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 1:1 to either fenebrutinib or teriflunomide. Open-Label Extension (OLE) phase is contingent on a positive benefit-risk result in the Primary Analysis 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; Neurologie & Psychiatrie
  • Wien, Austria, 1090
    • Medizinische Universität Wien; Univ.Klinik fuer Neurologie
• Brazil
  • DF
    • Brasilia, DF, Brazil, 70200-730
      • L2 Ip Instituto de Pesquisas Clinicas Ltda ME; Centro Medico Hospitalar
  • MG
    • Belo Horizonte, MG, Brazil, 30150-221
      • Santa Casa de Misericordia; de Belo Horizonte
  • PR
    • Curitiba, PR, Brazil, 81210-310
      • Instituto de Neurologia de Curitiba
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
      • Hospital Sao Lucas - PUCRS
    • Porto Alegre, RS, Brazil, 90110-000
      • IMV Pesquisa Neurológica
    • Porto Alegre, RS, Brazil, 90430-001
      • Núcleo de Pesquisa do Rio Grande do Sul
  • SC
    • Joinville, SC, Brazil, 89202-190
      • Clinica Neurologica; Neurocirurgica de Joinville
  • SP
    • Santo Andre, SP, Brazil, 09090-790
      • Praxis Pesquisa Medica
    • Sao Bernardo Do Campo, SP, Brazil, 09715-090
      • CEMEC - Centro Multidisciplinar de Estudos Clínicos
    • Sao Paulo, SP, Brazil, 01228-200
      • Centro de Pesquisas Clinicas; CPCLIN
    • Sao Paulo, SP, Brazil, 04515-000
      • Jordy Sinapse Medicina LTDA ME
    • Sao Paulo, SP, Brazil, 08270-070
      • Hospital Santa Marcelina; AME - Ambulatório de Especialidades Médicas
• Bulgaria
  • Pleven, Bulgaria, 5800
    • UMHAT Dr. Georgi Stranski; 2nd Neurology Clinic, Occupational Diseases
  • 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; Department of Neurology - Multiple Sclerosis
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • CIUSSS du Saguenay Lac-Saint-Jean, Chicoutimi Hospital
    • Greenfield Park, Quebec, Canada, J4V 2J2
      • Recherche Sepmus Inc.
    • Montreal, Quebec, Canada, H3A 2B4
      • MUCH - Montreal Neurological Institute & Hospital
    • Quebec City, Quebec, Canada, G1J 1Z4
      • CHU de Québec
• Denmark
  • Aabenraa, Denmark, 6200
    • Hjerne- og nervesygdomme, Ambulatorium, Skleroseklinikken
  • Esbjerg, Denmark, 6700
    • Sydvestjysk Sygehus Esbjerg; Neurologisk Afd., Skleroseklinikken
• France
  • Clermont-Ferrand, France, 63003
    • Hopital Gabriel Montpied CHU de Clermont-Ferrand; Service de Neurologie B
  • Nice, France, 06002
    • Hôpital Pasteur; Service de Neurologie
  • Rouen, France, 76031
    • Hôpital Charles Nicolle; Service de Neurologie
  • Toulouse, France, 31059
    • CHU toulouse - Hôpital Purpan; Departement de Neurologie
• Greece
  • Athens, Greece, 115 28
    • Hospital Eginition; First Department of Neurology
  • Larisa, Greece, 411 10
    • University General Hospital of Larisa; Neurology Clinic
  • Thessaloniki, Greece, 546 36
    • AHEPA Univ. General Hospital of Thessaloniki; B' Neurology Dept.
  • Ιωαννινα, Greece, 455 00
    • University General Hospital of Ioannina; Neurology Clinic
• Guatemala
  • Ciudad Guatemala, Guatemala, 01015
    • Nucare
• India
  • Chandigarh, India, 160012
    • Postgraduate Institute of Medical Education and Research
  • Delhi
    • NEW Delhi Delhi, Delhi, India, 110060
      • Sir Gangaram Hospital
    • New Delhi, Delhi, India, 110017
      • Max Super Speciality Hospital
  • Gujarat
    • Ahmadabad CITY, Gujarat, India, 380054
      • Zydus Hospital; Department of Neuro Sciences
  • Maharashtra
    • Mumbai, Maharashtra, India, 400012
      • Seth G.S Medical College K.E.M Hospital
    • Pune, Maharashtra, India, 411004
      • Deenanath Mangeshkar Hospital & Research Centre
    • Pune City, Maharashtra, India, 411006
      • Sahyadri Superspeciality 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; Dipartimento di Neuroscienze, Imaging e Scienze Cliniche
  • Campania
    • Napoli, Campania, Italy, 80131
      • A. O. U. Federico II; Dip Neuroscienze, Scienze Riproduttive ed Odontostomatologiche
  • Lazio
    • Roma, Lazio, Italy, 00178
      • NCL Institute Neuroscience
    • Roma, Lazio, Italy, 00168
      • Policlinico Universitario A. Gemelli; UOC Neurologia - Centro Sclerosi Multipla
    • Roma, Lazio, Italy, 00152
      • Ospedale S.Camillo Forlanini; UOSD Day Hospital Neurologico e Neurochirurgico
  • Liguria
    • Genova, Liguria, Italy, 16132
      • Irccs A.O.U.San Martino Ist; Dinogmi
  • Lombardia
    • Milano, Lombardia, Italy, 20133
      • Fond. Istituto Neurologico C.Besta; UO Neurologia IV - Neuroimmunologia Malattie Neuromuscolari
    • Montichiari, Lombardia, Italy, 25018
      • Ospedale Civile di Montichiari; Centro Sclerosi Multipla
    • Pavia, Lombardia, Italy, 27100
      • IRCCS Istituto Neurologico C. Mondino?Dip. Neurologia Neuroriabilitazione S.S. Sclerosi Multipla
  • Molise
    • Pozzilli, Molise, Italy, 86077
      • IRCCS Istituto Neurologico Neuromed; Centro per lo Studio e la Cura della Sclerosi Multipla
  • Puglia
    • Bari, Puglia, Italy, 70124
      • Azienda Ospedaliero-Universitaria Consorziale Pol. di Bari; Neuroscienze e Organi di Senso
  • Sardegna
    • Cagliari, Sardegna, Italy, 09126
      • Ospedale Binaghi; Centro Sclerosi Multipla
  • Sicilia
    • Palermo, Sicilia, Italy, 90129
      • AOU Policlinico Giaccone; UOC Neurologia e Neurofisiopatologia-Amb Sclerosi Multipla
• Korea, Republic of
  • Daegu, Korea, Republic of, 41931
    • Keimyung University Dongsan Medical Center
  • Goyang-si, Korea, Republic of, 10408
    • National Cancer Center
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
• Mexico
  • Chihuahua, Mexico, 31203
    • Unidad de Investigación en Salud; Psiquiatria
  • Ciudad de México, Mexico, 14050
    • Unidad de investigacion en salud (UIS); Neurociencias
  • Mexico CITY (federal District)
    • Ciudad de México, Mexico CITY (federal District), Mexico, 03100
      • Mexico Centre for Clinical Research
    • Ciudad de México, Mexico CITY (federal District), Mexico, 03600
      • Grupo Médico Camino S.C.
    • Mexico City, Mexico CITY (federal District), Mexico, 06700
      • Clinstile S.A de C.V.
• 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; Oddzia? Neurologiczny
  • 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
  • Oswiecim, 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
  • Pozna?, Poland, 61-853
    • NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partn. Lek
  • Poznan, Poland, 60-693
    • MedPolonia
  • Rybnik, Poland, 44-200
    • Wojewódzki Szpital Specjalistyczny Nr 3
  • Warszawa, 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
• Russian Federation
  • Krasnodar, Russian Federation, 350086
    • Regional clinical hospital named after prof. S.V. Ochapovsky
  • Novosibirsk, Russian Federation, 630087
    • State Novosibirsk Regional Clinical Hospital
  • Tomsk, Russian Federation, 634009
    • Nebbiolo Center for Clinical Trials
  • Krasnojarsk
    • Krasnoyarsk, Krasnojarsk, Russian Federation, 660037
      • FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency
    • Krasnoyarsk, Krasnojarsk, Russian Federation, 660049
      • Krasnoyarsk State Medical Academy
  • Leningrad
    • Sankt-peterburg, Leningrad, Russian Federation, 197110
      • National Center of Social Significant Disease
  • Moskovskaja Oblast
    • Moskva, Moskovskaja Oblast, Russian Federation, 117997
      • Federal center of brain research and neurotechnologies
  • Niznij Novgorod
    • Nizhny Novgorod, Niznij Novgorod, Russian Federation, 603126
      • Regional Clinical Hospital N.A. Semashko; Neurology
• Turkey
  • Ankara, Turkey, 06100
    • Hacettepe University Medical Faculty; Neurology
  • Ankara, Turkey, 06500
    • Gazi University Medical Faculty; Departmant of Norology
  • Istanbul, Turkey, 34098
    • Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi; Noroloji Anabilim Dali
  • Istanbul, Turkey, 34000
    • Bakirkoy State Mental Hospital
  • Istanbul, Turkey, 42131
    • Selcuk University Medical Faculty; Norology department
  • Istanbul, Turkey, 34785
    • Sancaktepe Training and Research Hospital; Neurology
  • Kocaeli, Turkey, 41380
    • Kocaeli University Hospital; Department of Neurology
  • Lzmir, Turkey, 35100
    • Ege Universitesi Tip Fakultesi
  • Mersin, Turkey, 33079
    • Mersin University Medical Faculty; Neurology
  • Samsun, Turkey, 55139
    • Ondokuz Mayis University School of Medicine; Neurology
  • Trabzon, Turkey, 61080
    • Karadeniz Tecnical Uni. Med. Fac.; Neurology
  • Van, Turkey, 65080
    • Van Yuzuncu Yil University Hospital; Neurology
  • Çankaya, Turkey, 06490
    • Baskent Universitesi Ankara Hastanesi; Noroloji Bolumu
• United Kingdom
  • Salford, United Kingdom, M6 8HD
    • Salford Royal NHS Foundation Trust
  • Winchester, United Kingdom, SO21 1HU
    • Recognition Health
• United States
  • Alabama
    • Cullman, Alabama, United States, 35058
      • North Central Neurology Associates
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Xenoscience
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center; Stanford Neuroscience Health Center
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute at Harbor-UCLA
  • Connecticut
    • Stamford, Connecticut, United States, 06905
      • KI Health Partners, LLC; New England Institute for Clinical Research
  • District of Columbia
    • Washington, 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
    • Foxboro, Massachusetts, United States, 02035
      • Neuro Institute of New England P.C.; Research
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University; Department of Neurology
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati; Department of Neurology
  • 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.

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 MS (PPMS) or non-active secondary progressive MS (SPMS).
• Any known or suspected active infection at screening, including but not limited to a positive screening tests for Hepatitis B and C, 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 disease.
• Rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
• Hypoproteinemia.
• 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 Inclusion Criteria:

• Completed the Double-Blind Treatment (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.

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 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 oral 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
Change from Baseline to Week 48 in the Concentration of Serum Neurofilament Light chain (NfL)		Up to 48 weeks
Percentage of Participants with Adverse Events (AEs)		Up to 4.5 years
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
Percentage Change in Total Brain Volume from Week 24 as Assessed by MRI		From Week 24 to Week 96
Plasma Concentrations of Fenebrutinib at Specified Timepoints		Up to 4.5 years
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
Change in Participant-Reported Physical Impacts of Multiple Sclerosis (MS) Measured by the Multiple Sclerosis, 29-Item [MSIS-29] Physical Scale	The MSIS-29, version 2 is a 29-item patient-reported measure of the physical and psychological impacts of MS. Participants are asked to rate how much their functioning and well-being has been impacted over the past 14 days on a 4-point scale, 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 brief, is easy to administer test, and involves 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 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

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 (Estimated): October 2, 2025
• Study Completion (Estimated): November 27, 2025

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): April 29, 2024
• Last Update Submitted That Met QC Criteria: April 26, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Teriflunomide
• Other Study ID Numbers: GN42272; 2020-001168-28 (EudraCT Number); 2022-502618-95-00 (Registry Identifier: EU Trial Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

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