A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Participants With Primary Progressive Multiple Sclerosis

Study Overview
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Brief Summary
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A study to evaluate the efficacy and safety of fenebrutinib on disability progression in adult participants with Primary Progressive Multiple Sclerosis (PPMS). All eligible participants will be randomized 1:1 to either daily oral fenebrutinib (and placebo) or intravenous (IV) ocrelizumab (and placebo) in a blinded fashion through an interactive voice or web-based response system (IxRS). Approximately 946 participants will be enrolled and will be recruited globally. Participants who discontinue study medication early or discontinue from the study will not be replaced. The Open-Label Extension (OLE) phase is contingent on a positive benefit-risk result in the Primary Analysis of the study.

Official Title
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A Phase III Multicenter, Randomized, Double-Blind, Double-Dummy, Parallel-Group Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Patients With Primary Progressive Multiple Sclerosis.

Conditions
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Multiple Sclerosis, Primary Progressive

Intervention / Treatment
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* Drug: Fenebrutinib
* Drug: Ocrelizumab
* Drug: Placebo matched to ocrelizumab
* Drug: Placebo matched to fenebrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For sites in Germany and Italy only, enrollment is restricted to participants aged 46-65 years A diagnosis of PPMS in accordance to the revised 2017 McDonald Criteria (Thompson et al. 2018). Disability progression in the 12 months prior to screening. Expanded Disability Status Scale (EDSS) score from 3.0 to 6.5 inclusive at screening. Pyramidal functional subscore >=2 at screening. For participants currently receiving proton pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), symptomatic treatment for MS (e.g. fampridine, cannabis) and/or physiotherapy: treatment at a stable dose during the screening period prior to the initiation of study treatment and plans to remain at a stable dose for the duration of study treatment. Neurologically stable for at least 30 days prior to randomization and baseline assessments. Ability to complete the 9-Hole Peg Test (9-HPT) for each hand in <240 seconds. Ability to perform Timed 25-Foot Walk Test (T25FWT) in <150 seconds. For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and refrain from donating eggs. For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and refrain from donating sperm. Exclusion Criteria: For participants enrolled in Germany and in Italy only: Presence of gadolinium-enhancing lesions on T1-weighted MRI (T1Gd +) lesion on the screening MRI Any known or suspected active infection (excluding onychomycosis) at screening, including but not limited to a positive screening test for Hepatitis B and C, an active or latent or inadequately treated infection with tuberculosis (TB), a confirmed or suspected progressive multifocal leukoencephalopathy (PML). Participants with a previous history of a serious Infusion-Related Reaction (IRR) (Common Terminology Criteria for Adverse Events [CTCAE] Grade >= 4) and/or any hypersensitivity reaction to ocrelizumab. History of cancer including hematologic malignancy and solid tumors within 10 years of screening. Exceptions: Basal/squamous cell carcinoma of skin cured by excision. In situ carcinoma of the cervix successfully treated by curative therapy >1 year prior to screening. Known presence of other neurological disorders, that could interfere with the diagnosis of MS or assessments of efficacy or safety during the study, clinically significant cardiovascular, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic or gastrointestinal disease. Presence of cirrhosis (Child-Pugh Class A, B, or C) Any concomitant disease that may require chronic treatment with systemic corticosteroids, immunosuppressants or specific medication that could impact the primary evaluation of the study. History of alcohol or other drug abuse within 12 months prior to screening. Female participants who are pregnant or breastfeeding or intending to become pregnant during the study or 6 or 12 months (as applicable from the local label for ocrelizumab) after final dose of study drug. Male participants intending to father a child during the study or for 28 days after final dose of study drug. Lack of peripheral venous access. Any previous treatment with immunomodulatory or immunosuppressive medication without an appropriate washout period. Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization. Immunocompromised state, history of primary or secondary (non-drug related) immunodeficiency, or history of transplantation or antirejection therapy Known bleeding diathesis, anemia, or history of hospitalization or transfusion for gastrointestinal (GI) bleed Any previous treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide OLE Inclusion Criteria: Completed the Double-Blind Treatment (DBT) phase of the study (remaining on study treatment; no other Disease-Modifying Therapy (DMT) administered) and who, in the opinion of the investigator, may benefit from treatment with fenebrutinib. For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and refrain from donating eggs. For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and refrain from donating sperm.

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: Fenebrutinib<br>Participants will receive oral fenebrutinib and intravenous (IV) ocrelizumab-matching placebo. | Drug: Fenebrutinib<br>* Participants will receive fenebrutinib.<br>Drug: Placebo matched to ocrelizumab<br>* Participants will receive ocrelizumab-matching placebo.<br>|
| Active Comparator: Ocrelizumab<br>Participants will receive intravenous (IV) ocrelizumab and oral fenebrutinib-matching placebo. | Drug: Ocrelizumab<br>* Participants will receive ocrelizumab.<br>Drug: Placebo matched to fenebrutinib<br>* Participants will receive fenebrutinib-matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of Composite 12-week Confirmed Disability Progression (cCDP12) |  | Minimum of 120 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of Composite 24-week CDP (cCDP24) |  | Minimum of 120 weeks | 
| Time to Onset of 12-week CDP (CDP12) |  | Minimum of 120 weeks | 
| Time to Onset of 24-week CDP (CDP24) |  | Minimum of 120 weeks | 
| Percentage Change in Total Brain Volume Assessed by Magnetic Resonance Imaging (MRI) |  | From Week 24 to Week 120 | 
| Change from Baseline in Participant-Reported Physical Impacts of Multiple Sclerosis (MS) Measured by the Multiple Sclerosis Impact Scale, 29-Item [MSIS-29] Physical Scale | The MSIS-29, Version 2 is a 29-item patient-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). The physical score is the sum of items 1-20, which is then transformed to a 0-100 scale. The psychological score is the sum of items 21-29, transformed to a 0-100 scale. Higher scores indicate a greater impact of MS. | Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 | 
| Time to Onset of 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) Score | The SDMT is used for detecting the presence of cognitive impairment and changes in cognitive functioning over time and in response to treatment. The SDMT is brief, easy to administer test, and involves a simple substitution task. Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses will be collected only orally, and administration time is approximately 5 minutes. The number of correct responses in 90 seconds will be considered the SDMT score. A decrease by 4 points on the SDMT score from baseline represents a clinically meaningful change in cognitive processing. The SDMT score ranges from 0 to 110. The higher the results, the better processing speed/working memory. | Minimum of 120 weeks | 
| Percentage of Participants with Adverse Events (AEs) |  | Up to 4.7 years | 
| Plasma Concentrations of Fenebrutinib at Specified Timepoints |  | Up to 4.7 years | 
| Percent Change from Screening in Serum Neurofilament Light Chain (NfL) Levels |  | Up to Week 120 |