A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of ocrelizumab ( Ocrevus®) compared with placebo in participants with primary progressive multiple sclerosis (PPMS), including participants later in their disease course. This study focuses on upper limit disability progression. This study will consist of the following phases: screening, double-blind treatment, follow-up 1 (FU1), an optional open-label extension (OLE), follow-up 2 (FU2), and B-cell monitoring (BCM).

Detailed Description
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The screening phase will last up to 24 weeks. In the double-blind treatment phase, participants will undergo at least 120 weeks of study treatment. Study drug (ocrelizumab or placebo) will be administered every 24 weeks. In the FU1 phase, all participants who discontinue prematurely from the double-blind treatment phase will enter the FU1 phase, including participants who receive post-double progression ocrelizumab (PDP OCR) treatment, other immunomodulatory or immunosuppressive treatment(s) for MS, commercial ocrelizumab, or no treatment. The FU1 phase will run in parallel with the double-blind treatment phase until the primary analysis is performed. If the primary analysis is positive, an optional OLE phase is planned for eligible participants who either have remained in the double-blind treatment phase or are on PDP OCR treatment at the time of the primary analysis and, in the opinion of the investigator, could benefit from ocrelizumab treatment. The follow-up 2 (FU2) phase will begin after the primary analysis is performed. The following participants will move into the FU2 phase: participants who are ongoing in the FU1 and not on PDP OCR treatment at the time of primary analysis; participants who are ongoing in the double-blind treatment phase or receiving PDP OCR at the time of the primary analysis and do not enter the OLE phase; participants who complete or withdraw from the OLE phase. At the end of the FU2, all participants will move into B-cell monitoring (BCM) phase until the end of the study. This study will end when all participants who are not being treated with an alternative B-cell depleting therapy have repleted his or her B-cells.

Official Title
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A Phase IIIb Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis

Conditions
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Multiple Sclerosis, Primary Progressive

Intervention / Treatment
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* Drug: Ocrelizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: EDSS score at screening and baseline >= 3.0 to 8.0, inclusive Disease duration from the onset of MS symptoms relative to randomization date: Less than 20 years in patients with an EDSS score at screening 7.0 - 8.0 Less than 15 years in patients with an EDSS at screening 5.5 - 6.5 Less than 10 years in patients with an EDSS at screening <= 5.0 Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen: Elevated IgG index or one or more IgG oligoclonal bands detected by isoelectric focusing Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands) Neurological stability for ≥ 30 days prior to baseline Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline Neurological stability for >/= 30 days prior to baseline Patients previously treated with immunosuppressants, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required. For female patients without reproductive potential: Women may be enrolled if surgically sterile (i.e hysterectomy, complete bilateral oophorectomy) or post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile Exclusion Criteria: History of relapsing-remitting or secondary progressive MS at screening Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML) Known active malignancy or are being actively monitored for recurrence of malignancy Immunocompromised state Receipt of a live-attenuated vaccine within 6 weeks prior to randomization Inability to complete an MRI or contraindication to Gd administration. Patients requiring symptomatic treatment of MS and/or physiotherapy who are not on a stable regimen. Patients must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization. Contraindications to mandatory premedications for infusion-related reactions, including: uncontrolled psychosis for corticosteroids and closed-angle glaucoma for antihistamines Known presence of other neurologic disorders Pregnant or breastfeeding, or intending to become pregnant during the study and for 6 or 12 months after last infusion of the study drug Lack of peripheral venous access Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study History of alcohol or other drug abuse History of primary or secondary immunodeficiency Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS Previous treatment with B-cell targeting therapies Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation Any previous history of transplantation or anti-rejection therapy Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization Systemic corticosteroid therapy within 4 weeks prior to screening Positive serum hCG measured at screening or positive urine β-hCG at baseline Positive screening tests for hepatitis B Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above Lack of MRI activity at screening/baseline if more than 650 patients without MRI activity have already been enrolled, as defined by T1 Gd+ lesion(s) and/or new and/or enlarged T2 lesion(s) in the screening, to ensure that at least 350 patients with MRI activity will be randomized Eligibility Criteria for Open-Label Extension Phase: Completed the double-blind treatment phase of the trial or have received PDP OCR in the FU1 phase, and who, in the opinion of the investigator, may benefit from treatment with Ocrelizumab. Patients who withdrew from study treatment and received another disease-modifying therapy (DMT) or commercial ocrelizumab will not be allowed to enter in the OLE phase. Meet the re-treatment criteria for ocrelizumab For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required. For female patients without reproductive potential: Women may be enrolled if surgically sterile (i.e. hysterectomy, complete bilateral oophorectomy) or post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ocrelizumab<br>Participants will receive ocrelizumab by IV infusion every 24 weeks. | Drug: Ocrelizumab<br>* The first dose of ocrelizumab will be administered as two 300 mg IV infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 600 mg infusion every 24 weeks. A minimum interval of 20 or 22 weeks, depending if the previous dose was administered in one or two infusion, should be maintained between each infusion.<br>* Other names: Ocrevus;|
| Placebo Comparator: Placebo<br>Participants will receive placebo matched to ocrelizumab by IV infusion every 24 weeks. | Drug: Placebo<br>* The first dose of placebo will be administered as two 300 mg IV infusions given 14 days apart. For the subsequent doses, placebo will be administered as a single 600 mg infusion every 24 weeks, with a minimum interval of 20 or 22 weeks, depending if the previous dose was administered in one or two infusion, should be maintained between each infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Upper Limb Disability Progression Confirmed For at Least 12 Weeks | 20% increase from baseline in Nine-Hole Peg Test (9-HPT) confirmed for at least 12 weeks. | Baseline up to approximately 5.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Upper Limb Disability Progression Confirmed For at Least 24 Weeks | 20% increases from baseline in 9-HPT confirmed for at least 24 weeks. | Baseline up to approximately 5.5 years | 
| Time to Disability Progression Confirmed For at Least 12 Weeks | Increase in EDSS Score is defined as an increase of >= 1.0 point from baseline EDSS score in participants with a baseline EDSS score <= 5.5 or an increase of >= 0.5 point in participants with a baseline EDSS score of > 5.5. | Baseline up to approximately 5.5 years | 
| Time to Disability Progression Confirmed For at Least 24 Weeks | Increase in EDSS Score is defined as an increase of >= 1.0 point from baseline EDSS score in participants with a baseline EDSS score <= 5.5 or an increase of >= 0.5 point in participants with a baseline EDSS score of > 5.5. | Baseline up to approximately 5.5 years | 
| Percent Change in Total Volume of T2 Lesions on MRI |  | Baseline up to week 120 | 
| Percent Change in Total Brain Volume on MRI Scans |  | Week 24 to Week 120 | 
| Percentage of Participants with Adverse Events |  | Baseline up to 8.5 years | 
| Percentage of Participants With Serious Adverse Events |  | Baseline up to 8.5 years | 
| Area Under the Serum Concentration-Time Curve (AUC) of Ocrelizumab |  | Baseline, Weeks 2, 12, 24, 48, 60, 72, and every 12 weeks till the end of the double-blind period and Weeks 0 and 48 of the OLE period | 
| Evaluation of Ocrelizumab Pharmacodynamics, as measured by B-Cell Levels in Blood |  | Baseline, Weeks 2, 24, 48, 72 and every 12 weeks till the end of the double-blind period and Weeks 0, 22, 46, 70 and 96 of the OLE period |