A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS)

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04548999

Collaborator

(none)

699

Enrollment

212

Locations

Arms

95.4

Anticipated Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks in participants with PPMS, in comparison to the approved 600 mg dose of ocrelizumab.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Ocrelizumab Drug: Ocrelizumab Drug: Antihistamine Drug: Methylprednisolone	Phase 3

Detailed Description

Participants will be treated for a minimum of 120 weeks in the double-blind phase. Upon positive primary results after the double-blind phase, an optional higher dose extension treatment (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 lower limit of normal.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

699 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase IIIB Multicenter, Randomized, Double-Blind, Controlled Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis

Actual Study Start Date :

Dec 3, 2020

Anticipated Primary Completion Date :

Mar 4, 2025

Anticipated Study Completion Date :

Nov 14, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ocrelizumab Higher Dose Participants will be randomized to receive a minimum of 5 higher treatment doses (1200 mg or 1800 mg) of ocrelizumab administered by intravenous (IV) infusion every 24 weeks in the double blind treatment (DBT) phase. During the optional open-label extension (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.	Drug: Ocrelizumab The actual higher dose of ocrelizumab will be assigned to participants based on their body weight at baseline: 1200 mg (participants's body weight <75 kg) or 1800 mg (participant's body weight >/=75 kg). The first dose of ocrelizumab will be administered as two 600 mg or 900 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 1200 mg or 1800 mg IV infusion every 24 weeks. Other Names: Ocrevus Drug: Antihistamine Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion. Other Names: Non-Investigational Medicinal Product Drug: Methylprednisolone Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion. Other Names: Non-Investigational Medicinal Product
Active Comparator: Ocrelizumab Approved Dose Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by intravenous (IV) infusion every 24 weeks 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.	Drug: Ocrelizumab Ocrelizumab will be administered at a dose of 600 milligram (mg) every 24 weeks. The first dose of ocrelizumab will be administered as two 300 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 600 mg IV infusion every 24 weeks. Other Names: Ocrevus Drug: Antihistamine Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion. Other Names: Non-Investigational Medicinal Product Drug: Methylprednisolone Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion. Other Names: Non-Investigational Medicinal Product

Arm

Intervention/Treatment

Experimental: Ocrelizumab Higher Dose

Participants will be randomized to receive a minimum of 5 higher treatment doses (1200 mg or 1800 mg) of ocrelizumab administered by intravenous (IV) infusion every 24 weeks in the double blind treatment (DBT) phase. During the optional open-label extension (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.

Drug: Ocrelizumab

The actual higher dose of ocrelizumab will be assigned to participants based on their body weight at baseline: 1200 mg (participants's body weight <75 kg) or 1800 mg (participant's body weight >/=75 kg). The first dose of ocrelizumab will be administered as two 600 mg or 900 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 1200 mg or 1800 mg IV infusion every 24 weeks.

Other Names:

Ocrevus

Drug: Antihistamine

Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion.

Other Names:

Non-Investigational Medicinal Product

Drug: Methylprednisolone

Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.

Other Names:

Non-Investigational Medicinal Product

Active Comparator: Ocrelizumab Approved Dose

Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by intravenous (IV) infusion every 24 weeks 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.

Drug: Ocrelizumab

Ocrelizumab will be administered at a dose of 600 milligram (mg) every 24 weeks. The first dose of ocrelizumab will be administered as two 300 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 600 mg IV infusion every 24 weeks.

Other Names:

Ocrevus

Drug: Antihistamine

Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion.

Other Names:

Non-Investigational Medicinal Product

Drug: Methylprednisolone

Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.

Other Names:

Non-Investigational Medicinal Product

Outcome Measures

Primary Outcome Measures

1. Reduction in cCDP sustained for at least 12 weeks, measured by time to onset of 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 EDSS, T25FWT or 9-HPT.

Secondary Outcome Measures

Time to Onset of 24-week cCDP (cCDP24) [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.
Time to Onset of 12-week CDP (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 24-week CDP (CDP24) [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 >/= 20% Increase in 12-week Confirmed by Timed 25-Foot Walk Test (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.
Time to >/= 20% Increase in 24-week Confirmed 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.
Time to >/= 20% Increase in 12-week Confirmed by 9-Hole Peg Test (9-HPT) [Baseline up to approximately 4.3 years]
The 9-HPT is a performance measure used to assess upper extremity (arm and hand) function. The test consists of a container containing nine pegs and a wood or plastic block containing nine empty holes. The participant is to pick up each of the nine pegs one at a time and as quickly as possible place them in the nine holes. Once all the pegs are in the holes, the participant is to remove them again one at a time as quickly as possible and replace them into the container. The total time to complete the task is recorded.
Time to >/= 20% Increase in 24-week Confirmed by 9-HPT [Baseline up to approximately 4.3 years]
The 9-HPT is a performance measure used to assess upper extremity (arm and hand) function. The test consists of a container containing nine pegs and a wood or plastic block containing nine empty holes. The participant is to pick up each of the nine pegs one at a time and as quickly as possible place them in the nine holes. Once all the pegs are in the holes, the participant is to remove them again one at a time as quickly as possible and replace them into the container. The total time to complete the task is recorded.
Change from Baseline in the Multiple Sclerosis Impact Scale (MSIS 29) Score [Baseline up to approximately 4.3 years]
The MSIS-29 is a 29-item participant-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).
Change from baseline in the Multiple Sclerosis Impact Scale-29 (MSIS-29) physical scale at Week 120 [Baseline, week 120]
Annual Rate of Percent Change from Baseline in Total Brain 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.
Serum Concentration 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]
Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood [Baseline up to approximately 4.3 years]
Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood in Participants with the High versus Low Affinity Fcgamma Receptor 3A (FcgR3A) Genotype per Arm [Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120]
Change from Baseline in the Anti-Drug Antibody (ADA) Levels [Week 0, 24, 48, 72, 96, 120]
Levels of Neurofilament Light Chain (NfL) in Blood [Baseline up to approximately 4.3 years]
Levels of Interleukin-6 (IL-6) in Blood [Baseline up to approximately 4.3 years]
Levels of Blood B-cells [Baseline up to approximately 4.3 years]
Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
Levels of Lymphocytes in Blood [Baseline up to approximately 4.3 years]
Proportion of Participants with Different DNA Genotypes [Week 0, 2, 12, 24, 48, 72, 96, 120]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of primary progressive multiple sclerosis (PPMS).
Expanded disability status scale (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 scale for the pyramidal system that was due to lower extremity findings at screening and baseline.
Documented 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 less or equal to 5, disease duration must be less than 10 years; If EDSS score at screening is more than 5, disease duration must be less than 15 years
Documented evidence of the presence of at least one cerebrospinal fluid-specific oligoclonal bands.
For females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods.
For female participants without reproductive potential, may be enrolled if post-menopausal unless receiving a hormonal therapy for her menopause or if surgically sterile.

Exclusion Criteria:

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 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-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 intravenous (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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Neurology Associates	Homewood	Alabama	United States	35209
2	21st Century Neurology	Phoenix	Arizona	United States	85004
3	Center for Neurosciences	Tucson	Arizona	United States	85718
4	University of California Irvine	Irvine	California	United States	92697
5	SC3 Research Group, Inc	Pasadena	California	United States	91105
6	University of California Davis Health System; Department of Neurology	Sacramento	California	United States	95817
7	Stanford University Medical Center; Stanford Neuroscience Health Center	Stanford	California	United States	94305
8	Los Angeles Biomedical Research Institute at Harbor-UCLA	Torrance	California	United States	90502
9	University of Colorado Denver	Aurora	Colorado	United States	80045
10	Mountain Neurological Research Center; Roaring Fork Neurologt, P.C.	Basalt	Colorado	United States	81621
11	Colorado Neurological Institute	Englewood	Colorado	United States	80113
12	Advanced Neurosciences Research LLC	Fort Collins	Colorado	United States	80524
13	KI Health Partners, LLC; New England Institute for Clinical Research	Stamford	Connecticut	United States	06905
14	SFM Clinical Research, LLC	Boca Raton	Florida	United States	33487
15	MS and Neuromuscular Center of Excellence	Clearwater	Florida	United States	33761
16	Elite Clinical Research	Miami	Florida	United States	33144
17	Infinity Clinical Research, LLC	Sunrise	Florida	United States	33351
18	Axiom Clinical Research of Florida	Tampa	Florida	United States	33609
19	University of South Florida	Tampa	Florida	United States	33612
20	University of Chicago Hospital	Chicago	Illinois	United States	60637
21	Baptist Health Lexington	Nicholasville	Kentucky	United States	40356
22	Maine Medical Center	Scarborough	Maine	United States	04074
23	International Neurorehabilitation Institute	Lutherville	Maryland	United States	21093
24	Massachusetts General Hospital.	Boston	Massachusetts	United States	02114
25	Neuro Institute of New England P.C.; Research	Foxboro	Massachusetts	United States	02035
26	Dragonfly Research, LLC	Wellesley	Massachusetts	United States	02481
27	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
28	Michigan Institute for Neurological Disorders	Farmington Hills	Michigan	United States	48334
29	Memorial Healthcare Institute for Neurosciences and Multiple Sclerosis	Owosso	Michigan	United States	48867
30	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
31	The MS Center for Innovations In Care	Saint Louis	Missouri	United States	63131
32	Jersey Shore University Medical Centre	Neptune	New Jersey	United States	07753
33	Northwell Health	Great Neck	New York	United States	11021
34	Lenox Hill Hospital	New York	New York	United States	10075
35	Atrium Health Neurosciences Institute - Charlotte	Charlotte	North Carolina	United States	28204
36	University of Cincinnati; Department of Neurology	Cincinnati	Ohio	United States	45267
37	Cleveland Clinic	Cleveland	Ohio	United States	44195
38	OhioHealth Research Institute	Columbus	Ohio	United States	43214
39	Premier Neurology	Greer	South Carolina	United States	29650
40	Neurology Clinic PC	Cordova	Tennessee	United States	38018
41	Wesley Neurology Clinic	Cordova	Tennessee	United States	38018
42	New Orleans Center for Clinical Research	Knoxville	Tennessee	United States	37920
43	Advanced Neurosciences Institute	Nashville	Tennessee	United States	37205
44	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
45	Baylor College of Medicine	Houston	Texas	United States	77030
46	Neurology Center of San Antonio	San Antonio	Texas	United States	78212
47	Texas Institute for Neurological Disorders	Sherman	Texas	United States	75092
48	Meridian Clinical Research	Norfolk	Virginia	United States	23502
49	Wheaton Franciscan Healthcare - St. Francis Outpatient Center; Center for Neurological Disorders	Milwaukee	Wisconsin	United States	53215
50	CEMIC Saavedra	Buenos Aires		Argentina	C1431FWO
51	Instituto DIABAID	Ciudad Autónoma de Buenos Aires		Argentina	C1061ABD
52	INECO; Neurociencias	Rosario		Argentina	S2000QGB
53	CH EpiCURA Site Ath	Ath		Belgium	7800
54	Revalidatie en MS Centrum	Overpelt		Belgium	3900
55	L2 Ip Instituto de Pesquisas Clinicas Ltda ME; Centro Medico Hospitalar	Brasilia	DF	Brazil	70200-730
56	Hospital das Clinicas - UFG	Goiania	GO	Brazil	74605-020
57	Instituto de Neurologia de Curitiba	Curitiba	PR	Brazil	81210-310
58	Instituto Méderi de Pesquisa e Saúde	Passo Fundo	RS	Brazil	99010-120
59	Hospital Moinhos de Vento	Porto Alegre	RS	Brazil	90035-000
60	IMV Pesquisa Neurológica	Porto Alegre	RS	Brazil	90110-000
61	Hospital Sao Lucas - PUCRS	Porto Alegre	RS	Brazil	90610-000
62	Clinica Neurologica; Neurocirurgica de Joinville	Joinville	SC	Brazil	89202-190
63	Hospital das Clinicas - UNICAMP	Campinas	SP	Brazil	13083-887
64	Praxis Pesquisa Médica	Santo Andre	SP	Brazil	09090-790
65	CPQuali Pesquisa Clinica Ltda	Sao Paulo	SP	Brazil	01228-000
66	Hospital das Clinicas - FMUSP	Sao Paulo	SP	Brazil	05403-900
67	UMHAT Dr. Georgi Stranski; 2nd Neurology Clinic, Occupational Diseases	Pleven		Bulgaria	5800
68	MHATNP Sveti Naum EAD	Sofia		Bulgaria	1113
69	University of British Columbia	Vancouver	British Columbia	Canada	V6T 1Z4
70	CIUSSS du Saguenay Lac-Saint-Jean, Chicoutimi Hospital	Chicoutimi	Quebec	Canada	G7H 5H6
71	Chum Campus Notre Dame	Montreal	Quebec	Canada	H2X 0A9
72	MUCH - Montreal Neurological Institute & Hospital	Montreal	Quebec	Canada	H3A 2B4
73	Hotel-Dieu de Levis	Quebec		Canada	G1W 4R4
74	Fakultni nemocnice u sv. Anny; Neurologicka klinika	Brno		Czechia	656 91
75	Fakultni nemocnice Ostrava; MS centrum	Ostrava-Poruba		Czechia	708 52
76	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	12808
77	Aalborg Universitetshospital; Neurologisk Afdeling og Neurofysiologisk Afdeling; Skleroseamb.	Aalborg		Denmark	9000
78	Rigshospitalet Glostrup; Neurologisk Klinik	Glostrup		Denmark	2600
79	Odense Universitetshospital, Neurologisk Afdeling N; Neurologisk Ambulatorium N5; Skleroseklinikken	Odense C		Denmark	5000
80	CHU de Besancon Hopital Jean Minjoz; Service de Neurologie	Besançon		France	25030
81	CHU Brest Hopital La Cavale Blanche; Neurologie	Brest		France	29609
82	Hopital Pierre Wertheimer; Neurologie D	Bron		France	69677
83	Hopital Cote De Nacre; Unite Neurologie Generale	Caen		France	14033
84	CHU Hopital Gabriel Montpied; Service de Neurologie	Clermont Ferrand		France	63003
85	CH St Vincent de Paul	Lille		France	59000
86	Hopital Central - CHU de Nancy; Service de Neurologie	Nancy		France	54035
87	Hopital Hautepierre - CHU Strasbourg; Service de Neurologie	Strasbourg		France	67098
88	Gesundheitszentrum St. Johannes Hospital; Neurolog. Gemeinschaftspraxis Dres. Schmidt, Neudecker etc	Bonn		Germany	53111
89	Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften	Dresden		Germany	01307
90	Universitätsmedizin Greifswald; Klinik und Poliklinik für Neurologie	Greifswald		Germany	17475
91	Universitätsmedizin Göttingen Georg-August-Universität	Göttingen		Germany	37075
92	Krankenhaus Martha-Maria Hallo-Dölau, Klinik für Neurologie	Halle (Saale)		Germany	06120
93	Medizinische Hochschule Hannover, Klinik für Neurologie	Hannover		Germany	30625
94	Universitätsklinikum Jena, Klinik für Neurologie	Jena		Germany	07747
95	Universitätsklinikum Schleswig-Holstein; Klinik für Neurologie	Kiel		Germany	24105
96	Universität Leipzig; Innere Medizin, Neurologie, Dermatologie	Leipzig		Germany	04103
97	Universitaetsklinikum Marburg; Klinik fuer Neurologie	Marburg		Germany	35043
98	Universitätsklinikum Münster; Klinik und Poliklinik für Neurologie	Münster		Germany	48149
99	Praxis Dr. med. Bergmann	Neuburg		Germany	86633
100	Neurozentrum Stuttgart Mitte Sophienstraße; Neurologische Gemeinschaftspraxis	Stuttgart		Germany	70178
101	Krankenhaus der Barmherzigen Brüder Trier; Neurologie, Neurophysiol. neurolog.Reha/Schlaganfalleinh	Trier		Germany	54292
102	Universitätsklinikum Tübingen, Zentrum für Neurologie	Tübingen		Germany	72076
103	Universitätsklinikum Ulm; Klinik für Neurologie	Ulm		Germany	89081
104	Deutsche Klinik für Diagnostik; DKD Helios Klinik Wiesbaden, Abt. Neurologie	Wiesbaden		Germany	65191
105	401 Military Hospital of Athens; Neurology Department	Athens		Greece	115 25
106	University General Hospital of Larisa; Neurology Clinic	Larisa		Greece	411 10
107	AHEPA Univ. General Hospital of Thessaloniki; B' Neurology Dept.	Thessaloniki		Greece	546 36
108	Hospital Eginition; First Department of Neurology	Αθηνα		Greece	115 28
109	Orszagos Mentalis, Ideggyogyaszati es Idegsebeszeti Intezet; Neurology	Budapest		Hungary	1145
110	UNO Medical Trials Kft.	Budapest		Hungary	1152
111	Petz Aladar Megyei Oktato Korhaz; Neurologiai Osztaly	Gyor		Hungary	9024
112	Somogy Megyei Kaposi Mor Oktato Korhaz; Department of Neurology	Kaposvár		Hungary	7400
113	Pest Megyei Flor Ferenc Korhaz; Neurology and Stroke Ambulance	Kistarcsa		Hungary	2143
114	A. O. U. Federico II; Dip Neuroscienze, Scienze Riproduttive ed Odontostomatologiche	Napoli	Campania	Italy	80131
115	AOU Seconda Università degli Studi; Dip.Assistenziale Integrato Medicina Int-I Clinica Neurologica	Napoli	Campania	Italy	80138
116	Ospedale S.Camillo Forlanini; UOSD Day Hospital Neurologico e Neurochirurgico	Roma	Lazio	Italy	00152
117	Azienda Ospedaliera Sant'Andrea; UOC Neurologia	Roma	Lazio	Italy	00189
118	ASST PAPA GIOVANNI XXIII Neurologia USS Malattie Autoimmuni Centro Sclerosi Multipla	Bergamo	Lombardia	Italy	24127
119	Ospedale S.Antonio Abate; Neurologia 2 - Sclerosi Multipla e Recupero Neurologico	Gallarate	Lombardia	Italy	21013
120	IRCCS Ospedale San Raffaele; Neurologia Neurofisiologia Neuroriabilitazione-Centro Sclerosi Multipla	Milano	Lombardia	Italy	20132
121	IRCCS Istituto Neurologico C. Mondino-Dip. Neurologia Neuroriabilitazione S.S. Sclerosi Multipla	Pavia	Lombardia	Italy	27100
122	AOU Città della Salute e della Scienza; Neurologia 1	Torino	Piemonte	Italy	10126
123	Ospedale Binaghi; Centro Sclerosi Multipla	Cagliari	Sardegna	Italy	09126
124	AOU Senese; UOC Clinica Neurologica e Malattie neurometaboliche	Siena	Toscana	Italy	53100
125	Grupo Médico Camino S.C.	Ciudad de México	Mexico CITY (federal District)	Mexico	03600
126	Clinstile S.A de C.V.	Mexico City	Mexico CITY (federal District)	Mexico	06700
127	Neurociencias Prisma, A.C	San Luis Potosí	SAN LUIS Potosi	Mexico	78216
128	Centro de Investigacion Medico Biologico y Terapia Avanzada, S.C.	Guadalajara		Mexico	44130
129	Hospital Nacional Guillermo Almenara Irigoyen	La Victoria, Lima		Peru	Lima 13
130	Hospital Nacional Dos de Mayo; Unidad de Investigacion de Neurologia	Lima		Peru	15003
131	Instituto Nacional de Ciencias Neurológicas - Hospital Mogrovejo; Peru	Lima		Peru	Lima 01
132	Clinica Sanchez Ferrer	Trujillo		Peru	13009
133	Neurocentrum Bydgoszcz sp. z o.o	Bydgoszcz		Poland	85-796
134	COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika; Oddział Neurologiczny	Gdansk		Poland	80-803
135	MA-LEK Clinical Sp. Z o.o.	Katowice		Poland	40-595
136	Specjalistyczny Szpital Sw. Lukasza	Konskie		Poland	26-200
137	Szpital Specjalistyczny im. Rydygiera w Krakowie; Oddzial Neurologii i Udarow Mozgu	Krakow		Poland	31-637
138	Centrum Neurologii Krzysztof Selmaj	Lodz		Poland	90-324
139	Indywidualna Praktyka Lekarska Prof. Dr Hab. N. Med. Konrad Rejdak.	Lublin		Poland	20-016
140	Wojewodzki Szpital Specjalistyczny	Olsztyn		Poland	10-561
141	Instytut Zdrowia Dr Boczarska-Jedynak Sp. z o.o. Sp. k.	Oswiecim		Poland	32-600
142	Neurologiczny Niepubliczny ZOZ Centrum Leczenia SM Osrodek Badań Klinicznych	Plewiska		Poland	62-064
143	EMC Instytut Medyczny SA	Poznań		Poland	60-309
144	Wojewódzki Szpital Specjalistyczny Nr 3	Rybnik		Poland	44-200
145	Nzoz Palomed	Rzeszów		Poland	35-232
146	NEURO-CARE Sp. z o.o. Sp. Komandytowa	Siemianowice Śląskie		Poland	41-100
147	Osrodek Badan Klinicznych Euromedis	Szczecin		Poland	70-111
148	Centrum Medyczne NeuroProtect	Warszawa		Poland	01-684
149	Instytut Psychiatrii i Neurologii II Klinika Neurologiczna	Warszawa		Poland	02-957
150	Wojskowy Instytut Medyczny Centralny Szpital Kliniczny MON	Warszawa		Poland	04-141
151	Hospital Garcia de Orta; Servico de Neurologia	Almada		Portugal	2801-951
152	Hospital de Braga; Centro Clínico Académico (Piso 1, Ala E)	Braga		Portugal	4710-243
153	Hospital Santo Antonio dos Capuchos; Servico de Neurologia	Lisboa		Portugal	1169-050
154	Centro Hospitalar de Lisboa Ocidental - Hospital Egas Moniz; Neurologia	Lisboa		Portugal	1349-019
155	Hospital Geral de Santo Antonio; Servico de Neurologia	Porto		Portugal	4099-001
156	Centro Hospitalar de Setubal, EPE - Hospital São Bernardo; Serviço de Neurologia	Setúbal		Portugal	2910-446
157	San Juan MS Center	Guaynabo		Puerto Rico	00968
158	FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency	Krasnoyarsk	Krasnojarsk	Russian Federation	660037
159	Krasnoyarsk State Medical Academy	Krasnoyarsk	Krasnojarsk	Russian Federation	660049
160	National Center of Social Significant Disease	Sankt-peterburg	Leningrad	Russian Federation	197110
161	Research Center of Neurology of RAMS	Moscow	Moskovskaja Oblast	Russian Federation	125367
162	Federal center of brain research and neurotechnologies	Moskva	Moskovskaja Oblast	Russian Federation	117997
163	City Clinical Hospital #24; Multipal Sclerosis department	Moskva	Moskovskaja Oblast	Russian Federation	127015
164	N.P. Bechtereva Institute of the Human Brain	Sankt-petersburg	Sankt Petersburg	Russian Federation	197376
165	City Hospital #40 of Kurortniy Administrative District	St. Petersburg	Sankt Petersburg	Russian Federation	197706
166	Ulyanovsk Regional Clinical Hospital	Ulyanovsk	Uljanovsk	Russian Federation	432063
167	SHI Sverdlovsk Regional Clinical Hospital #1;Neurology	Ekaterinburg		Russian Federation	620102
168	State Autonomous Healthcare Institution "Republican Clinical Neurological Center	Kazan		Russian Federation	420021
169	Center of Cardiology and Neurology	Kirov		Russian Federation	610007
170	Regional clinical hospital named after prof. S.V. Ochapovsky	Krasnodar		Russian Federation	350086
171	FSBIH Siberian Regional Medical Centre of FMBA of Russia	Novosibirsk		Russian Federation	630007
172	Perm SMA n.a. academ. E.A. Vagner	Perm		Russian Federation	614990
173	Leningrad Regional Clinical Hospital	St Petersburg		Russian Federation	194291
174	SBEI of HPE "Bashkir State Medical University" of MoH RF	Ufa		Russian Federation	450000
175	Hospital Quiron de Madrid; Servicio de Neurologia	Pozuelo de Alarcon	Madrid	Spain	28223
176	Hospital Universitario Virgen de Arrixaca; Servicio de Neurología	EL Palmar (EL Palmar)	Murcia	Spain	30120
177	Hospital Universitari Vall d'Hebron; Servicio de Neumo-Inmunologia	Barcelona		Spain	08035
178	Hospital Universitario Puerta de Hierro; Servicio de Neurologia	Madrid		Spain	28222
179	Kantonsspital Aarau AG Medizin Neurologie; Neurologie	Aarau		Switzerland	5001
180	Inselspital Bern Medizin Neurologie; Neurologische Poliklinik	Bern		Switzerland	3010
181	Ospedale Regionale di Lugano - Civico; Neurologia	Lugano		Switzerland	6903
182	Gazi University Medical Faculty	Ankara		Turkey	06500
183	Haseki Training and Research Hospital; Department of Neurology	Istanbul		Turkey	34096
184	Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi; Noroloji Anabilim Dali	Istanbul		Turkey	34098
185	Sancaktepe Training and Research Hospital; Neurology	Istanbul		Turkey	34785
186	Erciyes Universitesi; Pediatric Neurology	Kayseri		Turkey	38039
187	Kocaeli University Hospital; Department of Neurology	Kocaeli		Turkey	41380
188	Selcuk University Medical Faculty; Norology department	Konya		Turkey	42131
189	Ege Üniversitesi Tip Fakültesi	Lzmir		Turkey	35100
190	Cumhuriyet Universitesi Tip Fakultesi; Noroloji Bolumu	Merkez		Turkey	58060
191	Mersin University Medical Faculty; Neurology	Mersin		Turkey	33079
192	Ondokuz Mayis University School of Medicine; Neurology	Samsun		Turkey	55139
193	Baskent Universitesi Ankara Hastanesi; Noroloji Bolumu	Çankaya		Turkey	06490
194	Medical Center Dopomoga Plus	Kyiv	Chernihiv Governorate	Ukraine	02123
195	Municipal Non-profit Enterprise Zaporizhzhya Regional Hospital Zaporizhzhya Regional Council	Zaporizhzhia	Katerynoslav Governorate	Ukraine	69600
196	Municipal Nonprofit Enterprise of Kharkiv Regional Council Regional Clinical Hospital	Kharkiv	Kharkiv Governorate	Ukraine	61058
197	State Institution Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine	Kharkiv	Kharkiv Governorate	Ukraine	61068
198	Medical Center of Private Execution First Private Clinic	Kyiv	KIEV Governorate	Ukraine	03037
199	Lvivska oblasna tsentralna likarnia	Lviv	KIEV Governorate	Ukraine	79010
200	Medical Clinical Research Center of Medical Center LLC Health Clinic	Vinnytsia	Podolia Governorate	Ukraine	21009
201	Sumy Regional Clinical Hospital	Sumy	Polissya Okruha	Ukraine	40031
202	Miska Klinichna Likarnia №16	Dnipropetrovsk	Tavria Okruha	Ukraine	49100
203	Municipal Institution Cherkasy Regional Hospital of Cherkasy Regional Council	Cherkasy		Ukraine	18009
204	Regional Clinical Hospital; Neurology Department	Ivano-Frankivsk		Ukraine	76008
205	St.In.Inst. of Neurol.Psych.and Narcol.of the AMSU; Dept. of Neuroinfection and Multiply Sclerosis	Kharkov		Ukraine	61068
206	Volyn Regional Clinical Hospital	Lutsk		Ukraine	43024
207	University Hospital of Wales	Cardiff		United Kingdom	CF14 4XW
208	Charing Cross Hospital	London		United Kingdom	W6 8RF
209	National Hospital for Neurology and Neurosurgery,; MRC Centre for Neuromuscular Diseases	London		United Kingdom	WC1 3BG
210	Royal Victoria Infirmary	Newcastle upon Tyne		United Kingdom	NE1 4LP
211	University of Nottingham	Nottingham		United Kingdom	NG7 2UH
212	Derriford Hospital	Plymouth		United Kingdom	PL6 8DH