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

Study Overview
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Brief Summary
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This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks in participants with PPMS, in comparison to the approved 600 mg dose of ocrelizumab.

Detailed Description
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Participants will be treated for a minimum of 120 weeks in the double-blind phase. Upon positive primary results after the double-blind phase, an optional higher dose extension treatment (OLE phase) is planned for eligible participants. The OLE will be carried out for approximately 96 weeks. Participants will be followed for safety for 48 weeks thereafter. Participants whose B-cell levels still did not replete to their baseline level or the lower limit of normal (LLN), whichever is lower, will move into the B-cell monitoring (BCM) phase following the safety follow-up phase. The study will end when all participants who were not treated with an alternative B-cell depleting therapy have repleted their B-cells to the baseline value or the lower limit of normal.

Official Title
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A Phase IIIB Multicenter, Randomized, Double-Blind, Controlled Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Ocrelizumab
* Drug: Ocrelizumab
* Drug: Antihistamine
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary progressive multiple sclerosis (PPMS). Expanded disability status scale (EDSS) score at screening and baseline, from 3 to 6.5 inclusive. Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds Average 9HPT score over four trials (two trials with each hand) at screening and over four trials (two trials with each hand) at baseline respectively, up to 250 (inclusive) seconds Score of >/= to 2.0 on the Functional Systems scale for the pyramidal system that was due to lower extremity findings at screening and baseline. Documented MRI of brain with abnormalities consistent with MS Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization. Participants must be neurologically stable for at least 30 days prior to randomization and baseline. Disease duration from the onset of MS symptoms; if EDSS score at screening is less or equal to 5, disease duration must be less than 10 years; If EDSS score at screening is more than 5, disease duration must be less than 15 years Documented evidence of the presence of at least one cerebrospinal fluid-specific oligoclonal bands. For females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods. For female participants without reproductive potential, may be enrolled if post-menopausal unless receiving a hormonal therapy for her menopause or if surgically sterile. Exclusion Criteria: History of relapsing remitting or secondary progressive MS at screening. Any known or suspected active infection at screening or baseline (except nailbed infections), or any major episode of infection requiring hospitalization or treatment with IV antimicrobials within 8 weeks or treatment with oral antimicrobials within 2 weeks, prior to and during screening. History of confirmed or suspected progressive multifocal leukoencephalopathy. History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening. Immunocompromised state. Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization. Inability to complete an MRI or contraindication to gadolinium administration. Contraindications to mandatory pre-medications for IRRs. Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study. Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study. Significant, uncontrolled disease that may preclude participant from participating in the study. History of or currently active primary or secondary, non-drug-related, immunodeficiency. Pregnant or breastfeeding or intending to become pregnant. Lack of peripheral venous access. History of alcohol or other drug abuse within 12 months prior to screening. Treatment with any investigational agent or treatment with any experimental procedure for MS. Previous use of anti-CD20s (including ocrelizumab), unless the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy. Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline Previous treatment with natalizumab within 4.5 months of baseline Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label. If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication. Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation. Any previous history of transplantation or anti-rejection therapy. Treatment with intravenous (IV) immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to randomization. Systemic corticosteroid therapy within 4 weeks prior to screening. Positive screening tests for active, latent, or inadequately treated hepatitis B Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab. Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ocrelizumab Higher Dose<br>Participants will be randomized to receive a minimum of 5 higher treatment doses (1200 mg or 1800 mg) of ocrelizumab administered by intravenous (IV) infusion every 24 weeks in the double blind treatment (DBT) phase. During the optional open-label extension (OLE) phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. | Drug: Ocrelizumab<br>* The actual higher dose of ocrelizumab will be assigned to participants based on their body weight at baseline: 1200 mg (participants's body weight <75 kg) or 1800 mg (participant's body weight >/=75 kg). The first dose of ocrelizumab will be administered as two 600 mg or 900 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 1200 mg or 1800 mg IV infusion every 24 weeks.<br>* Other names: Ocrevus;Drug: Antihistamine<br>* Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion.<br>* Other names: Non-Investigational Medicinal Product;Drug: Methylprednisolone<br>* Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.<br>* Other names: Non-Investigational Medicinal Product;|
| Active Comparator: Ocrelizumab Approved Dose<br>Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by intravenous (IV) infusion every 24 weeks in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. | Drug: Ocrelizumab<br>* Ocrelizumab will be administered at a dose of 600 milligram (mg) every 24 weeks. The first dose of ocrelizumab will be administered as two 300 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 600 mg IV infusion every 24 weeks.<br>* Other names: Ocrevus;Drug: Antihistamine<br>* Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion.<br>* Other names: Non-Investigational Medicinal Product;Drug: Methylprednisolone<br>* Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.<br>* Other names: Non-Investigational Medicinal Product;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Reduction in cCDP sustained for at least 12 weeks, measured by time to onset of cCDP sustained for at least 12 weeks. | Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT. | Baseline up to approximately 4.3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of 24-week cCDP (cCDP24) | Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT. | Baseline up to approximately 4.3 years | 
| Time to Onset of 12-week CDP (CDP12) | CDP, defined as a sustained increase from baseline in EDSS score of >/=1.0 point in participants with a baseline EDSS score of </=5.5 or a sustained increase of >/=0.5 points in participants with a baseline EDSS score of >5.5. | Baseline up to approximately 4.3 years | 
| Time to Onset of 24-week CDP (CDP24) | CDP, defined as a sustained increase from baseline in EDSS score of >/=1.0 point in participants with a baseline EDSS score of </=5.5 or a sustained increase of >/=0.5 points in participants with a baseline EDSS score of >5.5. | Baseline up to approximately 4.3 years | 
| Time to >/= 20% Increase in 12-week Confirmed by Timed 25-Foot Walk Test (T25FWT) | The T25FWT is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant is directed to start at one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible. | Baseline up to approximately 4.3 years | 
| Time to >/= 20% Increase in 24-week Confirmed T25FWT | The T25FWT is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant is directed to start at one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible. | Baseline up to approximately 4.3 years | 
| Time to >/= 20% Increase in 12-week Confirmed by 9-Hole Peg Test (9-HPT) | The 9-HPT is a performance measure used to assess upper extremity (arm and hand) function. The test consists of a container containing nine pegs and a wood or plastic block containing nine empty holes. The participant is to pick up each of the nine pegs one at a time and as quickly as possible place them in the nine holes. Once all the pegs are in the holes, the participant is to remove them again one at a time as quickly as possible and replace them into the container. The total time to complete the task is recorded. | Baseline up to approximately 4.3 years | 
| Time to >/= 20% Increase in 24-week Confirmed by 9-HPT | The 9-HPT is a performance measure used to assess upper extremity (arm and hand) function. The test consists of a container containing nine pegs and a wood or plastic block containing nine empty holes. The participant is to pick up each of the nine pegs one at a time and as quickly as possible place them in the nine holes. Once all the pegs are in the holes, the participant is to remove them again one at a time as quickly as possible and replace them into the container. The total time to complete the task is recorded. | Baseline up to approximately 4.3 years | 
| Change from Baseline in the Multiple Sclerosis Impact Scale (MSIS 29) Score | The MSIS-29 is a 29-item participant-reported measure of the physical and psychological impacts of MS. Participants are asked to rate how much their functioning and well-being has been impacted over the past 14 days on a 4-point scale, from Not at all (1) to Extremely (4). | Baseline up to approximately 4.3 years | 
| Change from baseline in the Multiple Sclerosis Impact Scale-29 (MSIS-29) physical scale at Week 120 |  | Baseline, week 120 | 
| Annual Rate of Percent Change from Baseline in Total Brain Volume |  | Baseline up to approximately 4.3 years | 
| Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) | The SDMT is a performance measure that has demonstrated sensitivity in detecting not only the presence of cognitive impairment but also changes in cognitive functioning over time and in response to treatment. Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses will be collected orally. A four-point change from baseline is typically considered clinically meaningful. | Baseline up to approximately 4.3 years | 
| Serum Concentration of Ocrelizumab at Specified Timepoints |  | Weeks 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120 | 
| Change in B-cell Levels in Blood |  | Baseline up to approximately 4.3 years | 
| Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood |  | Baseline up to approximately 4.3 years | 
| Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood in Participants with the High versus Low Affinity Fcgamma Receptor 3A (FcgR3A) Genotype per Arm |  | Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120 | 
| Change from Baseline in the Anti-Drug Antibody (ADA) Levels |  | Week 0, 24, 48, 72, 96, 120 | 
| Levels of Neurofilament Light Chain (NfL) in Blood |  | Baseline up to approximately 4.3 years | 
| Levels of Interleukin-6 (IL-6) in Blood |  | Baseline up to approximately 4.3 years | 
| Levels of Blood B-cells | Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood | Baseline up to approximately 4.3 years | 
| Levels of Lymphocytes in Blood |  | Baseline up to approximately 4.3 years | 
| Proportion of Participants with Different DNA Genotypes |  | Week 0, 2, 12, 24, 48, 72, 96, 120 |