Study to Evaluate the Effectiveness and Safety of Ocrelizumab in Participants With Early Stage Relapsing Remitting Multiple Sclerosis (RRMS)
- Registration Number
- NCT03085810
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This is a prospective, multicenter, open-label, single-arm, phase 3b study which evaluates effectiveness and safety of ocrelizumab in participants with early stage RRMS. The study will consist of an open-label treatment period of 192 weeks and follow-up period of at least 48 weeks.
The optional shorter infusion substudy will evaluate the safety of a shorter infusion of ocrelizumab in a subgroup of participants with early stage RRMS enrolled in the main MA30143 study. Approximately 700 patients will be enrolled in the substudy, and will receive additional 600 mg ocrelizumab administered in a shorter time frame.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 1225
- Have a definite diagnosis of RRMS, as per the revised McDonald 2010 criteria
- Have a length of disease duration, from first documented clinical attack consistent with MS disease of less than or equal to (</=) 3 years
- Within the last 12 months one or more clinically reported relapse(s) or one or more signs of MRI activity
- EDSS of 0.0 to 3.5 inclusive, at screening
- An agreement to use an acceptable birth control method for women of childbearing potential, during the treatment period and for at least 6 months or longer after the last dose of study drug
- Secondary progressive multiple sclerosis or history of primary progressive or progressive relapsing MS
- Inability to complete an MRI
- Known presence of other neurological disorders
Exclusions Related to General Health:
- Pregnancy or lactation
- Participants intending to become pregnant during the study or within 6 months after the last dose of the study drug
- Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
- History or currently active primary or secondary immunodeficiency
- Lack of peripheral venous access
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
- Significant or uncontrolled somatic disease or any other significant disease that may preclude participant from participating in the study
- Congestive heart failure (New York Heart Association III or IV functional severity)
- Known active bacterial, viral, fungal, mycobacterial infection or other infection, (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks prior to screening or oral antibiotics 2 weeks prior to screening
- History of malignancy, major opportunistic infections, alcohol or drug abuse, recurrent or chronic infection, and/or coagulation disorders
Exclusions Related to Medications:
- Received any prior approved disease modifying treatment (DMT) with a label for MS, for example, interferons, glatiramer acetate, natalizumab, alemtuzumab, daclizumab, fingolimod, teiflunomide and dimethylfumarate
- Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the baseline visit
- Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab)
- Any previous treatment with immunosuppressants/ immunomodulators/ antineoplastic therapies (cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, cladribine, mitoxantrone, laquinimod, total body irradiation, or bone marrow transplantation)
- Treatment with investigational DMT
- Treatment with fampridine/dalfamipridine unless on stable dose for >/=30 days prior to screening
Exclusion related to Shorter Infusion Substudy:
- Any previous serious IRRs experienced with ocrelizumab treatment
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ocrelizumab Ocrelizumab Ocrelizumab will be administered intravenously (IV) as two 300-milligram (mg) infusions (infusion length=2.5 hours) on Days 1 and 15, followed by one 600-mg infusion dose every 24 weeks (+/- 14 days) for a maximum of 8 doses throughout the 192 weeks treatment period. Substudy Group 1 Ocrelizumab At week 24 of the main study, eligible participants will be randomized to receive 600 mg ocrelizumab infused over approximately 3.5 hours every 24 weeks for the remainder of the study duration Substudy Group 2 Ocrelizumab At week 24 of the main study, eligible participants will be randomized to receive 600 mg ocrelizumab infused over approximately 2 hours followed by sodium chloride given as a slow infusion over the remaining 1.5 hours to mimic the standard-length infusion (3.5 hour) every 24 weeks for the remainder of the study duration
- Primary Outcome Measures
Name Time Method Sub Study: Number of Participants With IRRs Occurring During or Within 24 Hours Following the First Infusion After Randomization to the Shorter Infusion Substudy Week 24 through Week 144 Mean Change From Baseline in EDSS Score at Week 96 Baseline, Week 96 Mean Change From Baseline in EDSS Score at Week 120 Baseline, Week 120 Mean Change From Baseline in EDSS Score at Week 144 Baseline, Week 144 Percentage of Participants Without Relapse Baseline up to 4 years Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment.
Annualized Relapse Rate Baseline up to 4 years Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. The adjusted annualized relapse rate is reported which is:
Adjusted by age at disease diagnosis, Baseline EDSS, Presence of T1 Gd-enhanced lesion at screening and Presence of relapses in the last year prior to enrollment. Log-transformed exposure time is included as an offset variable.
The report contains data up to week 192 of the treatment period of each individual participant.Mean Change From Baseline in EDSS Score at Week 168 Baseline, Week 168 Mean Change From Baseline in EDSS Score at Week 192 Baseline, Week 192 Time to Onset of Confirmed Disability Progression (CDP) Sustained for at Least 24 Weeks and 48 Weeks as Measured Using Expanded Disability Status Scale (EDSS) Baseline up to 4 years The EDSS-Expanded Disability Status Scale is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Disability progression as measured by EDSS is defined as ≥1 point increase in EDSS score from a baseline EDSS score of 1-5 inclusive, a 0.5-increase from a baseline EDSS score higher than 5 and a 1.5-increase from a baseline EDSS score from 0 to 1 exclusive. Disability progression was considered confirmed if a sustained change in EDSS for a minimum of 24 weeks (-2 weeks) from the initial progression event was seen i.e. the change in EDSS must have been sustained at all available visits for a minimum of 24 weeks/48 weeks.
Percentage of Participants With 24-Week and 48-Week Confirmed Disability Improvement (CDI) During the Year 1 Treatment Period, as Measured Using EDSS At Weeks 24 and 48 during Year 1 CDI is defined as an improvement of ≥1 point on the EDSS score confirmed at a regular scheduled visit at least 24/48 weeks after the initial documentation of neurological worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death).
Percentage of Participants Event-Free for CDP Sustained for at Least 24 and 48 Weeks at Year 1, as Measured Using EDSS Year 1 (Weeks 24 and 48) The EDSS-Expanded Disability Status Scale is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Disability progression as measured by EDSS is defined as ≥1 point increase in EDSS score from a baseline EDSS score of 1-5 inclusive, a 0.5-increase from a baseline EDSS score higher than 5 and a 1.5-increase from a baseline EDSS score from 0 to 1 exclusive. Disability progression was considered confirmed if a sustained change in EDSS for a minimum of 24 weeks (-2 weeks) from the initial progression event was seen i.e. the change in EDSS must have been sustained at all available visits (during Year 1) for a minimum of 24 weeks/48 weeks. Percentage of participants who did not have CPD sustained for 24 and 48 weeks are reported here.
Percentage of Participants With 24-Week and 48-Week CDI During the Year 2 Treatment Period, as Measured Using EDSS At Weeks 48, 72 and 96 during Year 2 CDI is defined as an improvement of 1 point on the EDSS score confirmed at a regular scheduled visit at least 24/48 weeks after the initial documentation of neurological worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death).
Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 2, as Measured Using EDSS Year 2 (Weeks 72 and 96) The EDSS-Expanded Disability Status Scale is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Disability progression as measured by EDSS is defined as ≥1 point increase in EDSS score from a baseline EDSS score of 1-5 inclusive, a 0.5-increase from a baseline EDSS score higher than 5 and a 1.5-increase from a baseline EDSS score from 0 to 1 exclusive. Disability progression was considered confirmed if a sustained change in EDSS for a minimum of 24 weeks (-2 weeks) from the initial progression event was seen i.e. the change in EDSS must have been sustained at all available visits (during Year 1) for a minimum of 24 weeks/48 weeks. Percentage of participants who did not have CPD sustained for 24 and 48 weeks are reported here.
Percentage of Participants With 24-Week and 48-Week CDI at Year 4, as Measured Using EDSS At Weeks 144, 168 and 192 during Year 4 CDI is defined as an improvement of 1 point on the EDSS score confirmed at a regular scheduled visit at least 24 weeks after the initial documentation of neurological worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death).
Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 4, as Measured Using EDSS Year 4 (Weeks 168 and 192) The EDSS-Expanded Disability Status Scale is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Disability progression as measured by EDSS is defined as ≥1 point increase in EDSS score from a baseline EDSS score of 1-5 inclusive, a 0.5-increase from a baseline EDSS score higher than 5 and a 1.5-increase from a baseline EDSS score from 0 to 1 exclusive. Disability progression was considered confirmed if a sustained change in EDSS for a minimum of 24 weeks (-2 weeks) from the initial progression event was seen i.e. the change in EDSS must have been sustained at all available visits (during Year 1) for a minimum of 24 weeks/48 weeks. Percentage of participants who did not have CPD sustained for 24 and 48 weeks are reported here.
Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 1, As Measured Using EDSS Year 1 (Week 48) Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 2, As Measured Using EDSS Year 2 (Week 96) Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 3, As Measured Using EDSS Year 3 Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 4, As Measured Using EDSS Year 4 Mean Change From Baseline in EDSS Score at Week 24 From Baseline to Week 24 Mean Change From Baseline in EDSS Score at Week 48 From Baseline to Week 48 Mean Change From Baseline in EDSS Score at Week 72 From Baseline to Week 72 Percentage of Participants Without Protocol-Defined Event of Disease Activity Baseline up to 4 years Protocol-defined event of disease activity is defined as having at least one of the following: (1). protocol defined relapse (occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis \[MS\], as determined using EDSS/Functional Systems Score \[FSS\] assessment). (2). CDP, as determined using EDSS. (3). a T1 Gd-enhanced lesion after Week 8 (4). a new and/or enlarging T2 hyperintense lesion on magnetic resonance imaging (MRI) after Week 8 compared to the Week 8 MRI scan.
- Secondary Outcome Measures
Name Time Method Substudy: IRRs Leading to Treatment Discontinuation From Week 24 to Week 144 Total Number of Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI Baseline, Weeks 8, 24, 48, 96, 144, 192 Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI was measured for its volumes.
Substudy: Severity of IRRs From Week 24 to Week 144 The number of participants with IRRs by most extreme intensity were reported (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 =life-threatening, grade 5 = fatal). Multiple IRRs in one participant are counted only once at the most extreme (highest) intensity observed.
Percentage of Participants Without Protocol-defined Event of Evidence of Progression (NEP) Weeks 96, 192 NEP is defined as no progression sustained for at least 24 weeks on all of the following three components (CDP; 20 percent \[%\] increase from baseline in timed 25 Foot Walk Test \[T25FWT\]; 20% increase from baseline in timed 9 hole peg test \[9HPT\]). CDP will be assessed using EDSS.
Percentage of Participants With no Evidence of Progression Sustained for At Least 24 Weeks and no Active Disease (NEPAD) Weeks 96, 192 NEPAD is defined as no progression on all of the three components of NEP (CDP, T25FWT, 9HPT), no new relapse and no enlarging or new T2 or T1 Gd-enhancing lesion. CDP will be assessed using EDSS. Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment.
Percentage of Participants Who Are Relapse Free Week 192 Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment.
Change From Baseline in Brain Volume as Detected by Brain MRI From Baseline to Weeks 24, 48, 96, 144, 192 Percentage change from Normalized brain volume in cm3 (cubic centimeter)values are reported
Percentage of Participants Without Treatment Discontinuation Baseline up to 4 years Secondary: Change From Baseline in Multiple Sclerosis Functional Composite Score (MSFC) Total Weeks 24, 48, 72, 96, 120, 144, 168, 192 MSFC combines the following: Timed 25 Foot Walk Test \[T25FWT\] for leg function \&ambulation measured in seconds (sec). The longer it takes to walk, higher the score indicating deterioration; 9 Hole Peg Test \[9HPT\] for arm \& handf unction measured in sec. Higher score=more time taken to complete test indicating deterioration. Paced Auditory Serial Addition Test \[PASAT\] for cognitive function (score range: 0-60, higher score=better cognitive processing speed). MSFC composite={\[Average(1/9-HPT)-Baseline Mean(1/9-HPT)/Baseline Std Dev(1/9-HPT)\]+\[-(Average T25FWT-Baseline Mean T25FWT)/Baseline Std-Dev T25FWT\]+\[(PASAT-3-BaselineMean PASAT-3)/Baseline Std Dev PASAT-3\]}/ 3.0. MSFC is based on the concept that scores for these 3 dimensions are combined to create a single score to detect change over time in a group of MS patients. Higher composite score=better overall function. Lower score=worse overall function. Higher mean change in total MSFC score=functional improvement at cohort level.
Change From Baseline in MSFC Composite Timed 25 Foot Walk Test (T25FW) Score. Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192 The change in the mean score of T25FW is reported below. The time taken to walk 25 feet, typically measured in seconds. The longer it takes to walk, the higher score, which indicates deterioration. Lower times indicate better performance and greater mobility. Higher times indicate worse performance and greater impairment. Subsequently, the lower the mean change in the score over time, the better performance.
Change From Baseline in MSFC Composite 9 Hole Peg Test (9HPT) Score Weeks 24, 48, 72, 96, 120, 144, 168, 192 The mean change in 9 Hole Peg Test (9HPT)-score is reported. Participants are instructed to place pegs one by one into each of nine holes arranged in a board stabilized with a plastic nonslip sheet on a solid table, and then to remove these pegs from the holes. Both the dominant and non-dominant hands are tested twice (two consecutive trials for each hand). The participants are required to complete two successful trials for each hand. The amount of time (in seconds) required to place and remove all nine pegs is recorded for each trial. The number of seconds it takes to complete the test, the higher raw scores, which indicates deterioration. The lower mean change in the score over time, the better the performance.
Change From Baseline in MSFC Composite (Paced Auditory Serial Addition Test [PASAT]) Score Weeks 24, 48, 72, 96, 120, 144, 168, 192 Mean change in the Paced Auditory Serial Addition Test \[PASAT\] score is reported. PASAT measures cognitive function. A total of 60 single digit numbers are presented by an audiotape/CD-rom at a constant rate in every 3 seconds (PASAT-3). Participants are required to add each new number to the one immediately before it. Due to the relative complexity of this test, a practice trial with a set of 10 numbers should be performed before the original test. Participants are allowed up to 3 practice trials. Two sets of numbers (forms A \& B) are developed to be used alternatively in every visit to minimize memorizing. The number of correct answers is recorded. The PASAT score ranges from 0 to 60, with higher values representing a better outcome in cognitive processing speed. Subsequently, higher values in mean changes from baseline over the study time indicate improvement in cognitive function.
Percentage of Participants With No Evidence of Protocol Defined Disease Activity Weeks 96, 144, 192 Protocol-defined disease activity is defined as having at least one of the following: (1). protocol defined relapse (occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis \[MS\], as determined using EDSS/Functional Systems Score \[FSS\] assessment). (2). CDP, as determined using EDSS. (3). a T1 Gd-enhanced lesion after Week 8. (4). a new and/or enlarging T2 hyperintense lesion on magnetic resonance imaging (MRI) after Week 8 compared to the Week 8 MRI scan. Event-free rate
Change From Baseline in Cognitive Performance as Measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) - Symbol Digits Modalities Test (SDMT) Baseline, Weeks 48, 96, 144, 192 BICAMS is assessing cognitive processing speed and verbal and visual memory. SDMT assesses processing speed/working memory. The SDMT presents a series of nine symbols, each paired with a single digit in a key at the top of a standard sheet of paper. Participants are asked to voice the digit associated with each symbol as rapidly as possible for 90 sec. There is a single outcome measure - the number correct over the 90 second time span. The higher the results, the better processing speed/working memory.
Change From Baseline in Cognitive Performance as Measured by BICAMS -California Verbal Learning Test-II (CVLT-II) Baseline, Weeks 48, 96, 144, 192 BICAMS assesses cognitive processing speed and verbal and visual memory. The CLVT-II is an assessment of verbal learning and memory which measures recall and recognition scores, encoding strategies, learning rates and error types. A list learning task with 16 words from 4 semantic categories are read over a series of 5 list presentations. Recall is assessed after learning and at a 20-minute delay. The maximum possible score is 80 and a minimum is 0. A higher score indicated better recall.
Change From Baseline in Cognitive Performance as Measured by BICAMS - Brief Visuospatial Memory Test-Revised (BVMT-R) Baseline, Weeks 48, 96, 144, 192 BICAMS assesses cognitive processing speed and verbal and visual memory. BVMT-R assesses visuospatial memory. In this test, six abstract designs are presented for 10 sec. The display is removed from view and patients render the stimuli via pencil on paper manual responses. Each design receives from 0 to 2 points representing accuracy and location. There are three learning trials, and the outcome measure is the total number of points earned over the three learning trials, thus the scale range is 0-36. The higher the result, the better visual/spatial memory.
Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI Weeks 24, 48, 96, 144, 192 Number of Lesions are categorized as followed: 1, 2, 3, \>1, \>3
Total Number of New and/or Enlarging T2 Lesion as Detected by Brain MRI Baseline, Weeks 24, 48, 96, 144, 192 Number of Lesions are categorized as followed: 1, 2, 3, \>1
Change From Baseline in Total T1 Hypointense Lesion Volume as Detected by Brain MRI Baseline, Weeks 48, 96, 144, 192 Employment Status: Work Productivity and Activity Impairment Questionnaire (WAPI) Score Baseline, Weeks 24, 48, 96, 120, 144, 192 WPAI scale measures impact of health problems on work productivity and regular activities: Absenteeism (Work Time Missed) measuring % of work time missed due to health issues; Presenteeism:Calculated as the percentage of impairment while working due to health problems. Overall Work Impairment:Calculated by combining absenteeism and presenteeism using the formula:Overall Work Impairment=Absenteeism+(1-Absenteeism)×Presenteeism Overall Work Impairment=Absenteeism+(1-Absenteeism)×Presenteeism This formula accounts for both the time missed and the reduced productivity while at work.
Activity Impairment: Calculated as the percentage of impairment in regular activities outside of work. Range: Each component is scored as 0%-100%). Higher % indicate greater impairment and worse outcomes.SymptoMScreen Composite Score Baseline, Weeks 24, 48, 96, 144, 192 The SMSS consists of 12 items which are assessed on a seven-point Likert scale that ranges from 0 (not at all affected) to 6 (total limitation) \[7\]. The total score ranges from 0 to 72, with higher scores indicating more severe symptom endorsement.
Quality of Life: Multiple Sclerosis Impact Scale (MSIS)-29 Questionnaire Score Baseline, Weeks 24, 48, 96, 144, 192 The 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a questionnaire to examine the impact of multiple sclerosis (MS) on physical and psychological functioning from a patient's perspective, which includes 29 items self-reported measures associated with a physical scale and 9 items with a psychological scale. MSIS-29 scales are generated by summing items and it's ranging from 29-145'. The higher total MSIS-29 scores indicate a greater degree of disability. The mean change in MSIS-29 scores from baseline is reported. The decreasing values in the mean change from baseline indicate functional improvement from patients' perspective
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Baseline up to 4 years Substudy: Number of Participants With IRR Overall and by Dose at Randomization From Week 24 to Week 144 Substudy: Number of IRR Symptoms From Week 24 to Week 144
Trial Locations
- Locations (193)
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Kane Hall Barry Neurology
🇺🇸Bedford, Texas, United States
MultiCare Health System Institute for Research and Innovation
🇺🇸Tacoma, Washington, United States
Wheaton Franciscan Healthcare - St. Francis Outpatient Center; Center for Neurological Disorders
🇺🇸Milwaukee, Wisconsin, United States
Centro de Especialidades Neurológicas y Rehabilitación - CENyR
🇦🇷Buenos Aires, Argentina
Hospital Churruca Visca
🇦🇷Buenos Aires, Argentina
Fundacion Rosarina de Neurorehabilitacion
🇦🇷Rosario, Argentina
Brain and Mind Centre
🇦🇺Camperdown, New South Wales, Australia
Liverpool Hospital
🇦🇺Liverpool, New South Wales, Australia
John Hunter Hospital
🇦🇺New Lambton, New South Wales, Australia
Royal North Shore Hospital; Department of Neurology
🇦🇺St Leonards, 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
Perron Institute for Neurological and Translational Science
🇦🇺Nedlands, Western Australia, Australia
Medizinische Universität Graz; Universitätsklinik für Neurologie
🇦🇹Graz, Austria
Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck; Department fuer Neurologie
🇦🇹Innsbruck, Austria
Christian-Doppler-Klinik - Universitätsklinikum; Universitätskliniik für Neurologie
🇦🇹Salzburg, Austria
Medizinische Universität Wien; Univ.Klinik fuer Neurologie
🇦🇹Wien, Austria
AZ Sint Jan
🇧🇪Brugge, Belgium
UZ Brussel
🇧🇪Brussel, Belgium
Cliniques Universitaires St-Luc
🇧🇪Bruxelles, Belgium
UZ Antwerpen
🇧🇪Edegem, Belgium
CHU Tivoli
🇧🇪La Louvière, Belgium
CHU Sart-Tilman
🇧🇪Liège, Belgium
Revalidatie en MS Centrum
🇧🇪Overpelt, Belgium
Hospital das Clinicas - UFMG
🇧🇷Belo Horizonte, MG, Brazil
Instituto de Neurologia de Curitiba
🇧🇷Curitiba, PR, Brazil
Hospital Sao Lucas - PUCRS
🇧🇷Porto Alegre, RS, Brazil
Hospital das Clinicas - FMUSP
🇧🇷Sao Paulo, SP, Brazil
Shat Np Sveti Naum; 3Rd Clinic of Neurology
🇧🇬Sofia, Bulgaria
Multiprofile Hosp. for Active Treatment;National Cardiology Hosp.
🇧🇬Sofia, Bulgaria
UMHAT Alexandrovska, EAD; Neurology
🇧🇬Sofia, Bulgaria
UBC Hospital; Div of Neurology, Dept of Medicine
🇨🇦Vancouver, British Columbia, Canada
London Health Sciences Centre Uni Campus
🇨🇦London, Ontario, Canada
Ottawa Hospital Research Institute
🇨🇦Ottawa, Ontario, Canada
Sunnybrook Health Science Centre
🇨🇦Toronto, Ontario, Canada
Clinique NeuroOutaouais
🇨🇦Gatineau, Quebec, Canada
Recherche Sepmus Inc.
🇨🇦Greenfield Park, Quebec, Canada
Montreal Neurological Institute and Hospital
🇨🇦Montreal, Quebec, Canada
Clinical Hospital Centre Zagreb
🇭🇷Zagreb, Croatia
Aalborg Universitetshospital; Neurologisk Afdeling og Neurofysiologisk Afdeling; Skleroseamb.
🇩🇰Aalborg, Denmark
Aarhus Universitetshospital; Neurologisk Afd. F, Skleroseklinikken
🇩🇰Aarhus N, Denmark
Rigshospitalet; Neurologisk Klinik Glostrup
🇩🇰Glostrup, Denmark
CHU Hopital Gabriel Montpied; Service de Neurologie
🇫🇷Clermont Ferrand, France
CHU de Besancon Hopital Jean Minjoz; Service de Neurologie
🇫🇷Besançon, France
Hopital Pellegrin-CHU de Bordeaux; Service de Neurologie
🇫🇷Bordeaux, France
Hopital Pierre Wertheimer; Neurologie D
🇫🇷Bron, France
CHU de Caen Hopital Cote de Nacre
🇫🇷Caen, France
CH de Gonesse; Neurologie
🇫🇷Gonesse, France
CHU de Grenoble; Neurologie
🇫🇷La Tronche, France
Hopital Gui de Chauliac; Neurologie
🇫🇷Montpellier, France
Hopital Central - CHU de Nancy; Service de Neurologie
🇫🇷Nancy, France
Hôpital Guillaume et René Laënnec; Service Neurologie
🇫🇷Nantes, France
Hôpital Pasteur; Service de Neurologie
🇫🇷Nice, France
CHU de Nîmes Hopital Caremeau; Service de Neurologie
🇫🇷Nimes, France
Hôpital de Poissy; Service neurologie
🇫🇷Poissy, France
Centre Hospitalier Universitaire de Rennes
🇫🇷Rennes, France
CHU de Rouen Hopital; Service de Neurologie
🇫🇷Rouen, France
CHU de Strasbourg
🇫🇷Strasbourg, France
Hopital Foch; Neurologie
🇫🇷Suresnes, France
HIA de Toulon hôpital militaire; Neurologie
🇫🇷Toulon, France
CHU toulouse - Hôpital Purpan; Departement de Neurologie
🇫🇷Toulouse, France
CHRU - Hôpital Bretonneau; Neurologie
🇫🇷Tours, France
Praxis Dr.med. Sylvia Menck, Fachärztin für Neurologie und Psychiatrie
🇩🇪Barsinghausen, Germany
Jüdisches Krankenhaus Berlin; Abteilung fur Neurologie
🇩🇪Berlin, Germany
St. Josef-Hospital, Klinik für Neurologie
🇩🇪Bochum, Germany
Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften
🇩🇪Dresden, Germany
Universitätsklinikum Düsseldorf; Klinik für Neurologie
🇩🇪Düsseldorf, Germany
NeuroCentrum Odenwald; Dres. Reifschneider, Unsorg, Ries, Schumann, Hoffmann, Knoblich
🇩🇪Erbach/Odenwald, Germany
Universitätsklinikum Essen (AöR); Klinik für Neurologie
🇩🇪Essen, Germany
MultipEL Studies - Institut für klinische Studien
🇩🇪Hamburg, Germany
Universitaetsklinikum Heidelberg
🇩🇪Heidelberg, Germany
Neurologische Gemeinschaftspraxis Kassel und Vellmar, Ch. Lassek, Dres. Ammerbach, Fetzer, M. Fische
🇩🇪Kassel, Germany
Uniklinik Schleswig-Holstein; Neuroimmunologie, Institut für Klinische Chemie + Klinik f. Neurologie
🇩🇪Kiel, Germany
Universitaetsklinikum Marburg; Klinik fuer Neurologie
🇩🇪Marburg, Germany
Klinikum rechts der Isar der TU Muenchen; Neurologische Klinik und Poliklinik im Neuro-Kopf-Zentrum
🇩🇪München, Germany
Universitätsklinikum Münster; Klinik und Poliklinik für Neurologie
🇩🇪Münster, Germany
Praxis Dr. med. Bergmann
🇩🇪Neuburg, Germany
Asklepios Kliniken Schildautal Seesen; Klinik für Neurologie
🇩🇪Seesen, Germany
Universitätsklinikum Tübingen, Zentrum für Neurologie
🇩🇪Tübingen, Germany
Semmelweis Egyetem AOK; Neurologiai Klinika
🇭🇺Budapest, Hungary
Budapesti Uzsoki Utcai Kórház
🇭🇺Budapest, Hungary
Jahn Ferenc Dél-Pesti Kórház
🇭🇺Budapest, Hungary
VALEOMED Diagnosztikai Központ
🇭🇺Esztergom, Hungary
Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ; Neurológiai Klinika
🇭🇺Szeged, Hungary
Ospedale Cattinara; Amb Studio Sclerosi Multipla, Clinica Neurlogica
🇮🇹Trieste, Friuli-Venezia Giulia, Italy
Policlinico Tor Vergata Dip. Neuroscienze-Clinica Neurologica-UOSD Sclerosi Multipla
🇮🇹Roma, Lazio, Italy
Azienda Ospedaliera Sant'Andrea; UOC Neurologia
🇮🇹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
A.O.U. Mater Domin; U.O. NEUROLOGIA
🇮🇹Catanzaro, Calabria, Italy
AO Ospedali Riuniti Villa Sofia-Cervello;PO Villa Sofia - UO Neurologia - U.O.S. Neuroimmunologia
🇮🇹Palermo, Sicilia, Italy
AOU Careggi; Neurologia 1-Dip. Neuroscienze Psicologia Area Farmaco Salute del Bambino(NEUROFARBA)
🇮🇹Firenze, Toscana, Italy
A. O. U. Federico II; Dip Neuroscienze, Scienze Riproduttive ed Odontostomatologiche
🇮🇹Napoli, Campania, Italy
Università degli Studi della Campania Luigi Vanvitelli; Dip. Ass. Integrato Med Int-II Clinica Neur
🇮🇹Napoli, Campania, Italy
Fond. Istituto Neurologico C.Besta; UO Neurologia IV - Neuroimmunologia Malattie Neuromuscolari
🇮🇹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
AOU Policlinico V. Emanuele - P.O G. Rodolico; Clinica Neurologica, Centro Sclerosi Multipla
🇮🇹Catania, Sicilia, Italy
Ospedale Misericordia USL9 di Grosseto; U.O. Neurologia
🇮🇹Grosseto, Toscana, Italy
Ospedale Le Scotte; Clinica Neurologica e Malattie Neurometaboliche
🇮🇹Siena, Toscana, Italy
Ibn Sina Hospital; Neurology Department
🇰🇼Kuwait, Kuwait
Unidad de investigacion en salud (UIS); Neurociencias
🇲🇽Ciudad de México, Mexico
American University of Beirut - Medical Center
🇱🇧Beirut, Lebanon
Neurociencias Estudios Clinicos S.C.
🇲🇽Culiacán, Sinaloa, Mexico
Hospital General de Mexico
🇲🇽Mexico, Tlaxcala, Mexico
Jeroen Bosch Ziekenhuis
🇳🇱'S Hertogenbosch, Netherlands
VU Medisch Centrum; Afdeling Neurologie
🇳🇱Amsterdam, Netherlands
Groene Hart Ziekenhuis
🇳🇱Gouda, Netherlands
Malopolskie Centrum Diagnostyczne MEDICAL Sp. z o. o.
🇵🇱Krakow, Poland
Centrum Neurologii Krzysztof Selmaj
🇵🇱Lodz, Poland
Zuyderland Medisch Centrum - Sittard Geleen
🇳🇱Sittard-Geleen, Netherlands
Akershus universitetssykehus HF; Nevroklinikken S203
🇳🇴Lørenskog, Norway
Stavanger Universitetssykehus, Helse Stavanger HF
🇳🇴Stavanger, Norway
Neurocentrum Bydgoszcz sp. z o.o
🇵🇱Bydgoszcz, Poland
COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika; Oddzia? Neurologiczny
🇵🇱Gdansk, Poland
Care Clinic
🇵🇱Katowice, Poland
Indywidualna Praktyka Lekarska Prof. Dr Hab. N. Med. Konrad Rejdak.
🇵🇱Lublin, Poland
Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie
🇵🇱Warszawa, Poland
Instytut Psychiatrii i Neurologii II Klinika Neurologiczna
🇵🇱Warszawa, Poland
Hospital Garcia de Orta; Servico de Neurologia
🇵🇹Almada, Portugal
Hospital de Braga; Servico de Neurologia
🇵🇹Braga, Portugal
HUC; Servico de Neurologia
🇵🇹Coimbra, Portugal
Hospital Beatriz Angelo; Servico de Neurologia
🇵🇹Loures, Portugal
Hospital Geral de Santo Antonio; Servico de Neurologia
🇵🇹Porto, Portugal
Spitalul Universitar de Urgenta Bucuresti
🇷🇴Bucharest, Romania
Spitalul Clinic Judetean Sibiu
🇷🇴Sibiu, Romania
Spitalul Clinic Judetean de Urgenta Mures
🇷🇴Targu-Mures, Romania
Univerzitna nemocnica Bratislava, Nemocnica Staré Mesto; I. Neurologická klinika SZU a UNB
🇸🇰Bratislava, Slovakia
GB NeuroPRAKTIK, s.r.o
🇸🇰Nitra, Slovakia
Univerzitna nemocnica Bratislava - Nemocnica Ruzinov; Neurologicka klinika SZU a UNB
🇸🇰Bratislava, Slovakia
Fakultna nemocnica Trnava
🇸🇰Trnava, Slovakia
University Medical Centre; Neurology
🇸🇮Ljubljana, Slovenia
University Medical Centre Maribor
🇸🇮Maribor, Slovenia
Complejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Neurologia
🇪🇸Santa Cruz De Tenerife, Tenerife, Spain
Hospital de Cruces; Servicio de Neurologia
🇪🇸Barakaldo, Vizcaya, Spain
Hospital General Universitario de Alicante; Servicio de Neurología
🇪🇸Alicante, Spain
Hospital del Mar; Servicio de Neurologia
🇪🇸Barcelona, Spain
Hospital Vall d'Hebron; Servicio de Neurología
🇪🇸Barcelona, Spain
Hospital Universitario Puerta De Hierro Majadahonda; Servicio de Neurología
🇪🇸Madrid, Spain
Hospital General Universitario Morales Meseguer; Servicio de Neurología
🇪🇸Murcia, Spain
Sahlgrenska Sjukhuset; Neurology
🇸🇪Göteborg, Sweden
Centralsjukhuset; Neurologi och rehabiliteringskliniken
🇸🇪Karlstad, Sweden
Centrum för Neurologi
🇸🇪Stockholm, Sweden
Universitätsspital Basel; Neurologie
🇨🇭Basel, Switzerland
Ospedale Regionale di Lugano - Civico; Neurologia
🇨🇭Lugano, Switzerland
Kantonsspital; Neurologische Klinik
🇨🇭St. Gallen, Switzerland
Inselspital Bern Medizin Neurologie; Neurologische Poliklinik
🇨🇭Bern, Switzerland
Hacettepe University Medical Faculty; Neurology
🇹🇷Ankara, Turkey
Luzerner Kantonsspital Luzern Medizin Neurologie
🇨🇭Luzern, Switzerland
Gazi University Medical Faculty; Departmant of Norology
🇹🇷Ankara, Turkey
Mustafa Kemal Ataturk UTF; Department of norology
🇹🇷Hatay, Turkey
Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi; Noroloji Anabilim Dali
🇹🇷Istanbul, Turkey
Istanbul University Istanbul Medical Faculty; Neurology
🇹🇷Istanbul, Turkey
Istanbul Bilim Universty Medical Fac.
🇹🇷Istanbul, Turkey
Selcuk University Medical Faculty; Norology department
🇹🇷Istanbul, Turkey
Ondokuz Mayis Univ. Med. Fac.; Neurology
🇹🇷Samsun, Turkey
Karadeniz Tecnical Uni. Med. Fac.; Neurology
🇹🇷Trabzon, Turkey
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
Queen Elizabeth University Hospital
🇬🇧Glasgow, United Kingdom
Royal Free Hospital
🇬🇧London, United Kingdom
King'S College Hospital
🇬🇧London, United Kingdom
Charing Cross Hospital
🇬🇧London, United Kingdom
National Hospital for Neurology and Neurosurgery,; MRC Centre for Neuromuscular Diseases
🇬🇧London, United Kingdom
Royal Victoria Infirmary
🇬🇧Newcastle upon Tyne, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Salford Royal NHS Foundation Trust
🇬🇧Salford, United Kingdom
Abertawe and Bro Morgannwg NHS Trust; Clinical Researdh Institute
🇬🇧Swansea, United Kingdom
Studienzentrum Dr. Bischof GmbH
🇩🇪Böblingen, Germany
University of California Irvine
🇺🇸Irvine, California, United States
Palo Alto Medical Foundation Research Center
🇺🇸Sunnyvale, California, United States
University of Colorado Denver
🇺🇸Aurora, Colorado, United States
Advanced Neurology of Colorado, LLC
🇺🇸Fort Collins, Colorado, United States
KI Health Partners, LLC; New England Institute for Clinical Research
🇺🇸Stamford, Connecticut, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
University of South Florida - Bradenton
🇺🇸Tampa, Florida, United States
Shepherd Center Inc.
🇺🇸Atlanta, Georgia, United States
College Park Family Care Ctr
🇺🇸Overland Park, Kansas, United States
The NeuroMedical Center
🇺🇸Baton Rouge, Louisiana, United States
Maine Medical Center
🇺🇸Scarborough, Maine, United States
University of Maryland Medical Center; Department of Neurology
🇺🇸Baltimore, Maryland, United States
Neurology Center of New England
🇺🇸Foxboro, Massachusetts, United States
Dragonfly Research, LLC
🇺🇸Wellesley, Massachusetts, United States
Minneapolis Clinic of Neurology
🇺🇸Golden Valley, Minnesota, United States
Cleveland Clinic Lou Ruvo; Center for Brain Research
🇺🇸Las Vegas, Nevada, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Island Neurological Associates, P.C.
🇺🇸Plainview, New York, United States
Neurology Associates PA
🇺🇸Hickory, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Cleveland Clinic Foundation; Cleveland Clinic Cancer Center/I40
🇺🇸Cleveland, Ohio, United States
Neurology Specialists, Inc
🇺🇸Dayton, Ohio, United States