent dose every 24 weeks for the remainder of the study treatment period (approximately 192 weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion 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 (confirmed disability progression [CDP]; ≥20% increase in timed 25-foot walk test [T25FWT]; ≥20% increase in nine-hole peg test [9HPT]) | From Baseline to Week 96, Week 96 to Week 192 and Baseline to Week 192 | 
| Proportion of Participants with no evidence of progression and no active disease (NEPAD) | NEPAD is defined as no progression sustained for at least 24 weeks on all of the three components of NEP (CDP, T25FWT, 9HPT), no protocol-defined relapse, no enlarging or new T2 lesion, and no T1 gadolinium (Gd+)-enhancing lesion | From Baseline to Week 96, Week 96 to Week 192 and Baseline to Week 192 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Patient-Reported Outcomes (PROs) | PROs collected in this study will be the Multiple Sclerosis Impact Scale (MSIS-29), the Multiple Sclerosis Walking scale (MSWS-12), the ABILHAND-56 Questionnaire, Fatigue Scale for Motor and Cognitive function (FSMC), SymptoMScreen, 88-item Multiple Sclerosis Spasticity Scale (MSSS-88), Numerical Pain Rating Scale (NPRS), and the Patient Global Impression of Severity (PGIS) for upper limb, lower limb and cognitive function | Baseline to end of study (Week 192) | 
| Change from Baseline in the number of falls and near-falls |  | Baseline to end of study (Week 192) | 
| Change in Whole Brain Volume (Whole, Cerebral White Matter, Cortical Grey Matter, Deep grey matter) |  | Baseline to end of study (Week 192) | 
| Change in thalamic volumes |  | Baseline to end of study (Week 192) | 
| Change in whole and regional cerebellar volume (cervical cord grey and white matter area) |  | Baseline to end of study (Week 192) | 
| Change in cervical cord cross-sectional area (total, white matter and grey matter) |  | Baseline to end of study (Week 192) | 
| Change in number of new/enlarging T2 lesions and total T2 Lesion Volume |  | Baseline to end of study (Week 192) | 
| Change in number of T1 Gadolinium (Gd)+ Lesions and total volume |  | 'Baseline to end of study (Week 192) | 
| Change in number of T1 lesions |  | Baseline to end of study (Week 192) | 
| Number in total volume of T1 lesions |  | Baseline to end of study (Week 192) | 
| Change in Slowly Evolving Lesions (SEL) |  | Baseline to end of study (Week 192) | 
| Change in normalised T1 intensity/T1 Gd+ enhancement in New Focal T2 Lesions, SELs, Persistent Areas of Non-SEL T2 Lesions, and Normal-Appearing Brain Tissue |  | Baseline to end of study (Week 192) | 
| Change in Gd-enhancing late-Fluid-Attenuated Inversion-Recovery (FLAIR) Meningeal Lesions |  | Baseline to end of study (Week 192) | 
| Change in the number/ spatial distribution of lesions in the cervical spinal cord |  | Baseline to end of study (Week 192) | 
| Spectroscopic MR: Measure of the Relative Signal Amplitude of N-Acetyl Aspartate (NAA), and Choline to Creatine | Only in centers with 1.5-Tesla MRI capable to perform it | Baseline to end of study (Week 192) | 
| Measure of phase rim lesions using a Susceptibility-Weighted Imaging [SWI]/T2 sequence | Only in centers with 3-Tesla MRI capable to perform it, where this sequence would replace the spectroscopic MR in the acquisition flow | Baseline to end of study (Week 192) | 
| Percentage of Participants with Adverse Events (AEs) |  | Baseline to end of study (Week 192) | 
| Rates of study treatment discontinuation due to adverse events |  | Baseline to Week 192 | 
| Change from Baseline in Cognitive Function, as Measured by the Symbol Digit Modalities Test (SDMT) |  | Baseline to end of study (Week 192) | 
| Change from Baseline in Cognitive Function, as Measured by Brief Visuospatial Memory Test - Revised (BVMT-R) |  | Baseline to end of study (Week 192) | 
| Mean Change from Baseline in the Expanded Disability Status Scale (EDSS) score over the course of the study |  | Baseline to end of study (Week 192) | 
| Time to Onset of First Confirmed Disability Progression (CDP) Sustained for at least 24 and 48 Weeks |  | Baseline to onset of first CDP (as measured by EDSS) sustained for at least 24 and 48 weeks | 
| Time to Onset of First >=20% Increase in Timed 25-foot Walk Test (T25FWT) Sustained for at least 24 Weeks |  | Baseline to onset of first >=20% increase in T25FWT sustained for at least 24 weeks | 
| Time to Onset of First >=20% Increase in 9 Hole Peg Test (9HPT) Sustained For At Least 24 Weeks |  | Baseline to onset of first >=20% increase in 9HPT sustained for at least 24 weeks | 
| Proportion of Participants with NEP |  | Week 24 to Week 96, Week 24 to Week 192, and Week 48 to Week 192 | 
| Proportion of Participants with NEPAD |  | Week 24 to Week 96, Week 24 to Week 192, Week 48 to Week 192 |