A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF FENEBRUTINIB COMPARED WITH TERIFLUNOMIDE IN ADULT PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS

The primary objective of this study is to evaluate the **efficacy** of fenebrutinib compared with teriflunomide in adult patients with **relapsing multiple sclerosis** (RMS) based on the annualized relapse rate (ARR). This is clinically relevant as ARR is a critical measure of disease activity in RMS, reflecting the frequency of relapses and providing insight into the effectiveness of the treatment in reducing disease progression.

Secondary objectives include:

• Evaluating the efficacy of fenebrutinib compared with teriflunomide based on various measures such as time to onset of 24-week confirmed composite disability progression (cCDP24), 12-week confirmed disability progression (cCDP12), and 24-week confirmed disability progression (CDP24). Additionally, the study will assess the total number of T1Gd+ lesions and new/enlarging T2-weighted lesions detected by MRI, rate of percent change in total brain volume from Week 24, change in patient-reported physical impacts of MS, time to onset of 12-week confirmed 4-point worsening in Symbol Digit Modalities Test (SDMT) score, and change in serum neurofilament light chain (NfL) concentration from baseline to Week 48.
• Evaluating the safety of fenebrutinib compared with teriflunomide.
• Characterizing the pharmacokinetic profile of fenebrutinib.

The clinical trial for **relapsing multiple sclerosis (RMS)** involves a total of 531 participants. The study population includes both male and female subjects, with an age range categorized under code "3," indicating a specific age group as per the trial's classification system. Participants were selected based on their diagnosis of RMS in accordance with the revised 2017 McDonald Criteria and an Expanded Disability Status Scale (EDSS) score of 0.0-5.5 at screening. The trial includes individuals who are neurologically stable for at least 30 days prior to randomization and baseline assessments. Participants must also demonstrate the ability to complete the 9-Hole Peg Test for each hand in less than 240 seconds and perform the timed 25-Foot Walk Test in under 150 seconds. The trial population includes a vulnerable population, as indicated by the selection criteria. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.

The clinical trial is a **Phase III**, multicenter, randomized, double-blind, double-dummy, parallel-group study designed to evaluate the efficacy and safety of fenebrutinib compared with teriflunomide in adult patients with **relapsing multiple sclerosis** (RMS). The primary objective is to assess the efficacy of fenebrutinib based on the annualized relapse rate (ARR). The trial is expected to run from May 2021 to December 2027, with participant involvement lasting until the end of the study or until early termination conditions are met.

Participants will be randomly assigned to receive either fenebrutinib or teriflunomide, with neither the participants nor the investigators aware of the treatment allocations, ensuring a double-blind design. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as an Expanded Disability Status Scale score of 0.0-5.5 and a diagnosis of RMS according to the revised 2017 McDonald Criteria. Follow-up visits will occur at regular intervals to monitor the primary and secondary endpoints, including the time to onset of confirmed disability progression and changes in MRI-detected lesions.

The end-of-study visit will conclude the participant's involvement, assessing the overall safety and efficacy outcomes. Participants may be withdrawn from the study early if they experience adverse events, serious adverse events, or if they no longer meet the study criteria. The trial will also monitor secondary endpoints such as changes in brain volume, patient-reported physical impacts, and serum neurofilament light chain concentrations. The study aims to provide comprehensive data on the comparative effectiveness of fenebrutinib and teriflunomide in managing RMS.

The clinical trial involves the evaluation of **fenebrutinib**, an experimental medication developed by Genentech, Inc. Fenebrutinib is identified by the sponsor product codes RO 701-0939/F57 and RO 701-0939/F41-01. It is a chemical substance with synonyms including RO7010939 and GDC-0853. The pharmaceutical form, dosage, route, and frequency of administration are not specified in the provided data. Fenebrutinib is not a paediatric formulation and is not classified as an orphan drug. The trial aims to assess its efficacy and safety in adult patients with **relapsing multiple sclerosis**.

The comparator treatment in this study is **teriflunomide**, a medication produced by Sanofi Winthrop Industrie. Teriflunomide is a chemically derived substance with the marketing authorization number EU/1/13/838/004 and is authorized in the European Union under the code EMEA/H/C/002514. The pharmaceutical form, dosage, route, and frequency of administration for teriflunomide are not detailed in the available data. It serves as the standard-of-care therapy against which fenebrutinib's efficacy is compared.

Additionally, the trial employs a **placebo** as part of the double-blind, double-dummy design. The placebo is a chemically inert substance used to maintain blinding and ensure unbiased results. The specific details regarding the placebo's pharmaceutical form, dosage, route, and frequency of administration are not provided. Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the protocol.

The efficacy of fenebrutinib compared with teriflunomide in adult patients with **relapsing multiple sclerosis** will be assessed primarily through the measurement of the annualized relapse rate (ARR). This primary endpoint will provide a direct comparison of the two treatments' effectiveness in reducing the frequency of relapses over a specified period. Secondary endpoints will include a variety of measures to further evaluate efficacy. These include the time to onset of confirmed disability progression at 12 and 24 weeks (cCDP12, CDP12, cCDP24, CDP24), the total number of gadolinium-enhancing lesions on T1-weighted MRI, and the total number of new and/or enlarging T2-weighted lesions as detected by MRI. Additionally, the rate of percent change in total brain volume from Week 24, as assessed by MRI, will be measured.

Patient-reported outcomes will also be considered, specifically the rate of change from baseline in the physical impacts of multiple sclerosis as measured by the Multiple Sclerosis Impact Scale (29-Item), Version 2 (MSIS-29 v2) physical scale. The time to onset of a 12-week confirmed 4-point worsening in the Symbol Digit Modalities Test (SDMT) score and the change from baseline to Week 48 in the concentration of serum neurofilament light chain (NfL) will be evaluated. The study will also monitor the nature, frequency, timing, and severity of adverse events, serious adverse events, and adverse events leading to study treatment discontinuation or dose interruptions. Changes from baseline in targeted vital signs, ECG parameters, and clinical laboratory results will be recorded, along with the proportion of patients with suicidal ideation or behavior. Plasma concentration of fenebrutinib at specified timepoints will be measured to assess pharmacokinetics.