A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Participants With Primary Progressive Multiple Sclerosis

Phase 3

Active, not recruiting

• Conditions: Multiple Sclerosis, Primary Progressive
• Interventions: Drug: Fenebrutinib; Drug: Ocrelizumab; Drug: Placebo matched to ocrelizumab; Drug: Placebo matched to fenebrutinib

• Registration Number: NCT04544449
• Lead Sponsor: Hoffmann-La Roche

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). Approximately 946 participants will be enrolled and will be 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-09-04
• Study First Submitted QC: 2020-09-04
• Study First Posted: 2020-09-10
• Study Start: 2020-10-26
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-28
• Last Update Posted: 2024-10-29
• Primary Completion: 2026-01-16
• Study Completion: 2026-12-18

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 985

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.

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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)
• 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 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fenebrutinib	Placebo matched to ocrelizumab	Participants will receive oral fenebrutinib and intravenous (IV) ocrelizumab-matching placebo.
Ocrelizumab	Placebo matched to fenebrutinib	Participants will receive intravenous (IV) ocrelizumab and oral fenebrutinib-matching placebo.
Fenebrutinib	Fenebrutinib	Participants will receive oral fenebrutinib and intravenous (IV) ocrelizumab-matching placebo.
Ocrelizumab	Ocrelizumab	Participants will receive intravenous (IV) ocrelizumab and oral fenebrutinib-matching placebo.

Primary Outcome Measures

Name	Time	Method
Time to Onset of Composite 12-week Confirmed Disability Progression (cCDP12)	Minimum of 120 weeks

Secondary Outcome Measures

Name	Time	Method
Time to Onset of 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) Score	Minimum of 120 weeks	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, 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.
Plasma Concentrations of Fenebrutinib at Specified Timepoints	Up to 4.7 years
Time to Onset of 24-week CDP (CDP24)	Minimum of 120 weeks
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	Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120	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.
Percentage of Participants with Adverse Events (AEs)	Up to 4.7 years
Percent Change from Screening in Serum Neurofilament Light Chain (NfL) Levels	Up to Week 120
Time to Onset of 12-week CDP (CDP12)	Minimum of 120 weeks
Percentage Change in Total Brain Volume Assessed by Magnetic Resonance Imaging (MRI)	From Week 24 to Week 120
Time to Onset of Composite 24-week CDP (cCDP24)	Minimum of 120 weeks

Trial Locations

Locations (193)

Focus CECIC; 🇦🇷 Buenos Aires, Argentina

Alabama Neurology Associates; 🇺🇸 Homewood, Alabama, United States

Sutter East Bay Medical Foundation; 🇺🇸 Berkeley, California, United States

Fullerton Neurology and Headache Center; 🇺🇸 Fullerton, California, United States

Palo Alto Medical Foundation Research Center; 🇺🇸 Sunnyvale, California, United States

University of Colorado Denver; 🇺🇸 Aurora, Colorado, United States

Yale University School Of Medicine; 🇺🇸 New Haven, Connecticut, United States

Georgetown University Medical Center; 🇺🇸 Washington, District of Columbia, United States

Uni of Miami School of Medicine; 🇺🇸 Miami, Florida, United States

Neurological Services of Orlando; 🇺🇸 Orlando, Florida, United States

University of South Florida; 🇺🇸 Tampa, Florida, United States

Josephson Wallack Munshower Neurology PC; 🇺🇸 Indianapolis, Indiana, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

Johns Hopkins University School Of Medicine; Outpatient Center; 🇺🇸 Baltimore, Maryland, United States

Dragonfly Research, LLC; 🇺🇸 Wellesley, Massachusetts, United States

Wayne State University; 🇺🇸 Detroit, Michigan, United States

Minneapolis Clinic of Neurology; 🇺🇸 Golden Valley, Minnesota, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

Cleveland Clinic Lou Ruvo; Center for Brain Research; 🇺🇸 Las Vegas, Nevada, United States

Hackensack U Med Ctr; 🇺🇸 Hackensack, New Jersey, United States

Barnabas Health Ambulatory Care Center; 🇺🇸 Livingston, New Jersey, United States

Jersey Shore University Medical Centre; 🇺🇸 Neptune, New Jersey, United States

Rutgers New Jersey Medical School; 🇺🇸 Newark, New Jersey, United States

Holy Name Hospital; Institute For Clinical Research; 🇺🇸 Teaneck, New Jersey, United States

Dent Neurological Institute; 🇺🇸 Amherst, New York, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

Stony Brook University Medical Center; 🇺🇸 Stony Brook, New York, United States

SUNY Upstate Medical University; 🇺🇸 Syracuse, New York, United States

Atrium Health Neurosciences Institute ? Charlotte; 🇺🇸 Charlotte, North Carolina, United States

Neurology Associates PA; 🇺🇸 Hickory, North Carolina, United States

Raleigh Neurology Associates; 🇺🇸 Raleigh, North Carolina, United States

Miami Valley Hospital South; Dayton Physician's Office; 🇺🇸 Centerville, Ohio, United States

UC Health, LLC.; 🇺🇸 Cincinnati, Ohio, United States

OhioHealth Riverside Methodist Hospital; Pharmacy Services; 🇺🇸 Columbus, Ohio, United States

Providence Brain and Spine Institute; 🇺🇸 Portland, Oregon, United States

Neurology Clinic PC; 🇺🇸 Cordova, Tennessee, United States

Hope Neurology; 🇺🇸 Knoxville, Tennessee, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Uni of Texas Health Science Center At Houston; 🇺🇸 Houston, Texas, United States

Texas Institute for Neurological Disorders; 🇺🇸 Sherman, Texas, United States

Evergreen MS Center; 🇺🇸 Kirkland, Washington, United States

Swedish Medical Center; 🇺🇸 Seattle, Washington, United States

West Virginia University; 🇺🇸 Charleston, West Virginia, United States

Medical College of Wisconsin, Inc.; 🇺🇸 Milwaukee, Wisconsin, United States

Centro de Especialidades Neurológicas y Rehabilitación - CENyR; 🇦🇷 Buenos Aires, Argentina

Instituto De Neurología Cognitiva - INECO; 🇦🇷 Caba, Argentina

Instituto Reumatológico Strusberg; 🇦🇷 Cordoba, Argentina

Fundacion Rosarina de Neurorehabilitacion; 🇦🇷 Rosario, Argentina

Centro de Investigaciones Médicas Tucuman; REUMATHOLOGY; 🇦🇷 San Miguel, Argentina

Brain and Mind Research Institute; 🇦🇺 Camperdown, New South Wales, Australia

Liverpool Hospital; 🇦🇺 Liverpool, New South Wales, Australia

John Hunter Hospital; 🇦🇺 New Lambton, New South Wales, Australia

Princess Alexandra Hospital; 🇦🇺 Woolloongabba, Queensland, Australia

Box Hill Hospital; Department of Neurology; 🇦🇺 Box Hill, Victoria, Australia

Austin Hospital; Department of Neurology; 🇦🇺 Heidelberg, Victoria, Australia

Royal Melbourne Hospital; Department of Neurology; 🇦🇺 Parkville, Victoria, Australia

Kepler Universitätsklinikum GmbH - Neuromed Campus; Neurologie; 🇦🇹 Linz, Austria

Medizinische Universität Wien; Univ.Klinik fuer Neurologie; 🇦🇹 Wien, Austria

Santa Casa de Misericordia; de Belo Horizonte; 🇧🇷 Belo Horizonte, MG, Brazil

Instituto de Neurologia de Curitiba; 🇧🇷 Curitiba, PR, Brazil

Hospital Universitario Gaffree e Guinle; 🇧🇷 Rio de Janeiro, RJ, Brazil

IMV Pesquisa Neurológica; 🇧🇷 Porto Alegre, RS, Brazil

Núcleo de Pesquisa do Rio Grande do Sul; 🇧🇷 Porto Alegre, RS, Brazil

Clinica Neurologica; Neurocirurgica de Joinville; 🇧🇷 Joinville, SC, Brazil

Centro de Pesquisas Clinicas; CPCLIN; 🇧🇷 Sao Paulo, SP, Brazil

UMHAT Dr. Georgi Stranski; 2nd Neurology Clinic, Occupational Diseases; 🇧🇬 Pleven, Bulgaria

Multiprofile Hospital for Active Treatment of Neurology and Psychiatry Sv. Naum EAD; 🇧🇬 Sofia, Bulgaria

University of Alberta Hospital; 🇨🇦 Edmonton, Alberta, Canada

Fraser Health Authority - Fraser Health Multiple Sclerosis; 🇨🇦 Burnaby, British Columbia, Canada

University of British Columbia; 🇨🇦 Vancouver, British Columbia, Canada

Regional health authority A vitalite health network; 🇨🇦 Moncton, New Brunswick, Canada

London Health Sciences Centre Uni Campus; 🇨🇦 London, Ontario, Canada

The Ottawa Hospital - General Campus; Department of Neurology - Multiple Sclerosis; 🇨🇦 Ottawa, Ontario, Canada

Sunnybrook Health Sciences Centre; 🇨🇦 Toronto, Ontario, Canada

St. Michael's Hospital; MS Clinic; 🇨🇦 Toronto, Ontario, Canada

Clinique NeuroOutaouais; 🇨🇦 Gatineau, Quebec, Canada

Recherche Sepmus Inc.; 🇨🇦 Greenfield Park, Quebec, Canada

Montreal Neurological Institute and Hospital; 🇨🇦 Montreal, Quebec, Canada

CeCim Biocinetic; 🇨🇱 Santiago, Chile

Clinica Alemana; 🇨🇱 Vitacura, Chile

Organizacion Sanitas Internacional; 🇨🇴 Bogota, D.C., Colombia

Fundacion Clinica Valle del Lili; Unidad de Investigaciones Clinicas; 🇨🇴 Cali, Colombia

Instituto Neurologico de Colombia INDEC; 🇨🇴 Medellin, Colombia

Aarhus Universitetshospital; Neurologisk Afd. F, Skleroseklinikken; 🇩🇰 Aarhus N, Denmark

Rigshospitalet; Neurologisk Klinik Glostrup; 🇩🇰 Glostrup, Denmark

Groupe Hospitalier Pellegrin; Service de neurochirurgie B; 🇫🇷 Bordeaux, France

Hopital Pierre Wertheimer; Neurologie D; 🇫🇷 Bron, France

CHRU de Montpellier, Hopital Gui de Chauliac; Service de Neuropediatrie; 🇫🇷 Montpellier, France

Hopital Guillaume Et Rene Laennec; 🇫🇷 Nantes, France

Hôpital Pasteur; Service de Neurologie; 🇫🇷 Nice, France

Hopitaux Universitaires de Strasbourg ; Service de Neurologie; 🇫🇷 Strasbourg, France

Charite - Universitatsmedizin Berlin; Klinik fur Neurologie; 🇩🇪 Berlin, Germany

Studienzentrum Dr. Bischof GmbH; 🇩🇪 Böblingen, Germany

Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften; 🇩🇪 Dresden, Germany

Universitätsklinikum Freiburg, Klinik für Neurologie und Neurophysiologie; 🇩🇪 Freiburg, Germany

Klinikum rechts der Isar der TU Muenchen; Neurologische Klinik und Poliklinik im Neuro-Kopf-Zentrum; 🇩🇪 München, Germany

Universitaetsklinikum Tuebingen; Abteilung Neurologie; 🇩🇪 Tuebingen, Germany

Deutsche Klinik für Diagnostik; DKD Helios Klinik Wiesbaden, Abt. Neurologie; 🇩🇪 Wiesbaden, Germany

401 Military Hospital of Athens; Neurology Department; 🇬🇷 Athens, Greece

Hospital Eginition; First Department of Neurology; 🇬🇷 Athens, Greece

AHEPA Univ. General Hospital of Thessaloniki; B' Neurology Dept.; 🇬🇷 Thessaloniki, Greece

Clinexpert Kft.; 🇭🇺 Budapest, Hungary

S-Medicon Egeszsegugyi Szolgaltato Kft.; 🇭🇺 Budapest, Hungary

Budapesti Jahn Ferenc Dél-pesti Kórház és Rendel?intézet; 🇭🇺 Budapest, Hungary

Markhot Ferenc Oktatokorhaz és Rendelointezet; Neurologiai és Stroke Osztaly; 🇭🇺 Eger, Hungary

Pest Megyei Flor Ferenc Korhaz; 🇭🇺 Kistarcsa, Hungary

Rambam Medical Center; Neurology Unit; 🇮🇱 Haifa, Israel

The Chaim Sheba Medical Center; Multiple Sclerosis Center; 🇮🇱 Ramat-Gan, Israel

Tel Aviv Sourasky Medical Center; Department of Neurology; 🇮🇱 Tel Aviv, Israel

AOU Seconda Università degli Studi; Dip.Assistenziale Integrato Medicina Int-I Clinica Neurologica; 🇮🇹 Napoli, Campania, Italy

A.O.U. di Parma; SC Neurologia, Amb. Sclerosi Multipla (malattie demielinizzanti); 🇮🇹 Parma, Emilia-Romagna, Italy

Policlinico Tor Vergata Dip. Neuroscienze-Clinica Neurologica-UOSD Sclerosi Multipla; 🇮🇹 Roma, Lazio, Italy

Irccs A.O.U.San Martino Ist; Dinogmi; 🇮🇹 Genova, Liguria, Italy

IRCCS Ospedale San Raffaele; Neurologia Neurofisiologia Neuroriabilitazione-Centro Sclerosi Multipla; 🇮🇹 Milano, Lombardia, Italy

Ospedale Civile di Montichiari; Centro Sclerosi Multipla; 🇮🇹 Montichiari, Lombardia, Italy

IRCCS Istituto Neurologico Neuromed; Centro per lo Studio e la Cura della Sclerosi Multipla; 🇮🇹 Pozzilli, Molise, Italy

A.R.N.A.S. Civico Di Cristina Benfratelli; U.O.C. Neurologia con Stroke Unit; 🇮🇹 Palermo, Sicilia, Italy

Mexico Centre for Clinical Research; 🇲🇽 Ciudad de México, Mexico CITY (federal District), Mexico

Grupo Médico Camino S.C.; 🇲🇽 Ciudad de México, Mexico CITY (federal District), Mexico

Hospital Juarez de Mexico; 🇲🇽 Ciudad de México, Mexico CITY (federal District), Mexico

Clinstile S.A de C.V.; 🇲🇽 Mexico City, Mexico CITY (federal District), Mexico

Clinical Research Institute; 🇲🇽 Tlalnepantla de Baz, Mexico CITY (federal District), Mexico

University Clinic of Neurology; Movement Disorders; 🇲🇰 Skopje, North Macedonia

Hospital IV Alberto Sabogal Sologuren; Unidad de Investigacion; 🇵🇪 Bellavista, Peru

Clinica Internacional; Unidad De Investigacion; 🇵🇪 Lima, Peru

Instituto Nacional de Ciencias Neurológicas - Hospital Mogrovejo; Peru; 🇵🇪 Lima, Peru

Neurocentrum Bydgoszcz sp. z o.o; 🇵🇱 Bydgoszcz, Poland

Care Clinic; 🇵🇱 Katowice, Poland

NEURO-CARE Sp. z o.o. Sp. Komandytowa; 🇵🇱 Katowice, Poland

Centrum Neurologii Krzysztof Selmaj; 🇵🇱 Lodz, Poland

Med Polonia; 🇵🇱 Pozna?, Poland

Centrum Medyczne "MEDYK"; 🇵🇱 Rzeszow, Poland

Nmedis sp. z o.o.; 🇵🇱 Rzeszów, Poland

Centrum Medyczne NeuroProtect; 🇵🇱 Warszawa, Poland

Wro Medica; 🇵🇱 Wroc?aw, Poland

SPSK nr 1; Klinika Neurologii; 🇵🇱 Zabrze, Poland

Hospital de Braga; Servico de Neurologia; 🇵🇹 Braga, Portugal

Hospital Santo Antonio dos Capuchos; Servico de Neurologia; 🇵🇹 Lisboa, Portugal

Hospital de Santa Maria; Servico de Neurologia; 🇵🇹 Lisboa, Portugal

Hospital Geral de Santo Antonio; Servico de Neurologia; 🇵🇹 Porto, Portugal

Hospital de Sao Joao; Servico de Neurologia; 🇵🇹 Porto, Portugal

San Juan MS Center; 🇵🇷 Guaynabo, Puerto Rico

FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency; 🇷🇺 Krasnoyarsk, Krasnojarsk, Russian Federation

Krasnoyarsk State Medical Academy; 🇷🇺 Krasnoyarsk, Krasnojarsk, Russian Federation

National Center of Social Significant Disease; 🇷🇺 Sankt-peterburg, Leningrad, Russian Federation

Federal center of brain research and neurotechnologies; 🇷🇺 Moskva, Moskovskaja Oblast, Russian Federation

City Clinical Hospital #24; Multipal Sclerosis department; 🇷🇺 Moskva, Moskovskaja Oblast, Russian Federation

City Hospital #40 of Resort Administrative District; 🇷🇺 St. Petersburg, Sankt Petersburg, Russian Federation

Sverdlovsk Regional Clinical Hospital 1; 🇷🇺 Yekaterinburg, Sverdlovsk, Russian Federation

Vertebronevrologiya LLC; 🇷🇺 Kazan, Tatarstan, Russian Federation

Regional Multiple Sclerosis Centre b/o CC ECM Neftyanik; Neurology; 🇷🇺 Tyumen, Tjumen, Russian Federation

Center of Cardiology and Neurology; 🇷🇺 Kirov, Russian Federation

State Novosibirsk Regional Clinical Hospital; 🇷🇺 Novosibirsk, Russian Federation

Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Neurologia; 🇪🇸 Coruña, LA Coruña, Spain

Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Neurología; 🇪🇸 Lleida, Lerida, Spain

Hospital Quiron de Madrid; Servicio de Neurologia; 🇪🇸 Pozuelo de Alarcon, Madrid, Spain

Hospital Alvaro Cunqueiro; Servicio de Neurologia; 🇪🇸 Vigo, Pontevedra, Spain

Hospital Universitari Vall d'Hebron; Servicio de Neumo-Inmunologia; 🇪🇸 Barcelona, Spain

Hospital Puerta del Mar; Sevicio de Neurologia; 🇪🇸 Cadiz, Spain

Hospital Ramon y Cajal; Servicio de Neurologia; 🇪🇸 Madrid, Spain

Hospital Regional Universitario de Malaga ? Hospital General; Servicio de Neurologia; 🇪🇸 Malaga, Spain

Hospital Universitario Virgen Macarena; Servicio de Neurologia; 🇪🇸 Sevilla, Spain

Universitätsspital Basel; Neurologie; 🇨🇭 Basel, Switzerland

Inselspital Bern Medizin Neurologie; 🇨🇭 Bern, Switzerland

Hacettepe University Medical Faculty; Neurology; 🇹🇷 Ankara, Turkey

Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi; Noroloji Anabilim Dali; 🇹🇷 Istanbul, Turkey

Sancaktepe Training and Research Hospital; Neurology; 🇹🇷 Istanbul, Turkey

Selcuk University Medical Faculty; Norology department; 🇹🇷 Istanbul, Turkey

Kocaeli University Hospital; Department of Neurology; 🇹🇷 Kocaeli, Turkey

Mersin University Medical Faculty; Neurology; 🇹🇷 Mersin, Turkey

Ondokuz Mayis Univ. Med. Fac.; Neurology; 🇹🇷 Samsun, Turkey

Karadeniz Tecnical Uni. Med. Fac.; Neurology; 🇹🇷 Trabzon, Turkey

Van Yuzuncu Yil University Hospital; Neurology; 🇹🇷 Van, Turkey

Baskent Universitesi Ankara Hastanesi; Noroloji Bolumu; 🇹🇷 Çankaya, Turkey

CNPE City Clinical Hospital #3 of Chernivtsi City Council; 🇺🇦 Chernivtsi, Chernihiv Governorate, Ukraine

MNE Lviv Territorial Medical Association Clinical Hospital for Palliative Care; 🇺🇦 Lviv, Chernihiv Governorate, Ukraine

Medical Centre of PE First Private Clinic; 🇺🇦 Zhytomir, Crimean Regional Governmenta, Ukraine

Municipal Nonprofit Enterprise of Kharkiv Regional Council Regional Clinical Hospital; 🇺🇦 Kharkiv, Kharkiv Governorate, Ukraine

Municipal Institution Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council; 🇺🇦 Zaporizhzhia, Kharkiv Governorate, Ukraine

MEDBUD; 🇺🇦 Kyiv, KIEV Governorate, Ukraine

Lviv Regional Clinical Hospital; 🇺🇦 Lviv, KIEV Governorate, Ukraine

Salutem Medical Center; 🇺🇦 Vinnytsia, KIEV Governorate, Ukraine

Medical Clinical Research Center of Medical Center LLC Health Clinic; 🇺🇦 Vinnytsia, Podolia Governorate, Ukraine

Separated structural unit ?University hospital? of Dnipro State Medical University; Neurology; 🇺🇦 Dnipro, Tavria Okruha, Ukraine

Regional Clinical Hospital; Neurology Department; 🇺🇦 Ivano-Frankivsk, Ukraine

Ams of Ukraine; Inst. of Neurology, Psychiatry & Narcology; 🇺🇦 Kharkov, Ukraine

Volyn Regional Clinical Hospital; 🇺🇦 Lutsk, Ukraine

Odesa Regional Clinical Hospital; Neurosurgery Department; 🇺🇦 Odesa, Ukraine

Queen Elizabeth University Hospital; 🇬🇧 Glasgow, United Kingdom

Charing Cross Hospital; 🇬🇧 London, United Kingdom

Nottingham University Hospitals NHS Trust; 🇬🇧 Nottingham, United Kingdom

Morriston Hospital; 🇬🇧 Swansea, United Kingdom