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Protocol No:

ECCT/23/01/06

Date of Protocol:

20-08-2021

Study Title:	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 CSF BIOMARKER SUBSTUDY ASSOCIATED WITH A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP STUDY (GN41851) TO EVALUATE THE EFFICACY AND SAFETY OF FENEBRUTINIB COMPARED WITH TERIFLUNOMIDE IN ADULT PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS
Study Objectives:	This study will evaluate the efficacy and safety of fenebrutinib compared with teriflunomide in adult patients with relapsing multiple sclerosis (RMS). The pharmacokinetics (PK) of fenebrutinib will also be evaluated. Primary Efficacy Objective The primary efficacy objective for this study is to evaluate the efficacy of fenebrutinib compared with teriflunomide on the basis of the following primary endpoint of Annualized relapse rate (ARR). Secondary Efficacy Objective The secondary efficacy objective for this study is to evaluate the efficacy of fenebrutinib treatment compared with teriflunomide on the basis of the following endpoints: Time to onset of composite 12-week confirmed disability progression (cCDP12) defined as the time from baseline to the first occurrence of a progression event according to at least one of the following three criteria; must be confirmed at a regularly scheduled visit that is at least 12 weeks after the initial disability progression: – An increase from baseline in Expanded Disability Status Scale (EDSS) score of 1.0 point in patients with a baseline EDSS score of 5.5 or an increase of 0.5 points in patients with a baseline EDSS score of 5.5 (confirmed disability progression [CDP]) – 20% increase in 12-week confirmed timed 25-foot walk test (T25FWT) – 20% increase from baseline in time to complete the 9-hole peg test (9-HPT) Time to onset of composite 24-week confirmed disability progression (cCDP24) Time to onset of 12-week confirmed disability progression (CDP12), defined as an increase from baseline in EDSS score of 1.0 point in patients with a baseline EDSS score of 5.5 or an increase 0.5 points in patients with a baseline EDSS score of 5.5 Time to onset of 24-week CDP (CDP24) Total number of gadolinium-enhancing lesions on T1-weighted MRI (T1Gd+) as detected by magnetic resonance imaging (MRI) Total number of new and/or enlarging T2-weighted lesions as detected by MRI Rate of percent change in total brain volume from Week 24 as assessed by MRI Change in patient-reported physical impacts of MS, as measured by the Multiple Sclerosis Impact Scale (29-Item), Version 2 (MSIS-29 v2) physical scale Time to onset of 12-week confirmed 4-point worsening in Symbol Digit Modalities Test (SDMT) score Change from baseline to Week 48 in the concentration of serum neurofilament light chain (NfL) The secondary endpoints above do not reflect order of statistical hierarchy. The statistical hierarchy for the secondary endpoints is further discussed in the protocol, and details can be found in the Statistical Analysis Plan (SAP). Exploratory Efficacy Objective The exploratory efficacy objective for this study is to evaluate the efficacy of fenebrutinib compared with teriflunomide based on, but not limited to, the following endpoints: Proportion of patients with worsening in SDMT by 4 points Time to onset of 20% increase in 12-week confirmed T25FWT Time to onset of 20% increase in 12-week confirmed 9-HPT Time to onset of 20% increase in 24-week confirmed T25FWT Time to onset of 20% increase in 24-week confirmed 9-HPT Proportion of patients with a meaningful deterioration from baseline in patient-reported psychological impacts of MS, as assessed by the MSIS-29 v2 psychological scale at Week 96 Total number of new T1-hypointense lesions (black holes) from baseline as detected by MRI Proportion of patients who are free of protocol-defined relapse at Week 96 and at the time of clinical cutoff of the primary analysis Proportion of patients with a meaningful deterioration from baseline in patient-reported physical impacts of MS, as assessed by the MSIS-29 v2 physical scale, at Week 96 Proportion of patients free of disability progression, as assessed by cCDP12, cCDP24, CDP12, and CDP24, at Week 96 and at the time of clinical cutoff of primary analysis Note: In this study, the screening MRI measurements are used as the baseline measurements Safety Objective The safety objective for this study is to evaluate the safety of fenebrutinib compared with teriflunomide on the basis of the following endpoints: The nature, frequency, timing, and severity of adverse events; serious adverse events; and adverse events leading to study treatment discontinuation or dose interruptions Change from baseline in targeted vital signs Change from baseline in targeted ECG parameters Change from baseline in clinical laboratory results Proportion of patients with suicidal ideation or behavior, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) Pharmacokinetic Objectives The PK objective for this study is to characterize the fenebrutinib PK profile on the basis of the following endpoint: Plasma concentration of fenebrutinib at specified timepoints Sparse PK samples will be collected in all patients. However, to better characterize fenebrutinib PK in patients with MS, more intensive PK samples will be collected in a small subset of patients who consent for further evaluation. The exploratory PK objectives for this study are as follows: To evaluate potential relationships between drug exposure and the efficacy and safety of fenebrutinib on the basis of the following endpoints: – Relationship between plasma concentrations of fenebrutinib and efficacy endpoints – Relationship between plasma concentrations of fenebrutinib and safety endpoints To evaluate potential relationships between selected covariates and exposure to fenebrutinib on the basis of the following endpoint: – Relationship between selected covariates and plasma concentrations of fenebrutinib BIOMARKER OBJECTIVE The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that are predictive of response to fenebrutinib (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with acquired resistance to fenebrutinib, are associated with susceptibility to developing adverse events or can lead to improved adverse event monitoring or investigation, can provide evidence of fenebrutinib activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the knowledge and understanding of disease biology and drug safety. Biomarker endpoints may include, but are not limited to, the following endpoints: Relationship between baseline biomarkers in blood (serum and/or plasma) and efficacy, PK, or other biomarker endpoints Relationship between change from baseline to post treatment sampling in blood biomarkers (serum and/or plasma) and efficacy, PK, or other biomarker endpoints Relationship between genetics (including, but not limited to human leukocyte antigen genotype) efficacy, PK, or other biomarker endpoints Exploratory biomarker analysis results may be reported separately from the GN41851 clinical study report. HEALTH STATUS UTILITY OBJECTIVE The exploratory health status utility objective for this study is to evaluate health status utility scores of patients treated with fenebrutinib on the basis of the following endpoints: Relationship between EuroQol 5 Dimension, 5 Level Questionnaire (EQ 5D 5L) index score and clinical measurements that may support pharmacoeconomic modeling Number of hospitalizations (e.g., collected since the last clinical visit) Number of emergency room visits
Laymans Summary:	Study GN41851 is a Phase III, randomized, multicenter, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of fenebrutinib compared with teriflunomide in adult patients with RRMS and active secondary progressive MS, collectively referred to as RMS. All eligible patients will be randomized 1:1 through an interactive voice or web-based response system (IxRS) to either one of two arms: Fenebrutinib treatment arm: fenebrutinib (200 mg by mouth [PO] BID) with teriflunomide-matching placebo Teriflunomide treatment arm: teriflunomide (14 mg PO QD) with fenebrutinib-matching placebo Approximately 736 patients will be enrolled and will be recruited globally. Patients who discontinue study treatment early or who discontinue from the study for any reason will not be replaced. This study will consist of the following phases: Screening phase Double-blind treatment (DBT) phase Post-DBTsafety follow-up (post-DBTSFU) phase Optional open-label extension (OLE) phase OLE safety follow-up (OLE-SFU) phase The study duration will vary for each patient as a result of the primary analysis being event driven. Randomization will be stratified according to the following criteria: Global Region (United States vs. non-United States) EDSS score (more than 4.0 vs. less than or equal to 4.0) Presence or absence of T1Gd+ lesions at screening Patient safety will be monitored by an iDMC both for the iDMC-ISA and at regular intervals throughout the DBT phase. Study GN41851 will enroll patients globally. Enrollment will be globally competitive. After completion of the global enrollment phase, additional patients may be enrolled in an extended China enrollment phase at sites in mainland China, Hong Kong, and Taiwan that are recognized by China’s National Medical Products Administration to ensure a total enrollment that is sufficient to support registration in China. Thus, the China subpopulation may include patients enrolled at sites in China during both the global enrollment phase and the China extension phase. Patients from the China extension phase will be randomized in a 1:1 ratio to the two treatment arms and follow the same schedule of activities as in the global study. Analyses based on the China extension phase will be reported separately from the global study. End of Study The end of this study is defined as the date when the last patient, last visit (LPLV) occurs in the OLE phase or the LPLV in the OLE-SFU phase, whichever occurs later. Length of Study The estimated duration of the DBT phase will be approximately 236 weeks or approximately 4.5 years (assuming last patient randomized after 140 weeks  96 weeks of DBT for the last patient into the study). The estimated maximum length of the study, from screening of the first patient to the end of the study, is expected to be approximately 340 weeks or approximately 6.5 years (assuming 140 weeks of recruitment + 96 weeks of DBT + 96 weeks in OLE+ 8 weeks of OLE SFU for the last patient into study). In addition, the Sponsor may decide to terminate the study at any time.
Abstract of Study:	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 and CSF BIOMARKER SUBSTUDY ASSOCIATED WITH A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP STUDY (GN41851) TO EVALUATE THE EFFICACY AND SAFETY OF FENEBRUTINIB COMPARED WITH TERIFLUNOMIDE IN ADULT PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS PROTOCOL NUMBER: GN41851 STUDY NAME: FENHANCE VERSION NUMBER: 4 and 2 respectively TEST COMPOUND(S): Fenebrutinib (RO7010939) Find attached (in the checklist section) the document titled: 9Dec20 Rationale for Fenebrutinib RMS Phase III Program that contains more details on the clinical trial rationale.