Efficacy and Safety Study of Satralizumab (SA237) as Add-on Therapy to Treat Participants With Neuromyelitis Optica (NMO) and NMO Spectrum Disorder (NMOSD)
- Conditions
- Neuromyelitis Optica (NMO)NMO Spectrum Disorder (NMOSD)
- Interventions
- Registration Number
- NCT02028884
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
The objective of this study is to evaluate the efficacy, safety, pharmacodynamic, pharmacokinetic, and immunogenic profiles of satralizumab, compared with placebo, in addition to baseline immunosuppressive treatment in participants with NMO and NMOSD.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 85
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Patients must be diagnosed as having either neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), defined as the following:
- NMO as defined by Wingerchuk et al. 2006 criteria (requires all of the following 3 criteria: I. Optic neuritis, II. Acute myelitis, III. At least two of three supportive criteria: Contiguous spinal cord lesion identified on a magnetic resonance imaging (MRI) scan extending over 3 vertebral segments; Brain MRI not meeting diagnostic criteria for multiple sclerosis (MS); NMO-IgG seropositive status)
- NMOSD as defined by either of the following Wingerchuk 2007 criteria with anti-AQP4 antibody (Ab) seropositive status at screening (i. Idiopathic single or recurrent events of longitudinally extensive myelitis [≥3 vertebral segment spinal cord MRI lesion]; ii. Optic neuritis: recurrent or simultaneous bilateral); For patients aged 12 to 17 years, a minimum of 4 patients should be positive for anti-AQP4Ab status at screening
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Clinical evidence of at least 2 documented relapses (including first attack) in the last 2 years prior to screening, at least one of which has occurred in the 12 months prior to screening
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EDSS score from 0 to 6.5 inclusive at screening
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Age 12 to 74 years, inclusive at the time of informed consent
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One of the following baseline treatments must be at stable dose as a monotherapy for 8 weeks prior to baseline: Azathioprine; Mycophenolate mofetil; Oral corticosteroids. For participants aged 12 to 17 years, either of the following baseline treatments for relapse prevention can be allowed: Azathioprine + oral corticosteroids; Mycophenolate mofetil + oral corticosteroids
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Ability and willingness to provide written informed consent and to comply with the requirements of the protocol
For adolescents who may be enrolled after the end of the double-blind period, the inclusion criterion 2 is as follows (other criteria are same): Clinical evidence of at least 2 documented relapses (including first attack) prior to screening.
Exclusion criteria related to previous or concomitant therapy:
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Any previous treatment with IL-6 inhibitory therapy (e.g. tocilizumab), alemtuzumab, total body irradiation or bone marrow transplantation at any time
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Any previous treatment with anti-CD20, eculizumab, belimumab, interferon, natalizumab, glatiramer acetate, fingolimod, teriflunomide or dimethyl fumarate within 6 months prior to baseline
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Any previous treatment with anti-CD4, cladribine or mitoxantrone within 2 years prior to baseline
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Treatment with any investigational agent within 3 months prior to baseline
Exclusions for general safety:
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Pregnancy or lactation
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For patients of reproductive potential, a positive result from a serum pregnancy test at screening, or not willing to use reliable means of contraception (physical barrier [patient or partner] in conjunction with a spermicidal product, contraceptive pill, patch, injectables, intrauterine device or intrauterine system) during the treatment period and for at least 3 months after the last dose of study drug
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Any surgical procedure (except for minor surgeries) within 4 weeks prior to baseline
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Evidence of other demyelinating disease or progressive multifocal leukoencephalopathy (PML)
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Evidence of serious uncontrolled concomitant diseases that may preclude patient participation, such as: other nervous system disease, cardiovascular disease, hematologic/hematopoiesis disease, respiratory disease, muscular disease, endocrine disease, renal/urologic disease, digestive system disease, congenital or acquired severe immunodeficiency
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Known active infection (excluding fungal infections of nail beds or caries dentium) within 4 weeks prior to baseline
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Evidence of chronic active hepatitis B or C
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History of drug or alcohol abuse within 1 year prior to baseline
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History of diverticulitis that, in the Investigator's opinion, may lead to increased risk of complications such as lower gastrointestinal perforation
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Evidence of active tuberculosis (TB; excluding patients receiving chemoprophylaxis for latent TB infection)
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Evidence of active interstitial lung disease
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Receipt of any live or live attenuated vaccine within 6 weeks prior to baseline
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History of malignancy within the last 5 years, including solid tumors, hematologic malignancies and in situ carcinoma (except basal cell and squamous cell carcinomas of the skin, or in situ carcinoma of the cervix uteri that have been completely excised and cured)
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History of severe allergic reaction to a biologic agent (e.g. shock, anaphylactic reactions)
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Active suicidal ideation within 6 months prior to screening, or history of suicide attempt within 3 years prior to screening
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Following laboratory abnormalities at screening*.
- White blood cells (WBC) <3.0 x10^3/microliter (μL)
- Absolute neutrophil count (ANC) <2.0 x10^3/μL
- Absolute lymphocyte count <0.5 x10^3/μL
- Platelet count <10 x 10^4/μL
- Aspartate aminotransferase (AST) or alanine aminotranferase (ALT) >1.5 times the upper limit of normal (ULN) * If retest is conducted, the last value of retest before randomization must meet study criteria.
For adolescents who may be enrolled after the end of the double-blind period, the annotation in the exclusion criterion 20 is as follows (other criteria are same): * If retest is conducted, the last value of retest before baseline must meet study criteria
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + Baseline Treatment Placebo Participants randomized to this arm for the double-blind period will receive placebo in addition to baseline treatment.The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021. Placebo + Baseline Treatment Baseline Treatment Participants randomized to this arm for the double-blind period will receive placebo in addition to baseline treatment.The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021. Satralizumab + Baseline Treatment Baseline Treatment Participants randomized to this arm for the double-blind period will receive satralizumab in addition to baseline treatment. The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021. Satralizumab + Baseline Treatment Satralizumab Participants randomized to this arm for the double-blind period will receive satralizumab in addition to baseline treatment. The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021.
- Primary Outcome Measures
Name Time Method Time to First Protocol-Defined Relapse (TFR) in the Double-Blind Period Up to Week 224 TFR was defined as time from randomization to first occurrence of relapse in the DB period. Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD) as adjudicated by an independent clinical endpoint committee (CEC). Symptoms had to persist for \>24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred \< 31 days following onset of a protocol-defined relapse were considered part of same relapse (i.e., if 2 relapses had onset days that were 30 days of one another, they were counted only as 1 relapse), and onset date used in analysis was the date of first relapse.
- Secondary Outcome Measures
Name Time Method Change From Baseline at Week 24 in the Visual Analogue Scale (VAS) Score for Pain During the DB Period Baseline, Week 24 The VAS is a subjective measure of pain consisting of a 100 mm line with two endpoints representing 0 = "no pain" and 100 = "pain as bad as it could be". Participants rated their pain by placing a mark on the line corresponding to their current level of pain. The distance along the line from the "no pain" marker was measured with a ruler giving a pain score out of 100. A higher score indicated more pain and lower scores reflected a better health state. A negative change from baseline indicates an improvement. ANCOVA was used for analysis to report the adjusted mean and standard error (SE).
Change From Baseline in Expanded Disability Status Scale (EDSS) Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The EDSS is an ordinal scale with values from 0 points (normal neurological examination) to 10 points (death) increasing in half-point increments once an EDSS of 1.0 has been reached. Higher scores represent increased disability. A negative change from baseline indicates an improvement.
Change From Baseline at Week 24 in the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score During the DB Period Baseline, Week 24 The FACIT Fatigue scale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the past 7 days. As each of the 13 items of the scale ranges from 0-4, the range of possible scores was computed using FACIT scoring algorithm as 0-52, where 0 is the worst possible score and 52 the best which indicated less fatigue. A positive change from baseline indicates an improvement. ANCOVA was used for analysis to report the adjusted mean and SE.
Relapse-Free Rate During the DB Period Up to Week 216 Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD). Symptoms had to persist for \>24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred \< 31 days following onset of a protocol-defined relapse were considered part of same relapse (i.e., if 2 relapses had onsets within 30 days of one another, they were counted as 1), and onset date used in analysis was the date of first relapse.
Annualized Relapse Rate (ARR) During the DB Period Up to Week 216 The ARR is calculated as the total number of participants with relapses experienced divided by the patient-years at risk. Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological NMO or NMOSD. Symptoms had to persist for \>24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred \< 31 days following onset of a protocol-defined relapse were considered part of same relapse (2 relapses with onset days in 30 days of one another was counted as 1 relapse), onset date used in analysis was the date of first relapse.
Change From Baseline in Modified Rankin Scale (mRS) Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The mRS is a 7-point disability scale that assesses the degree of disability in participants with neurological impairment. Possible scores range from 0 (no symptoms at all) up to 6 (death). Higher scores reflect increased disability. A negative change from baseline indicates an improvement.
Change From Baseline in Zarit Burden Interview (ZBI) Scores at 24 Week Intervals During the DB Period Baseline up to Week 168 The ZBI is the measurement to assess caregiver burden. The 22 items ask for the strain caregivers perceive. Responses range from 0 (never) to 4 (nearly always). The overall ZBI score ranges from 0 to 88. The higher the total score, the heavier the perceived burden. A negative change from baseline indicates an improvement.
Change From Baseline in SF-36 General Health Domain Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in SF-36 Mental Health Domain Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in Visual Acuity (Snellen Chart) at 24 Week Intervals During the DB Period Baseline up to Week 216 Visual acuity was measured using Snellen 20-foot wall chart and then converted to logMAR visual acuity scoring. Lower values indicate better visual acuity. Data are reported for right eye (OD) and left eye (OS). A negative change from baseline indicates an improvement.
Change From Baseline in Short Form Generic Health Survey (SF-36) Mental Component Summary Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health summary measures and a preference-based health utility index. The component scores were transformed to a 0-100 scale, where higher score indicates better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in SF-36 Physical Component Summary Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health summary measures and a preference-based health utility index. The component scores were transformed to a 0-100 scale, where higher score indicates better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in SF-36 Bodily Pain Domain Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in SF-36 Physical Functioning Domain Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in SF-36 Role-Emotional Domain Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in SF-36 Role-Physical Domain Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in SF-36 Social Role Functioning Domain Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in SF-36 Vitality Domain Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.
Change From Baseline in EuroQoL-5 Dimensions (EQ-5D) Index Scores at 24 Week Intervals During the DB Period Baseline up to Week 216 The EQ-5D is a participant-answered questionnaire measuring 5 dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression with 3 possible response categories: 1) no problems; 2) some problems; 3) severe problems. The scores from 5 dimensions are used as input to generate EQ-5D index score using scoring algorithm. The EQ-5D index score is scored on a scale of -0.2 to 1. A higher score reflects a better health state. A positive change from baseline indicates an improvement.
Serum Satralizumab Concentration During the DB Period Baseline, Weeks 2, 4, 5, 6, 8, and every 4 weeks thereafter up to Week 224 Serum Soluble IL-6 Receptor (sIL-6R) Concentration During the DB Period Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 224 Serum High Sensitivity C-Reactive Protein (hsCRP) Concentration During the DB Period Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 224 Serum Interleukin-6 (IL-6) Concentration During the DB Period Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 224 Number of Participants With at Least One Adverse Event in the DB Period Up to Week 224 An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events.
Number of Participants With at Least One Serious Adverse Event in the DB Period Up to Week 224 A serious adverse event is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is medically significant or requires intervention to prevent one or other of the outcomes listed above.
Number of Participants With Non-Serious Adverse Events of Special Interest in the DB Period Up to Week 224 Non-serious adverse events of special interest for this study included: 1) cases of an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice, 2) suspected transmission of an infectious agent by the study treatment.
Number of Participants With Selected Adverse Events in the DB Period Up to Week 224 Selected adverse events for this study included: 1) non-serious infections that required treatments with intravenous (IV) antibiotic, antifungal, antiviral, 2) opportunistic infections that required treatments with oral antibiotics, antifungals, or antivirals, 3) injection-related reactions (IRRs; an AE which occured within 24 hours after study treatment injection except where the event was not considered an allergic reaction), and 4) anaphylaxis (an acute allergic/hypersensitivity reaction).
Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia-Suicide Severity Rating Scale in the DB Period Baseline and Post-Baseline (up to Week 224) The Columbia-Suicide Severity Rating Scale (C-SSRS) is an assessment tool to evaluate suicidal ideation and behavior. Categories have binary responses (yes/no) and include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation or behavior is indicated by a "yes" answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. A score of 1 or higher indicates suicidal ideation or behavior.
Percentage of Participants With Anti-Drug Antibodies to Satralizumab in the DB Period Up to approximately Week 224 Reported here is the percentage of participants with at least one positive anti-drug antibody measurement during the DB period.
Percentage of Participants With Anti-Drug Antibodies to Satralizumab Overall S237 Period Up to approximately Week 368 Reported here is the percentage of participants with at least one positive anti-drug antibody measurement during Overall S237 period.
Trial Locations
- Locations (40)
Hopital de Hautepierre CHRU de Strasbourg
🇫🇷Strasbourg, France
NeuroCure Clinical Research Center (NCRC)
🇩🇪Berlin, Germany
M.A. - LEK A. M. Maciejowscy SC. Centrum Terapii SM
🇵🇱Katowice, Poland
St. Josef-Hospital, Klinik für Neurologie
🇩🇪Bochum, Germany
Tohoku University Hospital; Neurology
🇯🇵Sendai, Japan
John Radcliffe Hospital; Neurosciences
🇬🇧Chinnor, United Kingdom
Juntendo University Hospital; Neurology
🇯🇵Bunkyo-ku, Japan
Great Ormond Street Hospital For Children; Neurology
🇬🇧London, United Kingdom
Ospedale San Raffaele
🇮🇹Milano, Lombardia, Italy
Fukushima Medical University Hospital; Neurology
🇯🇵Fukushima, Japan
Fond. Ist. S. Raffaele - giglio
🇮🇹Cefalu, Sicilia, Italy
Kindai University Hospital; Neurology
🇯🇵Osaka, Japan
Osaka University Hospital; Neurology
🇯🇵Suita, Japan
Heinrich-Heine Universitätsklinik Düsseldorf
🇩🇪Düsseldorf, Germany
NZOZ Wielospecjalistyczna Poradnia Lekarska SYNAPSIS
🇵🇱Katowice, Poland
University Hospital of Wales; Dept of Neurology
🇬🇧Cardiff, United Kingdom
The National Hospital for Neurology & Neurosurgery
🇬🇧London, United Kingdom
Hospital Clinico San Carlos; Servicio de Nefrologia
🇪🇸Madrid, Spain
KZ "Dnipropetrovska oblasna dytiacha klinichna likarnia" DOR
🇺🇦Dnipropetrovsk, Tavria Okruha, Ukraine
Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
🇵🇱Lublin, Poland
Kharkivska miska dytiacha likarnia # 5
🇺🇦Kharkiv, Kharkiv Governorate, Ukraine
Centrum Medyczne Dendryt
🇵🇱Katowice, Poland
Szpital Kliniczny im. H.Swiecickiego UM w Poznaniu
🇵🇱Pozna?, Poland
Chang Gung Medical Foundation - LinKou Chang Gung Memorial Hospital - Neurology
🇨🇳Kwei Shen, Taiwan
China Medical University Hospital; Neurology - Taichung
🇨🇳Taichung, Taiwan
Samodzielny Publiczny Centralny Szpital Klinicznyi
🇵🇱Warszawa, Poland
Instytut Psychiatrii i Neurologii
🇵🇱Warsaw, Poland
National Taiwan University Hospital; Neurology
🇨🇳Taipei, Taiwan
National Cheng Kung University Hospital; Neurology
🇨🇳Tainan, Taiwan
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Jahn Ferenc Dél-Pesti Kórház
🇭🇺Budapest, Hungary
Azienda Ospedaliera Sant'Andrea-Universitr di Roma La Sapien
🇮🇹Roma, Lazio, Italy
Kyushu University Hospital; Neurology
🇯🇵Fukuoka, Japan
PO G.Rodolico, AOU Policlinico-Vittorio Emanuele Catania
🇮🇹Catania, Sicilia, Italy
Niigata University Medical and Dental Hospital; Neurology
🇯🇵Niigata, Japan
Kagoshima University Medical And Dental Hospital; Neurology and Geriatorics
🇯🇵Kagoshima, Japan
National Center of Neurology and Psychiatry
🇯🇵Tokyo, Japan
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Taipei Veterans General Hospital-Neurology
🇨🇳Taipei, Taiwan
Tokyo Women's Medical University Hospital; Neurology
🇯🇵Shinjuku-ku, Japan