Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Relapsing Multiple Sclerosis (RMS) (FENhance 2)

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

A study to evaluate the efficacy and safety of fenebrutinib on disability progression and relapse rate in adult participants with RMS. Eligible participants will be randomized in a 1:1 ratio to receive either fenebrutinib or teriflunomide. At the end of the double-blind treatment (DBT) phase (after disclosure of the DBT results), the Sponsor will determine whether or not to initiate the open-label extension (OLE) phase of the study.

Study Overview

• Status: Active, not recruiting
• Conditions: Relapsing Multiple Sclerosis
• Intervention / Treatment: Drug: Fenebrutinib; Drug: Placebo; Drug: Teriflunomide

• Study Type: Interventional
• Enrollment (Actual): 751
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4021
    • Kepler Universitätskliniken GmbH - Med Campus III
• Brazil
  • São Paulo, Brazil
    • Jordy Sinapse Medicina LTDA ME
  • Federal District
    • Brasília, Federal District, Brazil, 70200-730
      • L2 Ip Instituto de Pesquisas Clinicas Ltda ME
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-221
      • Santa Casa de Misericordia
  • Paraná
    • Curitiba, Paraná, Brazil, 81210-310
      • Instituto de Neurologia de Curitiba
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90610-000
      • Hospital Sao Lucas - PUCRS
    • Porto Alegre, Rio Grande do Sul, Brazil, 90110-000
      • IMV Pesquisa Neurológica
    • Porto Alegre, Rio Grande do Sul, Brazil, 90430-001
      • Núcleo de Pesquisa do Rio Grande do Sul
  • Santa Catarina
    • Joinville, Santa Catarina, Brazil, 89202-190
      • Clinica Neurologica
  • São Paulo
    • Santo André, São Paulo, Brazil, 09090-790
      • Praxis Pesquisa Médica
    • São Bernardo do Campo, São Paulo, Brazil, 09715-090
      • CEMEC - Centro Multidisciplinar de Estudos Clínicos
    • São Paulo, São Paulo, Brazil, 01228-200
      • Centro de Pesquisas Clinicas
    • São Paulo, São Paulo, Brazil, 08270-070
      • Hospital Santa Marcelina
• Bulgaria
  • Pleven, Bulgaria, 5800
    • UMHAT Dr. Georgi Stranski
  • Sofia, Bulgaria, 1113
    • MHATNP Sveti Naum EAD
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z1
      • University of Alberta Hospital
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - General Campus
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • CIUSSS du Saguenay Lac-Saint-Jean, Chicoutimi Hospital
    • Montreal, Quebec, Canada, H3A 2B4
      • MUCH - Montreal Neurological Institute & Hospital
    • Québec, Quebec, Canada, G1J 1Z4
      • Chu De Quebec
• Denmark
  • Esbjerg, Denmark, 6700
    • Sydvestjysk Sygehus Esbjerg
  • Sønderborg, Denmark, 6400
    • Hjerne- og nervesygdomme, Ambulatorium, Skleroseklinikken
• France
  • Clermont-Ferrand, France, 63003
    • Hopital Gabriel Montpied CHU de Clermont-Ferrand
  • Nice, France, 06002
    • Hôpital Pasteur
  • Rouen, France, 76031
    • Hopital Charles Nicolle
  • Toulouse, France, 31059
    • CHU Toulouse - Hôpital Purpan
• Greece
  • Athens, Greece, 115 28
    • Hospital Eginition
  • Larissa, Greece, 411 10
    • University General Hospital of Larisa
  • Thessaloniki, Greece, 54636
    • AHEPA Univ. General Hospital of Thessaloniki
• Guatemala
  • Guatemala City, Guatemala, 01015
    • Nucare
• India
  • Chandigarh, India, 160012
    • Postgraduate Institute of Medical Education and Research
  • Gujarat
    • Ahmedabad, Gujarat, India, 380054
      • Zydus Hospital
  • Maharashtra
    • Mumbai, Maharashtra, India, 400012
      • Seth G.S Medical College K.E.M Hospital
    • Pune, Maharashtra, India, 411004
      • Deenanath Mangeshkar Hospital & Research Centre
    • Pune, Maharashtra, India, 411006
      • Sahyadri Superspeciality Hospital
  • National Capital Territory of Delhi
    • New Delhi, National Capital Territory of Delhi, India, 110017
      • Max Super Speciality Hospital
    • New Delhi, National Capital Territory of Delhi, India, 110060
      • Sir Gangaram Hospital
  • Punjab
    • Ludhiana, Punjab, India, 141008
      • Christian Medical College and Hospital
  • Tamil Nadu
    • Vadapalani, Tamil Nadu, India, 600026
      • SRM Institute of Medical Sciences
• Italy
  • Abruzzo
    • Chieti, Abruzzo, Italy, 66100
      • Universita? G. D'Annunzio
  • Apulia
    • Bari, Apulia, Italy, 70124
      • Azienda Ospedaliero-Universitaria Consorziale Pol. di Bari
  • Campania
    • Napoli, Campania, Italy, 80131
      • A. O. U. Federico II
  • Lazio
    • Rome, Lazio, Italy, 00168
      • Policlinico Universitario A. Gemelli
    • Rome, Lazio, Italy, 00152
      • Ospedale S.Camillo Forlanini
    • Rome, Lazio, Italy, 00178
      • NCL Institute Neuroscience
  • Liguria
    • Genoa, Liguria, Italy, 16132
      • Irccs A.O.U.San Martino Ist
  • Lombardy
    • Milan, Lombardy, Italy, 20133
      • Fond. Istituto Neurologico C.Besta
    • Montichiari, Lombardy, Italy, 25018
      • Ospedale Civile di Montichiari
    • Pavia, Lombardy, Italy, 27100
      • IRCCS Istituto Neurologico C. Mondino?Dip. Neurologia Neuroriabilitazione S.S. Sclerosi Multipla
  • Molise
    • Pozzilli, Molise, Italy, 86077
      • IRCCS Istituto Neurologico Neuromed
  • Sardinia
    • Cagliari, Sardinia, Italy, 09126
      • Ospedale Binaghi
  • Sicily
    • Palermo, Sicily, Italy, 90129
      • AOU Policlinico Giaccone
• Mexico
  • Chihuahua City, Mexico, 31203
    • Unidad de Investigacion en Salud
  • Mexico City, Mexico, 14050
    • Unidad de investigacion en salud (UIS)
  • Mexico CITY (federal District)
    • Mexico City, Mexico CITY (federal District), Mexico, 06700
      • Clinstile S.A de C.V.
    • Mexico City, Mexico CITY (federal District), Mexico, 03100
      • Mexico Centre for Clinical Research
    • México, Mexico CITY (federal District), Mexico, 03600
      • Grupo Medico Camino S.C.
• Poland
  • Bydgoszcz, Poland, 85-079
    • NZOZ Vitamed
  • Bydgoszcz, Poland, 85-796
    • Neurocentrum Bydgoszcz sp. z o.o
  • Gdansk, Poland, 80-803
    • COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika
  • Kielce, Poland, 25-726
    • RESMEDICA Spolka z o.o.
  • Krakow, Poland, 31-637
    • Malopolskie Centrum Diagnostyczne MEDICAL Sp. z o. o.
  • Krakow, Poland, 31-505
    • Centrum Neurologii Klinicznej
  • Lodz, Poland, 90-324
    • Centrum Neurologii Krzysztof Selmaj
  • Oświęcim, Poland, 32-600
    • Instytut Zdrowia Dr Boczarska-Jedynak Sp. z o.o. Sp. k.
  • Plewiska, Poland, 62-064
    • Neurologiczny Niepubliczny ZOZ Centrum Leczenia SM Osrodek Bada? Klinicznych
  • Poznan, Poland, 60-693
    • MedPolonia
  • Późna, Poland, 61-853
    • NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partn. Lek
  • Rybnik, Poland, 44-200
    • Wojewódzki Szpital Specjalistyczny Nr 3
  • Warsaw, Poland, 02-097
    • Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie
  • Wroc?aw, Poland, 51-685
    • Wro Medica
  • Zabrze, Poland, 41-800
    • IBISMED Wielospecjalistyczne Centrum Medyczne
• Russia
  • Krasnodar, Russia, 350086
    • Regional clinical hospital named after prof. S.V. Ochapovsky
  • Tomsk, Russia, 634009
    • Nebbiolo Center for Clinical Trials
  • Krasnoyarsk Krai
    • Krasnoyarsk, Krasnoyarsk Krai, Russia, 660022
      • Krasnoyarsk State Medical Academy
    • Krasnoyarsk, Krasnoyarsk Krai, Russia, 660037
      • FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency
  • Moscow Oblast
    • Moskva, Moscow Oblast, Russia, 117997
      • Federal center of brain research and neurotechnologies
  • Niznij Novgorod
    • Nizhny Novgorod, Niznij Novgorod, Russia, 603126
      • Regional Clinical Hospital N.A. Semashko
  • Sankt-Peterburg
    • Saint Petersburg, Sankt-Peterburg, Russia, 197110
      • National Center of Social Significant Disease
• South Korea
  • Daegu, South Korea, 41931
    • Keimyung University Dongsan Medical Center
  • Goyang-si, South Korea, 10408
    • National Cancer Center
  • Seoul, South Korea, 03080
    • Seoul National University Hospital
  • Seoul, South Korea, 06351
    • Samsung Medical Center
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06500
    • Gazi University Medical Faculty
  • Istanbul, Turkey (Türkiye), 34000
    • Bakirkoy State Mental Hospital
  • Istanbul, Turkey (Türkiye), 34785
    • Sancaktepe Training and Research Hospital
  • Istanbul, Turkey (Türkiye), 42131
    • Selcuk University Medical Faculty
  • Kocaeli, Turkey (Türkiye), 41380
    • Kocaeli University Hospital
  • Lzmir, Turkey (Türkiye), 35100
    • Ege Universitesi Tip Fakultesi
  • Mersin, Turkey (Türkiye), 33079
    • Mersin University Medical Faculty
  • Samsun, Turkey (Türkiye), 55139
    • Ondokuz Mayis University School of Medicine
  • Trabzon, Turkey (Türkiye), 61080
    • Karadeniz Tecnical Uni. Med. Fac.
  • Van, Turkey (Türkiye), 65080
    • Van Yuzuncu Yil University Hospital
  • Çankaya, Turkey (Türkiye), 06490
    • Baskent Universitesi Ankara Hastanesi
• United Kingdom
  • Salford, United Kingdom, M6 8HD
    • Salford Royal NHS Foundation Trust
• United States
  • Alabama
    • Cullman, Alabama, United States, 35058
      • North Central Neurology Associates
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Xenoscience
  • California
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute at Harbor-UCLA
  • Connecticut
    • Stamford, Connecticut, United States, 06905
      • KI Health Partners, LLC
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Indiana
    • Avon, Indiana, United States, 46123
      • American Health Network Institute, LLC
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Massachusetts
    • Foxborough, Massachusetts, United States, 02035
      • Neuro Institute of New England P.C.
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
  • Tennessee
    • Knoxville, Tennessee, United States, 37922
      • Hope Neurology
  • Virginia
    • Falls Church, Virginia, United States, 22043
      • Integrated Neurology Services PLLC
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3596
      • Medical College of Wisconsin, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Expanded Disability Status Scale (EDSS) score of 0 - 5.5 at screening
• A diagnosis of RMS in accordance with the revised 2017 McDonald Criteria
• Ability to complete the 9-hole Peg Test (9-HPT) for each hand in < 240 seconds
• Ability to perform the 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

OLE Inclusion Criteria:

• Completed the 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
• Participants randomized to the teriflunomide treatment arm during the DBT phase must undergo the accelerated teriflunomide elimination procedure (ATEP) prior to the first administration of open-label 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

Exclusion Criteria:

• Disease duration of > 10 years from the onset of symptoms and an EDSS score at screening < 2.0
• Female participants who are pregnant or breastfeeding, or intending to become pregnant
• Male participants who intend to father a child during the study
• A diagnosis of primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (SPMS)
• Any known or suspected active infection at screening, including but not limited to a positive screening tests for hepatitis B (HBV) and hepatitis C (HCV), an active or latent or inadequately treated infection with tuberculosis (TB), a confirmed or suspected progressive multifocal leukoencephalopathy (PML)
• History of cancer including hematologic malignancy and solid tumors within 10 years of screening
• Known presence of other neurological disorders, that could interfere with the diagnosis of MS or assessments of efficacy or safety during the study and clinically significant cardiovascular, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic or gastrointestinal (GI) disease
• Rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption
• Hypoproteinemia
• Acute liver disease
• Chronic liver disease unless considered stable for > 6 months
• Presence of cirrhosis (Child-Pugh Class A, B, or C) or Gilbert's syndrome
• Participants with significantly impaired bone marrow function or significant anemia, leukopenia, neutropenia or thrombocytopenia
• Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
• History of alcohol or other drug abuse within 12 months prior to screening
• History of or currently active primary or secondary (non-drug-related) immunodeficiency, including known history of human immunodeficiency virus (HIV) infection
• Inability to complete an MRI scan
• Adrenocorticotropic hormone or systemic corticosteroid therapy within 4 weeks prior to screening (inhaled and topical corticosteroids are allowed)
• Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
• Any previous treatment with immunomodulatory or immunosuppressive medication without an appropriate washout period

OLE Exclusion Criteria:

• Chronic liver disease unless considered stable for > 6 months
• Acute liver disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fenebrutinib; Participants will receive oral (PO) fenebrutinib, with teriflunomide-matching placebo.	Drug: Fenebrutinib; Participants will receive fenebrutinib.; Drug: Placebo; Participants will receive teriflunomide-matching placebo or fenebrutinib-matching placebo.
Active Comparator: Teriflunomide; Participants will receive PO teriflunomide, with fenebrutinib-matching placebo in a blinded fashion.	Drug: Placebo; Participants will receive teriflunomide-matching placebo or fenebrutinib-matching placebo.; Drug: Teriflunomide; Participants will receive teriflunomide.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Annualized Relapse Rate (ARR)	Minimum of 96 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Onset of Composite 12-week Confirmed Disability Progression (cCDP12)		Minimum of 96 weeks
Time to Onset of Composite 24-week Confirmed Disability Progression (cCDP24)		Minimum of 96 weeks
Time to Onset of 12-week Confirmed Disability Progression (CDP12)		Minimum of 96 weeks
Time to Onset of 24-week Confirmed Disability Progression (CDP24)		Minimum of 96 weeks
Plasma Concentrations of Fenebrutinib at Specified Timepoints		Up to 4.5 years
Time to Onset of Composite 12-week Confirmed Progression Independent of Relapse Activity (cPIRA12)		Minimum of 96 weeks
Total Number of T1 Gadolinium-enhancing (Gd+) Lesions, New and/or Enlarging T2-weighted Lesions, as Detected by Magnetic Resonance Imaging (MRI)		Baseline, Weeks 12, 24, 48 and 96
Percentage Change in Total Brain Volume From Week 24, as Assessed by MRI		From Week 24 to Week 96
Change in Participant-reported Physical Impacts of Multiple Sclerosis (MS), Measured by the Multiple Sclerosis, Impact Scale (29-Item), Version 2 (MSIS-29 v2) Physical Scale	The MSIS-29 v2 is a 29-item participant-reported measure of the physical and psychological impacts of MS. Participants are asked to rate how much their functioning and well-being have been impacted over the past 14 days on a 4-point scale, ranging 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 and 96
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 a brief, easy-to-administer test, involving 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 the 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 96 weeks
Change From Baseline to Week 48 in the Concentration of Blood Neurofilament Light Chain (NfL)		Up to 48 weeks
Percentage of Participants With Adverse Events (AEs)		Up to 4.5 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2021
• Primary Completion (Actual): September 5, 2025
• Study Completion (Estimated): July 9, 2027

Study Registration Dates

• First Submitted: October 8, 2020
• First Submitted That Met QC Criteria: October 8, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis; Substandard Drugs; Pharmaceutical Preparations; teriflunomide; fenebrutinib
• Other Study ID Numbers: GN42272; 2020-001168-28 (EudraCT Number); 2022-502618-95-00 (Ctis: EU Trial Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No