Clinical trial NCT04544449: A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Participants With Primary Progressive Multiple Sclerosis
Official title: A Phase III Multicenter, Randomized, Double-Blind, Double-Dummy, Parallel-Group Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Patients With Primary Progressive Multiple Sclerosis.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Sclerosis, Primary Progressive
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2020-09-10
Enrollment: 985
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A study to evaluate the efficacy and safety of fenebrutinib on disability progression in adult participants with Primary Progressive Multiple Sclerosis (PPMS). All eligible participants will be randomized 1:1 to either daily oral fenebrutinib (and placebo) or intravenous (IV) ocrelizumab (and placebo) in a blinded fashion through an interactive voice or web-based response system (IxRS). 985 participants were enrolled and recruited globally. Participants who discontinue study medication early or discontinue from the study will not be replaced. The Open-Label Extension (OLE) phase is contingent on a positive benefit-risk result in the Primary Analysis of the study.


Eligibility criteria: Inclusion Criteria:

* For sites in Germany and Italy only, enrollment is restricted to participants aged 46-65 years
* A diagnosis of PPMS in accordance to the revised 2017 McDonald Criteria (Thompson et al. 2018).
* Disability progression in the 12 months prior to screening.
* Expanded Disability Status Scale (EDSS) score from 3.0 to 6.5 inclusive at screening.
* Pyramidal functional subscore \>=2 at screening.
* For participants currently receiving proton pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), symptomatic treatment for MS (e.g. fampridine, cannabis) and/or physiotherapy: treatment at a stable dose during the screening period prior to the initiation of study treatment and plans to remain at a stable dose for the duration of study treatment.
* Neurologically stable for at least 30 days prior to randomization and baseline assessments.
* Ability to complete the 9-Hole Peg Test (9-HPT) for each hand in \<240 seconds.
* Ability to perform 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 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.
* 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:

* For participants enrolled in Germany and in Italy only: Presence of gadolinium-enhancing lesions on T1-weighted MRI (T1Gd +) lesion on the screening MRI
* Any known or suspected active infection (excluding onychomycosis) at screening, including but not limited to a positive screening test for Hepatitis B and C, an active or latent or inadequately treated infection with tuberculosis (TB), a confirmed or suspected progressive multifocal leukoencephalopathy (PML).
* Participants with a previous history of a serious Infusion-Related Reaction (IRR) (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade \>= 4) and/or any hypersensitivity reaction to ocrelizumab.
* History of cancer including hematologic malignancy and solid tumors within 10 years of screening. Exceptions: Basal/squamous cell carcinoma of skin cured by excision. In situ carcinoma of the cervix successfully treated by curative therapy \>1 year prior to screening.
* Known presence of other neurological disorders, that could interfere with the diagnosis of MS or assessments of efficacy or safety during the study, clinically significant cardiovascular, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic or gastrointestinal disease.
* Presence of cirrhosis (Child-Pugh Class A, B, or C)
* Chronic liver disease unless considered stable for \>6 months
* Acute liver disease
* Any concomitant disease that may require chronic treatment with systemic corticosteroids, immunosuppressants or specific medication that could impact the primary evaluation of the study.
* History of alcohol or other drug abuse within 12 months prior to screening.
* Female participants who are pregnant or breastfeeding or intending to become pregnant during the study or 6 or 12 months (as applicable from the local label for ocrelizumab) after final dose of study drug.
* Male participants intending to father a child during the study or for 28 days after final dose of study drug.
* Lack of peripheral venous access.
* Any previous treatment with immunomodulatory or immunosuppressive medication without an appropriate washout period.
* Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization.
* Immunocompromised state, history of primary or secondary (non-drug related) immunodeficiency, or history of transplantation or antirejection therapy
* Known bleeding diathesis, anemia, or history of hospitalization or transfusion for gastrointestinal (GI) bleed
* Any previous treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide

OLE Exclusion Criteria:

* Chronic liver disease unless considered stable for \> 6 months
* Acute liver disease

Primary outcomes:
measure: Time to Onset of Composite 12-week Confirmed Disability Progression (cCDP12)
timeFrame: Minimum of 120 weeks
Secondary outcomes:
measure: Time to Onset of Composite 24-week CDP (cCDP24)
timeFrame: Minimum of 120 weeks
measure: Time to Onset of 12-week CDP (CDP12)
timeFrame: Minimum of 120 weeks
measure: Time to Onset of 24-week CDP (CDP24)
timeFrame: Minimum of 120 weeks
measure: Percentage Change in Total Brain Volume Assessed by Magnetic Resonance Imaging (MRI)
timeFrame: From Week 24 to Week 120
measure: Change from Baseline in Participant-Reported Physical Impacts of Multiple Sclerosis (MS) Measured by the Multiple Sclerosis Impact Scale, 29-Item [MSIS-29] Physical Scale
timeFrame: Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120
measure: Time to Onset of 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) Score
timeFrame: Minimum of 120 weeks
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Up to 4.7 years
measure: Plasma Concentrations of Fenebrutinib at Specified Timepoints
timeFrame: Up to 4.7 years
measure: Percent Change from Screening in Blood Neurofilament Light Chain (NfL) Levels
timeFrame: Up to Week 120
Other outcomes:
Locations:
city: Homewood
country: United States
facility: Alabama Neurology Associates
state: Alabama
city: Berkeley
country: United States
facility: Sutter East Bay Medical Foundation
state: California
city: Fullerton
country: United States
facility: Fullerton Neurology and Headache Center
state: California
city: Sunnyvale
country: United States
facility: Palo Alto Medical Foundation Research Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Fairfield
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Maitland
country: United States
facility: Neurology Associates PA
state: Florida
city: Orlando
country: United States
facility: Neurological Services of Orlando
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Indianapolis
country: United States
facility: Josephson Wallack Munshower Neurology PC
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University School Of Medicine
state: Maryland
city: Wellesley
country: United States
facility: Dragonfly Research, LLC
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Golden Valley
country: United States
facility: Minneapolis Clinic of Neurology
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo
state: Nevada
city: Hackensack
country: United States
facility: Hackensack U Med Ctr
state: New Jersey
city: Livingston
country: United States
facility: Barnabas Health Ambulatory Care Center
state: New Jersey
city: Neptune
country: United States
facility: Jersey Shore University Medical Centre
state: New Jersey
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: Teaneck
country: United States
facility: Holy Name Hospital
state: New Jersey
city: Amherst
country: United States
facility: Dent Neurological Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: Atrium Health Neurosciences Institute ? Charlotte
state: North Carolina
city: Raleigh
country: United States
facility: Raleigh Neurology Associates
state: North Carolina
city: Centerville
country: United States
facility: Miami Valley Hospital South
state: Ohio
city: Cincinnati
country: United States
facility: UC Health, LLC.
state: Ohio
city: Columbus
country: United States
facility: OhioHealth Riverside Methodist Hospital
state: Ohio
city: Portland
country: United States
facility: Providence Brain and Spine Institute
state: Oregon
city: Cordova
country: United States
facility: Neurology Clinic PC
state: Tennessee
city: Knoxville
country: United States
facility: Hope Neurology
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Uni of Texas Health Science Center At Houston
state: Texas
city: Sherman
country: United States
facility: Texas Institute for Neurological Disorders
state: Texas
city: Kirkland
country: United States
facility: Evergreen MS Center
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin, Inc.
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Centro de Especialidades Neurológicas y Rehabilitación - CENyR
city: Buenos Aires
country: Argentina
facility: Focus CECIC
city: Cordoba
country: Argentina
facility: Instituto Reumatológico Strusberg
city: Rosario
country: Argentina
facility: Fundacion Rosarina de Neurorehabilitacion
city: San Miguel
country: Argentina
facility: Centro de Investigaciones Médicas Tucuman
city: Camperdown
country: Australia
facility: Brain and Mind Research Institute
state: New South Wales
city: New Lambton
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Linz
country: Austria
facility: Kepler Universitätsklinikum GmbH - Neuromed Campus
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia
state: Minas Gerais
city: Curitiba
country: Brazil
facility: Instituto de Neurologia de Curitiba
state: Paraná
city: Porto Alegre
country: Brazil
facility: IMV Pesquisa Neurológica
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Núcleo de Pesquisa do Rio Grande do Sul
state: Rio Grande Do Sul
city: Joinville
country: Brazil
facility: Clinica Neurologica
state: Santa Catarina
city: Sao Paulo
country: Brazil
facility: Centro de Pesquisas Clinicas
state: São Paulo
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitario Gaffree e Guinle
city: Pleven
country: Bulgaria
facility: UMHAT Dr. Georgi Stranski
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment of Neurology and Psychiatry Sv. Naum EAD
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Burnaby
country: Canada
facility: Fraser Health Authority - Fraser Health Multiple Sclerosis
state: British Columbia
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre Uni Campus
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Gatineau
country: Canada
facility: Clinique NeuroOutaouais
state: Quebec
city: Greenfield Park
country: Canada
facility: Recherche Sepmus Inc.
state: Quebec
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Santiago
country: Chile
facility: CeCim Biocinetic
city: Vitacura
country: Chile
facility: Clinica Alemana
city: Bogota
country: Colombia
facility: Organizacion Sanitas Internacional
city: Cali
country: Colombia
facility: Fundacion Clinica Valle del Lili
city: Medellin
country: Colombia
facility: Instituto Neurologico de Colombia INDEC
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital
city: Glostrup
country: Denmark
facility: Rigshospitalet
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin
city: Bron
country: France
facility: Hopital Pierre Wertheimer
city: Montpellier
country: France
facility: CHRU de Montpellier, Hopital Gui de Chauliac
city: Nantes
country: France
facility: Hopital Guillaume Et Rene Laennec
city: Nice
country: France
facility: Hôpital Pasteur
city: Strasbourg
country: France
facility: Hopitaux Universitaires de Strasbourg
city: Berlin
country: Germany
facility: Charite - Universitatsmedizin Berlin
city: Böblingen
country: Germany
facility: Studienzentrum Dr. Bischof GmbH
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg, Klinik für Neurologie und Neurophysiologie
city: München
country: Germany
facility: Klinikum rechts der Isar der TU Muenchen
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Wiesbaden
country: Germany
facility: Deutsche Klinik für Diagnostik
city: Athens
country: Greece
facility: Hospital Eginition
city: Athens
country: Greece
facility: 401 Military Hospital of Athens
city: Thessaloniki
country: Greece
facility: AHEPA Univ. General Hospital of Thessaloniki
city: Budapest
country: Hungary
facility: Clinexpert Kft.
city: Budapest
country: Hungary
facility: S-Medicon Egeszsegugyi Szolgaltato Kft.
city: Budapest
country: Hungary
facility: Budapesti Jahn Ferenc Dél-pesti Kórház és Rendel?intézet
city: Eger
country: Hungary
facility: Markhot Ferenc Oktatokorhaz és Rendelointezet
city: Kistarcsa
country: Hungary
facility: Pest Megyei Flor Ferenc Korhaz
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Ramat-Gan
country: Israel
facility: The Chaim Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Napoli
country: Italy
facility: AOU Seconda Università degli Studi
state: Campania
city: Parma
country: Italy
facility: A.O.U. di Parma
state: Emilia-Romagna
city: Roma
country: Italy
facility: Policlinico Tor Vergata Dip. Neuroscienze-Clinica Neurologica-UOSD Sclerosi Multipla
state: Lazio
city: Genova
country: Italy
facility: Irccs A.O.U.San Martino Ist
state: Liguria
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
state: Lombardia
city: Montichiari
country: Italy
facility: Ospedale Civile di Montichiari
state: Lombardia
city: Pozzilli
country: Italy
facility: IRCCS Istituto Neurologico Neuromed
state: Molise
city: Palermo
country: Italy
facility: A.R.N.A.S. Civico Di Cristina Benfratelli
state: Sicilia
city: Ciudad de México
country: Mexico
facility: Mexico Centre for Clinical Research
state: Mexico CITY (federal District)
city: Ciudad de México
country: Mexico
facility: Hospital Juarez de Mexico
state: Mexico CITY (federal District)
city: Mexico City
country: Mexico
facility: Clinstile S.A de C.V.
state: Mexico CITY (federal District)
city: Mexico
country: Mexico
facility: Grupo Médico Camino S.C.
state: Mexico CITY (federal District)
city: Tialnepantla
country: Mexico
facility: Clinical Research Institute
city: Skopje
country: North Macedonia
facility: University Clinic of Neurology
city: Bellavista
country: Peru
facility: Hospital IV Alberto Sabogal Sologuren
city: Lima
country: Peru
facility: Clinica Internacional
city: Lima
country: Peru
facility: Instituto Nacional de Ciencias Neurológicas - Hospital Mogrovejo
city: Bydgoszcz
country: Poland
facility: Neurocentrum Bydgoszcz sp. z o.o
city: Katowice
country: Poland
facility: Care Clinic
city: Katowice
country: Poland
facility: NEURO-CARE Sp. z o.o. Sp. Komandytowa
city: Lodz
country: Poland
facility: Centrum Neurologii Krzysztof Selmaj
city: Pozna?
country: Poland
facility: Med Polonia
city: Rzeszow
country: Poland
facility: Centrum Medyczne "MEDYK"
city: Rzeszów
country: Poland
facility: Nmedis sp. z o.o.
city: Warszawa
country: Poland
facility: Centrum Medyczne NeuroProtect
city: Wroc?aw
country: Poland
facility: Wro Medica
city: Zabrze
country: Poland
facility: SPSK nr 1
city: Braga
country: Portugal
facility: Hospital de Braga
city: Lisboa
country: Portugal
facility: Hospital Santo Antonio dos Capuchos
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria
city: Porto
country: Portugal
facility: Hospital Geral de Santo Antonio
city: Porto
country: Portugal
facility: Hospital de Sao Joao
city: Guaynabo
country: Puerto Rico
facility: San Juan MS Center
city: Krasnoyarsk
country: Russian Federation
facility: Krasnoyarsk State Medical Academy
state: Krasnojarsk
city: Krasnoyarsk
country: Russian Federation
facility: FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency
state: Krasnojarsk
city: Sankt-peterburg
country: Russian Federation
facility: National Center of Social Significant Disease
state: Leningrad
city: Moskva
country: Russian Federation
facility: Federal center of brain research and neurotechnologies
state: Moskovskaja Oblast
city: Moskva
country: Russian Federation
facility: City Clinical Hospital #24
state: Moskovskaja Oblast
city: St. Petersburg
country: Russian Federation
facility: City Hospital #40 of Resort Administrative District
state: Sankt Petersburg
city: Yekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Clinical Hospital 1
state: Sverdlovsk
city: Kazan
country: Russian Federation
facility: Vertebronevrologiya LLC
state: Tatarstan
city: Tyumen
country: Russian Federation
facility: Regional Multiple Sclerosis Centre b/o CC ECM Neftyanik
state: Tjumen
city: Kirov
country: Russian Federation
facility: Center of Cardiology and Neurology
city: Novosibirsk
country: Russian Federation
facility: State Novosibirsk Regional Clinical Hospital
city: Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña (CHUAC)
state: LA Coruna
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
state: Lerida
city: Pozuelo de Alarcon
country: Spain
facility: Hospital Quiron de Madrid
state: Madrid
city: Vigo
country: Spain
facility: Hospital Alvaro Cunqueiro
state: Pontevedra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Cadiz
country: Spain
facility: Hospital Puerta del Mar
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga ? Hospital General
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bern
country: Switzerland
facility: Inselspital Bern Medizin Neurologie
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Istanbul
country: Turkey
facility: Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi
city: Istanbul
country: Turkey
facility: Sancaktepe Training and Research Hospital
city: Istanbul
country: Turkey
facility: Selcuk University Medical Faculty
city: Kocaeli
country: Turkey
facility: Kocaeli University Hospital
city: Samsun
country: Turkey
facility: Ondokuz Mayis Univ. Med. Fac.
city: Trabzon
country: Turkey
facility: Karadeniz Tecnical Uni. Med. Fac.
city: Van
country: Turkey
facility: Van Yuzuncu Yil University Hospital
city: Çankaya
country: Turkey
facility: Baskent Universitesi Ankara Hastanesi
city: Chernivtsi
country: Ukraine
facility: CNPE City Clinical Hospital #3 of Chernivtsi City Council
state: Chernihiv Governorate
city: Zhytomir
country: Ukraine
facility: Medical Centre of PE First Private Clinic
state: Crimean Regional Governmenta
city: Kharkiv
country: Ukraine
facility: Ams of Ukraine
state: Kharkiv Governorate
city: Zaporizhzhia
country: Ukraine
facility: Municipal Institution Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council
state: Kharkiv Governorate
city: Kyiv
country: Ukraine
facility: MEDBUD
state: KIEV Governorate
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospital
state: KIEV Governorate
city: Vinnytsia
country: Ukraine
facility: Salutem Medical Center
state: KIEV Governorate
city: Dnipro
country: Ukraine
facility: Separated structural unit ?University hospital? of Dnipro State Medical University
state: Tavria Okruha
city: Lviv
country: Ukraine
facility: MNE Lviv Territorial Medical Association Clinical Hospital for Palliative Care
state: Volhynian Governorate
city: Ivano-Frankivsk
country: Ukraine
facility: Regional Clinical Hospital
city: Lutsk
country: Ukraine
facility: Volyn Regional Clinical Hospital
city: Odesa
country: Ukraine
facility: Odesa Regional Clinical Hospital
city: Vinnytsia
country: Ukraine
facility: Medical Clinical Research Center of Medical Center LLC Health Clinic
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Swansea
country: United Kingdom
facility: Morriston Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: