A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS)
- Conditions
- Multiple Sclerosis
- Interventions
- Registration Number
- NCT04548999
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and PK of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks (Q24W) in participants with PPMS, in comparison to the approved 600 milligrams (mg) dose of ocrelizumab.
- Detailed Description
Participants will be treated for a minimum of 120 weeks in the double-blind treatment (DBT) phase. Upon positive primary results after the DBT phase, an optional higher dose extension treatment, open-label extension (OLE) phase is planned for eligible participants. The OLE will be carried out for approximately 96 weeks. Participants will be followed for safety for 48 weeks thereafter. Participants whose B-cell levels still did not replete to their baseline level or the lower limit of normal (LLN), whichever is lower, will move into the B-cell monitoring (BCM) phase following the safety follow-up phase. The study will end when all participants who were not treated with an alternative B-cell depleting therapy have repleted their B-cells to the baseline value or the LLN.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 769
- Diagnosis of PPMS
- EDSS score at screening and baseline, from 3 to 6.5 inclusive
- Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds
- Average 9HPT score over four trials (two trials with each hand) at screening and over four trials (two trials with each hand) at baseline respectively, up to 250 (inclusive) seconds
- Score of ≥ to 2.0 on the Functional Systems (FS) scale for the pyramidal system that was due to lower extremity findings at screening and baseline
- Documented magnetic resonance imaging (MRI) of brain with abnormalities consistent with MS
- Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization
- Participants must be neurologically stable for at least 30 days prior to randomization and baseline
- Disease duration from the onset of MS symptoms; if EDSS score at screening is ≤ 5, disease duration must be less than 10 years; If EDSS score at screening is > 5, disease duration must be less than 15 years
- Documented evidence of the presence of at least one cerebrospinal fluid-specific oligoclonal bands
- Females of childbearing potential: agreement to remain abstinent or use adequate contraceptive methods
- Female participants, without reproductive potential may be enrolled e.g. if post-menopausal or if surgically sterile
- History of relapsing remitting or secondary progressive MS at screening
- Any known or suspected active infection at screening or baseline (except nailbed infections), or any major episode of infection requiring hospitalization or treatment with IV antimicrobials within 8 weeks or treatment with oral antimicrobials within 2 weeks, prior to and during screening
- History of confirmed or suspected progressive multifocal leukoencephalopathy
- History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
- Immunocompromised state
- Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization
- Inability to complete an MRI or contraindication to gadolinium administration
- Contraindications to mandatory pre-medications for infusion-related reaction (IRRs)
- Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study
- Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
- Significant, uncontrolled disease that may preclude participant from participating in the study
- History of or currently active primary or secondary, non-drug-related, immunodeficiency
- Pregnant or breastfeeding or intending to become pregnant
- Lack of peripheral venous access
- History of alcohol or other drug abuse within 12 months prior to screening
- Treatment with any investigational agent or treatment with any experimental procedure for MS
- Previous use of anti-cluster of differentiation 20 (CD20s) (including ocrelizumab), unless the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy
- Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab
- Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline
- Previous treatment with natalizumab within 4.5 months of baseline
- Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline
- Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label. If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication
- Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
- Any previous history of transplantation or anti-rejection therapy
- Treatment with IV immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to randomization
- Systemic corticosteroid therapy within 4 weeks prior to screening
- Positive screening tests for active, latent, or inadequately treated hepatitis B
- Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab
- Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ocrelizumab Higher Dose Ocrelizumab Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Higher Dose Antihistamine Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Approved Dose Ocrelizumab Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Approved Dose Antihistamine Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Higher Dose Methylprednisolone Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Approved Dose Methylprednisolone Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
- Primary Outcome Measures
Name Time Method Time to Onset of Composite Confirmed Disability Progression (cCDP) Sustained for at least 12 Weeks Baseline up to approximately 4.3 years Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by Expanded Disability Status Scale (EDSS), Timed 25-foot Walk Test (T25FWT) or 9-hole Peg Test (9-HPT)
- Secondary Outcome Measures
Name Time Method Time to Onset of 12-week Confirmed Disability Progression (CDP12) Baseline up to approximately 4.3 years CDP, defined as a sustained increase from baseline in EDSS score of ≥1.0 point in participants with a baseline EDSS score of ≤5.5 or a sustained increase of ≥0.5 points in participants with a baseline EDSS score of \>5.5
Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12) Independent of Protocol-defined Relapses (PDR) Baseline up to approximately 4.3 years Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT independent of PDR
Time to ≥ 20% Increase in 12-week Confirmed by T25FWT Baseline up to approximately 4.3 years The T25FWT is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant is directed to start at one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible.
Change in Neurofilament Light (NfL) at Week 96 Baseline up to Week 96 Biomarker for neurodegeneration NfL
Time to 12-week Confirmed 8-point Increase in 12-item Multiple Sclerosis Walking Scale (MSWS12) Baseline up to approximately 4.3 years Self-reported measure of the impact of multiple sclerosis (MS) on the individual's ability to walk
Annual Rate of Percent Change From Baseline in Total Brain Volume Baseline up to approximately 4.3 years Annual Rate of Percent Change From Baseline in Thalamic Volume Baseline up to approximately 4.3 years Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) Baseline up to approximately 4.3 years The SDMT is a performance measure that has demonstrated sensitivity in detecting not only the presence of cognitive impairment but also changes in cognitive functioning over time and in response to treatment. Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses will be collected orally. A four-point change from baseline is typically considered clinically meaningful.
Change in NfL (i.e. Ratio to Baseline) at Week 96 for Participants in the Approved Dose Ocrelizumab Group Baseline up to Week 96 Biomarker for neurodegeneration NfL
Change in NfL (i.e. Ratio to Baseline) at Week 96 for Participants in the Higher Dose Ocrelizumab Group Baseline up to Week 96 Biomarker for neurodegeneration NfL
Time to Onset of 24-week Composite Confirmed Disability Progression (cCDP24) Independent of PDR Baseline up to approximately 4.3 years Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT independent of PDR
Percentage of Participants With Adverse Events (AEs) Baseline up to approximately 8 years Serum Concentrations of Ocrelizumab at Specified Timepoints Weeks 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120 Change in B-cell Levels in Blood Baseline up to approximately 4.3 years Percentage of Participants Achieving 5 or Less B-cells per Microliter of Blood Baseline up to approximately 4.3 years Change From Baseline in the Anti-drug Antibody (ADA) Levels Week 0, 24, 48, 72, 96, 120
Trial Locations
- Locations (149)
COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika
🇵🇱Gdansk, Poland
MA-LEK Clinical Sp. Z o.o.
🇵🇱Katowice, Poland
Szpital Specjalistyczny im. Rydygiera w Krakowie
🇵🇱Krakow, Poland
Centrum Neurologii Krzysztof Selmaj
🇵🇱Lodz, Poland
Indywidualna Praktyka Lekarska Prof. Dr Hab. N. Med. Konrad Rejdak.
🇵🇱Lublin, Poland
Instytut Zdrowia Dr Boczarska-Jedynak Sp. z o.o. Sp. k.
🇵🇱Oswiecim, Poland
Neurologiczny Niepubliczny ZOZ Centrum Leczenia SM Osrodek Bada? Klinicznych
🇵🇱Plewiska, Poland
EMC Instytut Medyczny SA
🇵🇱Pozna?, Poland
Wojewódzki Szpital Specjalistyczny Nr 3
🇵🇱Rybnik, Poland
Nmedis sp. z o.o.
🇵🇱Rzeszów, Poland
Osrodek Badan Klinicznych Euromedis
🇵🇱Szczecin, Poland
Centrum Medyczne NeuroProtect
🇵🇱Warszawa, Poland
Instytut Psychiatrii i Neurologii II Klinika Neurologiczna
🇵🇱Warszawa, Poland
Hospital de Braga
🇵🇹Braga, Portugal
Hospital Santo Antonio dos Capuchos
🇵🇹Lisboa, Portugal
Centro Hospitalar de Lisboa Ocidental - Hospital Egas Moniz
🇵🇹Lisboa, Portugal
Hospital Geral de Santo Antonio
🇵🇹Porto, Portugal
Erciyes Universitesi
🇹🇷Kayseri, Turkey
Orszagos Mentalis, Ideggyogyaszati es Idegsebeszeti Intezet
🇭🇺Budapest, Hungary
UNO Medical Trials Kft.
🇭🇺Budapest, Hungary
Instituto Méderi de Pesquisa e Saúde
🇧🇷Passo Fundo, Rio Grande Do Sul, Brazil
Hospital Moinhos de Vento
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
IMV Pesquisa Neurológica
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital Sao Lucas - PUCRS
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Clinica Neurologica
🇧🇷Joinville, Santa Catarina, Brazil
Hospital das Clinicas - UNICAMP
🇧🇷Campinas, São Paulo, Brazil
Praxis Pesquisa Médica
🇧🇷Santo Andre, São Paulo, Brazil
CPQuali Pesquisa Clinica Ltda
🇧🇷Sao Paulo, São Paulo, Brazil
UMHAT Dr. Georgi Stranski
🇧🇬Pleven, Bulgaria
MHATNP Sveti Naum EAD
🇧🇬Sofia, Bulgaria
Chum Campus Notre Dame
🇨🇦Montreal, Quebec, Canada
MUCH - Montreal Neurological Institute & Hospital
🇨🇦Montreal, Quebec, Canada
Hotel-Dieu de Levis
🇨🇦Quebec, Canada
Aalborg Universitetshospital
🇩🇰Aalborg, Denmark
Rigshospitalet Glostrup
🇩🇰Glostrup, Denmark
CHU de Besancon Hopital Jean Minjoz
🇫🇷Besançon, France
CHU Brest Hopital La Cavale Blanche
🇫🇷Brest, France
Hopital Cote De Nacre
🇫🇷Caen, France
CHU Hopital Gabriel Montpied
🇫🇷Clermont Ferrand, France
CH St Vincent de Paul
🇫🇷Lille, France
Hopital Central - CHU de Nancy
🇫🇷Nancy, France
Hopital Hautepierre - CHU Strasbourg
🇫🇷Strasbourg, France
Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften
🇩🇪Dresden, Germany
Alabama Neurology Associates
🇺🇸Homewood, Alabama, United States
21st Century Neurology
🇺🇸Phoenix, Arizona, United States
University of California Irvine
🇺🇸Irvine, California, United States
Stanford University Medical Center
🇺🇸Stanford, California, United States
Universitätsmedizin Greifswald
🇩🇪Greifswald, Germany
Medizinische Hochschule Hannover, Klinik für Neurologie
🇩🇪Hannover, Germany
Universität Leipzig
🇩🇪Leipzig, Germany
University of Colorado Denver
🇺🇸Aurora, Colorado, United States
Advanced Neurosciences Research LLC
🇺🇸Fort Collins, Colorado, United States
MS and Neuromuscular Center of Excellence
🇺🇸Clearwater, Florida, United States
Universitätsklinikum Münster
🇩🇪Münster, Germany
Universitätsklinikum Tübingen, Zentrum für Neurologie
🇩🇪Tübingen, Germany
Universitätsklinikum Ulm
🇩🇪Ulm, Germany
Deutsche Klinik für Diagnostik
🇩🇪Wiesbaden, Germany
Hospital Eginition
🇬🇷Athens, Greece
University of South Florida
🇺🇸Tampa, Florida, United States
Baptist Health Lexington
🇺🇸Nicholasville, Kentucky, United States
401 Military Hospital of Athens
🇬🇷Athens, Greece
International Neurorehabilitation Institute
🇺🇸Lutherville, Maryland, United States
Massachusetts General Hospital.
🇺🇸Boston, Massachusetts, United States
Petz Aladar Megyei Oktato Korhaz
🇭🇺Gyor, Hungary
Somogy Megyei Kaposi Mor Oktato Korhaz
🇭🇺Kaposvár, Hungary
Advanced Neurosciences Institute
🇺🇸Nashville, Tennessee, United States
Kistarcsai Flor Ferenc Korhaz
🇭🇺Kistarcsa, Hungary
A. O. U. Federico II
🇮🇹Napoli, Campania, Italy
AOU Seconda Università degli Studi
🇮🇹Napoli, Campania, Italy
Azienda Ospedaliera Sant'Andrea
🇮🇹Roma, Lazio, Italy
Lone Star Neurology of San Antonio
🇺🇸San Antonio, Texas, United States
Texas Institute for Neurological Disorders
🇺🇸Sherman, Texas, United States
Wheaton Franciscan Healthcare - St. Francis Outpatient Center
🇺🇸Milwaukee, Wisconsin, United States
CEMIC Saavedra
🇦🇷Buenos Aires, Argentina
Centro de Especialidades Neurológicas y Rehabilitación - CENyR
🇦🇷Buenos Aires, Argentina
INECO
🇦🇷Rosario, Argentina
Revalidatie en MS Centrum
🇧🇪Overpelt, Belgium
L2 Ip Instituto de Pesquisas Clinicas Ltda ME
🇧🇷Brasilia, Distrito Federal, Brazil
Hospital das Clinicas - UFG
🇧🇷Goiania, Goiás, Brazil
Instituto de Neurologia de Curitiba
🇧🇷Curitiba, Paraná, Brazil
Ospedale S.Antonio Abate
🇮🇹Gallarate, Lombardia, Italy
IRCCS Ospedale San Raffaele
🇮🇹Milano, Lombardia, Italy
Krasnoyarsk State Medical Academy
🇷🇺Krasnoyarsk, Krasnojarsk, Russian Federation
City Clinical Hospital #24
🇷🇺Moskva, Moskovskaja Oblast, Russian Federation
Kocaeli University Hospital
🇹🇷Kocaeli, Turkey
Ege Üniversitesi Tip Fakültesi
🇹🇷Lzmir, Turkey
Cumhuriyet Universitesi Tip Fakultesi
🇹🇷Merkez, Turkey
Mersin University Medical Faculty
🇹🇷Mersin, Turkey
Ondokuz Mayis University School of Medicine
🇹🇷Samsun, Turkey
Baskent Universitesi Ankara Hastanesi
🇹🇷Çankaya, Turkey
Medical Center Dopomoga Plus
🇺🇦Kyiv, Katerynoslav Governorate, Ukraine
IRCCS Istituto Neurologico C. Mondino?Dip. Neurologia Neuroriabilitazione S.S. Sclerosi Multipla
🇮🇹Pavia, Lombardia, Italy
AOU Città della Salute e della Scienza
🇮🇹Torino, Piemonte, Italy
Centro de Investigacion Medico Biologico y Terapia Avanzada, S.C.
🇲🇽Guadalajara, Jalisco, Mexico
Clinstile S.A de C.V.
🇲🇽Mexico City, Mexico CITY (federal District), Mexico
Neurociencias Prisma, A.C
🇲🇽San Luis Potosí, SAN LUIS Potosi, Mexico
Grupo Médico Camino S.C.
🇲🇽Mexico, Mexico
Hospital Nacional Guillermo Almenara Irigoyen
🇵🇪La Victoria, Lima, Peru
Instituto Nacional de Ciencias Neurológicas - Hospital Mogrovejo
🇵🇪Lima, Peru
Hospital Nacional Dos de Mayo
🇵🇪Lima, Peru
Neurocentrum Bydgoszcz sp. z o.o
🇵🇱Bydgoszcz, Poland
Gazi University Medical Faculty
🇹🇷Ankara, Turkey
Haseki Training and Research Hospital
🇹🇷Istanbul, Turkey
Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi
🇹🇷Istanbul, Turkey
Sancaktepe Training and Research Hospital
🇹🇷Istanbul, Turkey
University of Massachusetts Medical School
🇺🇸Worcester, Massachusetts, United States
Michigan Institute for Neurological Disorders
🇺🇸Farmington Hills, Michigan, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Selcuk University Medical Faculty
🇹🇷Istanbul, Turkey
Jersey Shore University Medical Centre
🇺🇸Neptune, New Jersey, United States
Northwell Health
🇺🇸Great Neck, New York, United States
Lenox Hill Hospital
🇺🇸New York, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Neurology Clinic PC
🇺🇸Cordova, Tennessee, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency
🇷🇺Krasnoyarsk, Krasnojarsk, Russian Federation
National Center of Social Significant Disease
🇷🇺Sankt-peterburg, Leningrad, Russian Federation
Research Center of Neurology of RAMS
🇷🇺Moscow, Moskovskaja Oblast, Russian Federation
Federal center of brain research and neurotechnologies
🇷🇺Moskva, Moskovskaja Oblast, Russian Federation
N.P. Bechtereva Institute of the Human Brain
🇷🇺Sankt-petersburg, Sankt Petersburg, Russian Federation
Leningrad Regional Clinical Hospital
🇷🇺St Petersburg, Sankt Petersburg, Russian Federation
City Hospital #40 of Kurortniy Administrative District
🇷🇺St. Petersburg, Sankt Petersburg, Russian Federation
SHI Sverdlovsk Regional Clinical Hospital #1
🇷🇺Yekaterinburg, Sverdlovsk, Russian Federation
Vertebronevrologiya LLC
🇷🇺Kazan, Tatarstan, Russian Federation
Ulyanovsk Regional Clinical Hospital
🇷🇺Ulyanovsk, Uljanovsk, Russian Federation
Center of Cardiology and Neurology
🇷🇺Kirov, Russian Federation
Regional clinical hospital named after prof. S.V. Ochapovsky
🇷🇺Krasnodar, Russian Federation
FSBIH Siberian Regional Medical Centre of FMBA of Russia
🇷🇺Novosibirsk, Russian Federation
Perm SMA n.a. academ. E.A. Vagner
🇷🇺Perm, Russian Federation
Hospital Quiron de Madrid
🇪🇸Pozuelo de Alarcon, Madrid, Spain
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario Puerta De Hierro Majadahonda
🇪🇸Madrid, Spain
Hospital Universitario Virgen de Arrixaca
🇪🇸Murcia, Spain
Inselspital Bern Medizin Neurologie
🇨🇭Bern, Switzerland
Municipal Non-profit Enterprise Zaporizhzhya Regional Hospital Zaporizhzhya Regional Council
🇺🇦Zaporizhzhia, Katerynoslav Governorate, Ukraine
State Institution Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine
🇺🇦Kharkiv, Kharkiv Governorate, Ukraine
5th Cherkasy City Center of Primary Health Care
🇺🇦Cherkasy, KIEV Governorate, Ukraine
SI USSRI of Medical and Social Problems of Disabilities of MOHU
🇺🇦Dnipro, KIEV Governorate, Ukraine
Medical Center of Private Execution First Private Clinic
🇺🇦Kyiv, KIEV Governorate, Ukraine
Lvivska oblasna tsentralna likarnia
🇺🇦Lviv, KIEV Governorate, Ukraine
Medical Clinical Research Center of Medical Center LLC Health Clinic
🇺🇦Vinnytsi, Podolia Governorate, Ukraine
Sumy Regional Clinical Hospital
🇺🇦Sumy, Polissya Okruha, Ukraine
Regional Clinical Hospital
🇺🇦Ivano-Frankivsk, Ukraine
St.In.Inst. of Neurol.Psych.and Narcol.of the AMSU
🇺🇦Kharkov, Ukraine
Volyn Regional Clinical Hospital
🇺🇦Lutsk, Ukraine
Charing Cross Hospital
🇬🇧London, United Kingdom
National Hospital for Neurology and Neurosurgery,
🇬🇧London, United Kingdom
Royal Victoria Infirmary
🇬🇧Newcastle upon Tyne, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom