Phase III Randomized Double‑Blind Study of Fenebrutinib versus Teriflunomide for Efficacy and Safety in Adults with Relapsing Multiple Sclerosis

The primary objective is to compare the efficacy of fenebrutinib with teriflunomide on the basis of annualized relapse rate in adults with relapsing multiple sclerosis, providing a direct measure of disease activity that is closely linked to long‑term disability outcomes. Secondary objectives include:

• Evaluation of efficacy on multiple dimensions of disease progression, such as time to onset of confirmed disability progression (composite 24‑week and 12‑week, as well as CDP12 and CDP24), quantitative MRI endpoints (total T1‑Gd+ lesions, new or enlarging T2 lesions, and percent change in total brain volume assessed by magnetic resonance imaging), patient‑reported physical impact, time to a confirmed 4‑point worsening on the Symbol Digit Modalities Test, and change in serum neurofilament light chain levels at week 48;
• Assessment of safety of fenebrutinib relative to teriflunomide;
• Characterisation of the fenebrutinib pharmacokinetic profile.

The trial enrolled 463 participants diagnosed with relapsing multiple sclerosis who were eligible for comparison of fenebrutinib versus teriflunomide. Both male and female adults were included; the population encompassed individuals considered vulnerable. Eligibility required an Expanded Disability Status Scale score between 0.0 and 5.5, a diagnosis according to the revised 2017 McDonald Criteria, and neurological stability for at least 30 days before randomization. Participants also needed to complete the 9‑Hand Peg Test within 240 seconds and the timed 25‑Foot Walk Test within 150 seconds, and those entering the open‑label extension had to have completed the double‑blind treatment phase without receiving another disease‑modifying therapy. The cohort represented patients with generally stable health status appropriate for assessment of the primary outcome, the annualized relapse rate.

The study is a Phase III, multicenter, randomized, double-blind, double-dummy, parallel-grouprelapsing multiple sclerosis. Participants are screened during an initial visit to confirm eligibility criteria, including an Expanded Disability Status Scale score of 0.0–5.5 and stability of neurological status for ≥30 days. Eligible subjects are then randomized to receive either fenebrutinib plus teriflunomide placebo or teriflunomide plus fenebrutinib placebo, maintaining blinding throughout the double‑blind treatment (DBT) phase. Follow‑up visits are scheduled approximately at Weeks 4, 12, 24, 36 and 48 to assess efficacy (primary endpoint: annualized relapse rate) and safety parameters, perform MRI assessments, collect laboratory samples, and record adverse events. The end‑of‑study visit occurs at Week 48, concluding the DBT phase and allowing for transition to an optional open‑label extension for participants who complete the double‑blind period without major protocol violations. Participant involvement therefore spans roughly 12 months, including the screening period. Early termination may occur for any of the following reasons: occurrence of a serious adverse event, emergence of contraindicating medical conditions, non‑adherence to study medication, need for an alternative disease‑modifying therapy, or withdrawal of consent by the investigator or participant.

The investigational arm receives Fenebrutinib as a 400 mg oral film‑coated tablet, administered once daily by the oral route throughout the treatment period.

The active comparator arm receives Teriflunomide (commercially known as Aubagio) as a 14 mg oral film‑coated tablet, also administered once daily by the oral route for the duration of the study.

Participants assigned to the double‑dummy design receive matching tablets that contain no active pharmaceutical ingredient, herein referred to as placebo, for both the fenebrutinib and teriflunomide formulations to maintain blinding.

Dosing occurs each morning with water, and treatment cycles are continuous without interruption unless a protocol‑specified discontinuation criterion is met. Compliance is assessed at each study visit by pill count, review of dosing diaries, and verification of returned tablet counts.

The primary efficacy assessment is the annualized relapse rate, calculated as the number of confirmed relapses per patient‑year over the treatment period. Relapse events are recorded throughout the study and the rate is derived using standard statistical models for count data.

Secondary efficacy evaluations include time‑to‑onset analyses for confirmed 12‑week and 24‑week disability progression (cCDP12, CDP12, cCDP24, CDP24) based on established disability scales, and magnetic resonance imaging endpoints such as the total number of gadolinium‑enhancing lesions on T1‑weighted scans, the total number of new or enlarging T2‑weighted lesions, and the percent change in total brain volume assessed from Week 24 onward. Patient‑reported physical impact is measured with the Multiple Sclerosis Impact Scale (29‑Item), Version 2 (MSIS‑29 v2) physical scale, and cognitive change is monitored using the Symbol Digit Modalities Test, with time to a 12‑week confirmed 4‑point worsening recorded. Serum neurofilament light chain concentration (neurofilament light chain) is quantified at baseline and Week 48. All imaging and biomarker data are collected at predefined visits, processed centrally, and analyzed using appropriate mixed‑effects or survival models to compare fenebrutinib with teriflunomide.