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

The primary objective of this study is to evaluate the **efficacy** of fenebrutinib compared with ocrelizumab in patients with **Primary Progressive Multiple Sclerosis (PPMS)**, regardless of adherence to randomized treatment. This is clinically relevant as it aims to determine the potential of fenebrutinib as an alternative therapeutic option for managing PPMS, a condition characterized by a steady progression of neurological disability.

Secondary objectives include:

• To evaluate the efficacy of fenebrutinib treatment compared with ocrelizumab.
• To evaluate the safety of fenebrutinib compared with ocrelizumab.
• To characterize the fenebrutinib pharmacokinetic (PK) profile.

The clinical trial involves a total of **688 participants** diagnosed with **Primary Progressive Multiple Sclerosis (PPMS)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their ability to comply with the study protocol and a confirmed diagnosis of PPMS according to the revised 2017 McDonald Criteria. The trial includes individuals who have experienced disability progression in the 12 months prior to screening, with an Expanded Disability Status Scale (EDSS) score ranging from 3.0 to 6.5, and a pyramidal functional subscore of 2 or higher at screening. The study also considers lifestyle factors, such as the stable use of proton pump inhibitors or H2 receptor antagonists, which must remain consistent throughout the trial. The trial population includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics.

The clinical trial is designed as a **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 (PPMS)**. The trial aims to assess the time to onset of composite 12-week confirmed disability progression as the primary endpoint, with secondary endpoints including various measures of disability progression, changes in brain volume, serum neurofilament light chain levels, and patient-reported impacts of multiple sclerosis. The study is expected to run from December 28, 2020, to May 17, 2028, with participant involvement lasting until the end of the study or until early termination conditions are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of PPMS according to the revised 2017 McDonald Criteria, disability progression in the 12 months prior to screening, and an EDSS score between 3.0 and 6.5. Follow-up visits will be conducted to monitor the progression of the disease and the safety and efficacy of the treatment. The end-of-study visit will conclude the participant's involvement, unless early termination is warranted due to adverse events, non-compliance with the study protocol, or withdrawal of consent.

Participants are expected to comply with the study protocol, including maintaining stable doses of any concurrent medications such as proton pump inhibitors or H2 receptor antagonists. The trial will be conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the evaluation of **Fenebrutinib**, an investigational medication, in adult patients with **Primary Progressive Multiple Sclerosis (PPMS)**. Fenebrutinib is a chemical compound developed by **GENENTECH, INC.** and is identified by the sponsor product code **RO 701-0939/F41-01**. The pharmaceutical form, dosage, route, and frequency of administration for Fenebrutinib are not specified in the provided data. The medication is not a paediatric formulation and is classified under the chemical origin category. Participant compliance with the dosing schedule will be monitored throughout the study.

**Ocrelizumab** serves as the comparator treatment in this study. It is a protein-based medication developed by **ROCHE REGISTRATION GMBH**. Ocrelizumab is authorized under the marketing authorization number **EU/1/17/1231/002** and is identified by the European medicinal product number **PRD5771884**. The pharmaceutical form, dosage, route, and frequency of administration for Ocrelizumab are not detailed in the provided data. This medication is also not a paediatric formulation and is categorized under the protein origin category. The study will ensure adherence to the dosing schedule and monitor participant compliance.

A **placebo** is utilized in the trial as a non-experimental treatment to maintain the double-blind, double-dummy design. The placebo is used to ensure that neither the participants nor the investigators know which treatment the participants are receiving, thereby reducing bias. The specific details regarding the pharmaceutical form, dosage, route, and frequency of administration for the placebo are not provided in the data.

The efficacy of fenebrutinib compared with ocrelizumab in adult patients with Primary Progressive Multiple Sclerosis (PPMS) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to onset of composite 12-week confirmed disability progression (**cCDP12**). Secondary endpoints include the time to onset of composite 24-week confirmed disability progression (**cCDP24**), time to onset of 12-week confirmed disability progression (**CDP12**), and time to onset of 24-week confirmed disability progression (**CDP24**). Additionally, the percent change in total brain volume from Week 24, as assessed by MRI scan, and the percent change from screening to Week 120 in serum neurofilament light chain (**NfL**) levels will be evaluated.

Other secondary endpoints involve changes in patient-reported physical impacts of MS, measured by the Multiple Sclerosis Impact Scale, 29-Item (**MSIS-29**) physical scale, and the time to onset of 12-week confirmed 4-point worsening in Symbol Digit Modality Test (**SDMT**) score. The study will also monitor the nature, frequency, timing, and severity of adverse events, serious adverse events, and adverse events leading to study treatment withdrawal. Changes from baseline in targeted vital signs, ECG parameters, and clinical laboratory results following study treatment administration will be recorded. The change from baseline in the proportion of patients with suicidal ideation or behavior, as assessed by the Columbia Suicide Severity Rating Scale (**C-SSRS**), and plasma concentration of fenebrutinib at specified timepoints will also be measured.