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

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04544436

Collaborator

(none)

786

Enrollment

203

Locations

Arms

89.6

Anticipated Duration (Months)

3.9

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 RMS, 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 low level 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 :

786 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 Relapsing Multiple Sclerosis

Actual Study Start Date :

Nov 26, 2020

Anticipated Primary Completion Date :

Aug 20, 2024

Anticipated Study Completion Date :

May 15, 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-Investigation 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-Investigation 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-Investigation 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-Investigation Medicinal Product

Outcome Measures

Primary Outcome Measures

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.
Change from baseline in the Multiple Sclerosis Impact Scale-29 (MSIS-29) physical scale at Week 120 [Baseline, Week 120]
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).
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 Time points [Week 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 relapsing multiple sclerosis (RMS) (i.e., RRMS or aSPMS where participants still experience relapses) in accordance with the revised McDonald Criteria 2017
At least two documented clinical relapses within the last 2 years prior to screening, or one clinical relapse in the year prior to screening. No relapse 30 days prior to screening and at baseline.
Participants must be neurologically stable for at least 30 days prior to randomization and baseline.
Expanded disability status scale (EDSS) score, at screening and baseline, from 0 to 5.5 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 at screening and over four trials at baseline respectively, up to 250 (inclusive) seconds
Documented MRI of brain with abnormalities consistent with MS at screening.
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.
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 primary 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 within 24 weeks prior to screening 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.
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
Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab
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	North Central Neurology Associates	Cullman	Alabama	United States	35058
2	Alabama Neurology Associates	Homewood	Alabama	United States	35209
3	21st Century Neurology	Phoenix	Arizona	United States	85004
4	North County Neurology Associates	Carlsbad	California	United States	92011
5	University of California Davis Medical Center	Sacramento	California	United States	95817
6	Stanford University Medical Center; Stanford Neuroscience Health Center	Stanford	California	United States	94305
7	Collaborative Neuroscience Network Inc.	Torrance	California	United States	90502
8	Mountain Neurological Research Center; Roaring Fork Neurologt, P.C.	Basalt	Colorado	United States	81621
9	Colorado Neurological Institute	Englewood	Colorado	United States	80113
10	Advanced Neurology of Colorado, LLC	Fort Collins	Colorado	United States	80528
11	SFM Clinical Research, LLC	Boca Raton	Florida	United States	33487
12	MS and Neuromuscular Center of Excellence	Clearwater	Florida	United States	33761
13	Neurology Associates, PA; Research Department	Maitland	Florida	United States	32751
14	University of South Florida	Tampa	Florida	United States	33612
15	Shepherd Center Inc.	Atlanta	Georgia	United States	30309
16	Consultants in Neurology Ltd	Northbrook	Illinois	United States	60062
17	American Health Network Institute, LLC	Avon	Indiana	United States	46123
18	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
19	The NeuroMedical Clinic of Central Louisiana	Alexandria	Louisiana	United States	71301
20	Maine Medical Center	Scarborough	Maine	United States	04074
21	Massachusetts General Hospital.	Boston	Massachusetts	United States	02114
22	Dragonfly Research, LLC	Wellesley	Massachusetts	United States	02481
23	Wayne State University; Department of Neurology	Detroit	Michigan	United States	48201
24	Henry Ford Health System	Detroit	Michigan	United States	48202
25	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
26	Cleveland Clinic Lou Ruvo; Center for Brain Research	Las Vegas	Nevada	United States	89106
27	Dent Neurological Institute	Amherst	New York	United States	14226
28	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
29	UC Health Neurology	Dayton	Ohio	United States	45417
30	Oklahoma Medical Research Foundation; MS Center of Excellence	Oklahoma City	Oklahoma	United States	73104
31	Abington Neurological Associates	Abington	Pennsylvania	United States	19001
32	Tri-State Mountain Neurology	Johnson City	Tennessee	United States	37604
33	Hope Neurology	Knoxville	Tennessee	United States	37922
34	Bhupesh Dihenia M.D. P.A.	Lubbock	Texas	United States	79410
35	Central Texas Neurology Consultants	Round Rock	Texas	United States	78681
36	Neurology Center of San Antonio	San Antonio	Texas	United States	78212
37	Evergreen MS Center	Kirkland	Washington	United States	98034
38	CEMIC	Buenos Aires		Argentina	C1431FWO
39	Instituto DIABAID	Ciudad Autónoma de Buenos Aires		Argentina	C1061ABD
40	Centro de Investigaciones Médicas Tucuman; REUMATHOLOGY	San Miguel		Argentina	T4000AXL
41	Concord Repatriation General Hospital	Concord	New South Wales	Australia	2139
42	Specialists on College; Neurology	Kent Town	South Australia	Australia	5067
43	Austin Hospital; Department of Neurology	Heidelberg	Victoria	Australia	3084
44	Hospital Erasme	Bruxelles		Belgium	1070
45	CHU Tivoli	La Louvière		Belgium	7100
46	Revalidatie en MS Centrum	Overpelt		Belgium	3900
47	Instituto de Neurologia de Curitiba	Curitiba	PR	Brazil	81210-310
48	IMV Pesquisa Neurológica	Porto Alegre	RS	Brazil	90110-000
49	Clinica Neurologica; Neurocirurgica de Joinville	Joinville	SC	Brazil	89202-190
50	CPQuali Pesquisa Clinica Ltda	Sao Paulo	SP	Brazil	01228-000
51	Hospital das Clinicas - FMUSP	Sao Paulo	SP	Brazil	05403-900
52	Foothills Medical Centre; Centre Dept of Medical Clinical Neuroscience	Calgary	Alberta	Canada	T2N 2T9
53	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 1Z1
54	Fraser Health Authority - Fraser Health Multiple Sclerosis	Burnaby	British Columbia	Canada	V5G 2X6
55	University of British Columbia	Vancouver	British Columbia	Canada	V6T 1Z4
56	The Ottawa Hospital - General Campus; Department of Neurology - Multiple Sclerosis	Ottawa	Ontario	Canada	K1H 8L6
57	St. Michael'S Hospital	Toronto	Ontario	Canada	M5B 1W8
58	Recherche Sepmus, Inc.	Greenfield Park	Quebec	Canada	J4V 2J2
59	Chum Campus Notre Dame	Montreal	Quebec	Canada	H2X 0A9
60	Centre Hospitalier Affilie Universitaire de Quebec - Hopital de L'Enfant Jesus	Quebec City	Quebec	Canada	G1J 1Z4
61	Hotel-Dieu de Levis	Quebec		Canada	G1W 4R4
62	Fakultni nemocnice u sv. Anny; Neurologicka klinika	Brno		Czechia	656 91
63	Charles University, Medical faculty, Hradec Kralove ;Department of Neurology	Hradec Králové		Czechia	500 05
64	Nemocnice Jihlava; NEU-Neurologicke oddeleni	Jihlava		Czechia	58633
65	Krajska Nemocnice Pardubice Neurologicka Klinika	Pardubice		Czechia	532 03
66	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	12808
67	Fakultni nemocnice Motol; Neurologicka klinika	Praha		Czechia	150 06
68	Nemocnice Teplice; Neurologicke Oddeleni - Ms Centrum	Teplice		Czechia	415 29
69	Rigshospitalet Glostrup; Neurologisk Klinik	Glostrup		Denmark	2600
70	CHU de Besancon Hopital Jean Minjoz; Service de Neurologie	Besançon		France	25030
71	Groupe Hospitalier Pellegrin; Service de Neurologie - 3ème étage	Bordeaux		France	33076
72	CHU Brest Hopital La Cavale Blanche; Neurologie	Brest		France	29609
73	Hopital Cote De Nacre; Unite Neurologie Generale	Caen		France	14033
74	CHU Hopital Gabriel Montpied; Service de Neurologie	Clermont Ferrand		France	63003
75	CH St Vincent de Paul	Lille		France	59000
76	Hôpital Charles Nicolle; Service de Neurologie	Rouen		France	76031
77	Charite - Universitätsmedizin Berlin	Berlin		Germany	12203
78	St. Josef-Hospital, Klinik für Neurologie	Bochum		Germany	44791
79	Gesundheitszentrum St. Johannes Hospital; Neurolog. Gemeinschaftspraxis Dres. Schmidt, Neudecker etc	Bonn		Germany	53111
80	Studienzentrum für Neurologie und Psychiatrie	Böblingen		Germany	71034
81	Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften	Dresden		Germany	01307
82	Gemeinschaftspraxis für Neurologie; Dr. Katrin Schulte, Dr. Nils Richter, Dr. Margarete Capito	Düsseldorf		Germany	40211
83	Krankenhaus Martha-Maria Hallo-Dölau, Klinik für Neurologie	Halle (Saale)		Germany	06120
84	Medizinische Hochschule Hannover, Klinik für Neurologie	Hannover		Germany	30625
85	Universitätsklinikum Jena, Klinik für Neurologie	Jena		Germany	07747
86	Neurologische Gemeinschaftspraxis Kassel und Vellmar, Ch. Lassek, Dres. Ammerbach, Fetzer, M. Fische	Kassel		Germany	34121
87	Universitätsklinikum Schleswig-Holstein; Klinik für Neurologie	Kiel		Germany	24105
88	Universität Leipzig; Innere Medizin, Neurologie, Dermatologie	Leipzig		Germany	04103
89	PANAKEIA - Arzneimittelforschung Leipzig GmbH	Leipzig		Germany	04275
90	Universitaetsklinikum Marburg; Klinik fuer Neurologie	Marburg		Germany	35043
91	Krankenhaus der Barmherzigen Brüder Trier; Neurologie, Neurophysiol. neurolog.Reha/Schlaganfalleinh	Trier		Germany	54292
92	Universitätsklinikum Tübingen, Zentrum für Neurologie	Tübingen		Germany	72076
93	Universitätsklinikum Ulm; Klinik für Neurologie	Ulm		Germany	89081
94	Neuropraxis München Süd	Unterhaching		Germany	82008
95	Deutsche Klinik für Diagnostik; DKD Helios Klinik Wiesbaden, Abt. Neurologie	Wiesbaden		Germany	65191
96	401 Military Hospital of Athens; Neurology Department	Athens		Greece	115 25
97	University General Hospital of Larisa; Neurology Clinic	Larisa		Greece	411 10
98	AHEPA Univ. General Hospital of Thessaloniki; B' Neurology Dept.	Thessaloniki		Greece	546 36
99	University General Hospital of Ioannina; Neurology Clinic	Ιωαννινα		Greece	455 00
100	Bajcsy-Zsilinszky Hospital	Budapest		Hungary	1106
101	UNO Medical Trials Kft.	Budapest		Hungary	1152
102	Somogy Megyei Kaposi Mor Oktato Korhaz; Department of Neurology	Kaposvár		Hungary	7400
103	Dr. HIBBEY Egeszsegugyi es Szolgaltato Kft	Tatabánya		Hungary	2800
104	Barzilai Medical Center; Neurology Department	Ashkelon		Israel	7830604
105	Rambam Medical Center; Neurology Unit	Haifa		Israel	3109601
106	Hadassah University Hospital - Ein Kerem	Jerusalem		Israel	9112001
107	The Chaim Sheba Medical Center; Multiple Sclerosis Center	Ramat-Gan		Israel	5262100
108	Tel Aviv Sourasky Medical Center; Department of Neurology	Tel Aviv		Israel	6423906
109	Universita' G. D'Annunzio; Dipartimento di Neuroscienze, Imaging e Scienze Cliniche	Chieti	Abruzzo	Italy	66100
110	AOU Seconda Università degli Studi; Dip. Assistenziale Integrato Medicina Int-II Clinica Neurologica	Napoli	Campania	Italy	80131
111	AOU Seconda Università degli Studi; Dip.Assistenziale Integrato Medicina Int-I Clinica Neurologica	Napoli	Campania	Italy	80138
112	Policlinico Tor Vergata Dip. Neuroscienze-Clinica Neurologica-UOSD Sclerosi Multipla	Roma	Lazio	Italy	00133
113	NCL Institute Neuroscience	Roma	Lazio	Italy	00178
114	Policlinico Umberto I; Centro Sclerosi Multipla DAI Neuroscienze e Salute Mentale	Roma	Lazio	Italy	00185
115	Fondazione IRCCS CA GRANDA Ospedale Maggiore Policlinico; Centro Dino Ferrari, Div. di Neurologia	Milano	Lombardia	Italy	20122
116	Fond. Istituto Neurologico C.Besta; UO Neurologia IV - Neuroimmunologia Malattie Neuromuscolari	Milano	Lombardia	Italy	20133
117	IRCCS Istituto Neurologico Neuromed; Centro per lo Studio e la Cura della Sclerosi Multipla	Pozzilli	Molise	Italy	86077
118	A.O. Universitaria S. Luigi Gonzaga Di Orbassano	Orbassano	Piemonte	Italy	10043
119	Azienda Ospedaliero-Universitaria Consorziale Pol. di Bari; Neuroscienze e Organi di Senso	Bari	Puglia	Italy	70124
120	Grupo Médico Camino S.C.	Ciudad de México	Mexico CITY (federal District)	Mexico	03600
121	Clinstile S.A de C.V.	Mexico City	Mexico CITY (federal District)	Mexico	06700
122	Clinical Research Institute	Tlalnepantla de Baz	Mexico CITY (federal District)	Mexico	54055
123	Neurociencias Prisma, A.C	San Luis Potosí	SAN LUIS Potosi	Mexico	78216
124	Neurociencias Estudios Clinicos S.C.	Culiacán	Sinaloa	Mexico	80020
125	Centro de Investigacion Medico Biologico y Terapia Avanzada, S.C.	Guadalajara		Mexico	44130
126	Zuyderland Medisch Centrum - Sittard Geleen	Sittard-Geleen		Netherlands	6162 BG
127	Hospital Nacional Carlos Alberto Seguin Escobedo	Arequipa		Peru	54
128	Hospital IV Alberto Sabogal Sologuren; Unidad de Investigacion	Bellavista		Peru	Callao 2
129	Clinica Internacional; Unidad De Investigacion	Lima		Peru	15001
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	Hospital Maria Auxiliadora	Lima		Peru	Lima 29
133	Clinica Sanchez Ferrer	Trujillo		Peru	13009
134	Neurocentrum Bydgoszcz sp. z o.o	Bydgoszcz		Poland	85-796
135	COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika; Oddział Neurologiczny	Gdansk		Poland	80-803
136	MA-LEK Clinical Sp. Z o.o.	Katowice		Poland	40-595
137	SPZOZ Uniwersytecki Szp. Klin. nr1 im.N.Barlickiego UM;Oddzial Kliniczny Neurologii	Lodz		Poland	90-153
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	Neurologiczny Niepubliczny ZOZ Centrum Leczenia SM Osrodek Badań Klinicznych	Plewiska		Poland	62-064
141	EMC Instytut Medyczny SA	Poznań		Poland	60-309
142	Nzoz Palomed	Rzeszów		Poland	35-232
143	Osrodek Badan Klinicznych Euromedis	Szczecin		Poland	70-111
144	Centrum Medyczne NeuroProtect	Warszawa		Poland	01-684
145	Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie	Warszawa		Poland	02-097
146	Instytut Psychiatrii i Neurologii II Klinika Neurologiczna	Warszawa		Poland	02-957
147	Wojskowy Instytut Medyczny Centralny Szpital Kliniczny MON	Warszawa		Poland	04-141
148	Hospital de Braga; Centro Clínico Académico (Piso 1, Ala E)	Braga		Portugal	4710-243
149	Centro Hospitalar de Lisboa Ocidental - Hospital Egas Moniz; Neurologia	Lisboa		Portugal	1349-019
150	Hospital de Santa Maria; Servico de Neurologia	Lisboa		Portugal	1649-035
151	Hospital Beatriz Angelo; Servico de Neurologia	Loures		Portugal	2674-514
152	FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency	Krasnoyarsk	Krasnojarsk	Russian Federation	660037
153	National Center of Social Significant Disease	Sankt-peterburg	Leningrad	Russian Federation	197110
154	Neiro Clinica LLC	Moscow	Moskovskaja Oblast	Russian Federation	117186
155	Research Center of Neurology of RAMS	Moscow	Moskovskaja Oblast	Russian Federation	125367
156	Federal center of brain research and neurotechnologies	Moskva	Moskovskaja Oblast	Russian Federation	117997
157	City Clinical Hospital #24; Multipal Sclerosis department	Moskva	Moskovskaja Oblast	Russian Federation	127015
158	N.P. Bechtereva Institute of the Human Brain	Sankt-petersburg	Sankt Petersburg	Russian Federation	197376
159	City Hospital #40 of Kurortniy Administrative District	St. Petersburg	Sankt Petersburg	Russian Federation	197706
160	KSMU Interregional Clinical Diagnostic Centre	Kazan	Tatarstan	Russian Federation	420101
161	Ulyanovsk Regional Clinical Hospital	Ulyanovsk	Uljanovsk	Russian Federation	432063
162	State institution of health care - Territorial Clinical Hospital	Barnaul		Russian Federation	656024
163	SHI Sverdlovsk Regional Clinical Hospital #1;Neurology	Ekaterinburg		Russian Federation	620102
164	State Autonomous Healthcare Institution "Republican Clinical Neurological Center	Kazan		Russian Federation	420021
165	NSHI "Central Clinical Hospital #2 of JSC "Russian Railways" n.a. N.A. Semashko"	Moscow		Russian Federation	129128
166	Saratov State Medical University of RosZdrav; Neurology	Saratov		Russian Federation	410012
167	Nebbiolo Center for Clinical Trials	Tomsk		Russian Federation	634009
168	Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Neurologia	Coruña	LA Coruña	Spain	15006
169	Hospital Quiron de Madrid; Servicio de Neurologia	Pozuelo de Alarcon	Madrid	Spain	28223
170	Hospital Alvaro Cunqueiro; Servicio de Neurologia	Vigo	Pontevedra	Spain
171	Hospital Universitari Vall d'Hebron; Servicio de Neumo-Inmunologia	Barcelona		Spain	08035
172	Hospital Puerta del Mar; Sevicio de Neurologia	Cadiz		Spain	11009
173	Hospital Regional Universitario de Malaga - Hospital General; Servicio de Neurologia	Malaga		Spain	29010
174	Kantonsspital Aarau AG Medizin Neurologie; Neurologie	Aarau		Switzerland	5001
175	Universitätsspital Basel Medizin Neurologie; Neurologische Poliklinik	Basel		Switzerland	4031
176	Inselspital Bern Medizin Neurologie; Neurologische Poliklinik	Bern		Switzerland	3010
177	Ospedale Regionale di Lugano - Civico; Neurologia	Lugano		Switzerland	6903
178	Gazi University Medical Faculty	Ankara		Turkey	06500
179	Istanbul University Istanbul Medical Faculty; Neurology	Istanbul		Turkey	34093
180	Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi; Noroloji Anabilim Dali	Istanbul		Turkey	34098
181	Sancaktepe Training and Research Hospital; Neurology	Istanbul		Turkey	34785
182	Kocaeli University Hospital; Department of Neurology	Kocaeli		Turkey	41380
183	Selcuk University Medical Faculty; Norology department	Konya		Turkey	42131
184	Ege Üniversitesi Tip Fakültesi	Lzmir		Turkey	35100
185	Mersin University Medical Faculty; Neurology	Mersin		Turkey	33079
186	Ondokuz Mayis University School of Medicine; Neurology	Samsun		Turkey	55139
187	Karadeniz Tecnical Uni. Med. Fac.; Neurology	Trabzon		Turkey	61080
188	Medical Center Dopomoga Plus	Kyiv	Chernihiv Governorate	Ukraine	02123
189	Municipal Non-profit Enterprise Zaporizhzhya Regional Hospital Zaporizhzhya Regional Council	Zaporizhzhia	Katerynoslav Governorate	Ukraine	69600
190	Zaporizhia City Multispecialty Clinical Hospital #9	Zaporizhzhye	Katerynoslav Governorate	Ukraine	69063
191	Municipal Nonprofit Enterprise of Kharkiv Regional Council Regional Clinical Hospital	Kharkiv	Kharkiv Governorate	Ukraine	61058
192	Medical Center of Private Execution First Private Clinic	Kyiv	KIEV Governorate	Ukraine	03037
193	Lvivska oblasna tsentralna likarnia	Lviv	KIEV Governorate	Ukraine	79010
194	Miska Klinichna Likarnia №16	Dnipropetrovsk	Tavria Okruha	Ukraine	49100
195	Municipal Institution Cherkasy Regional Hospital of Cherkasy Regional Council	Cherkasy		Ukraine	18009
196	Mun.Med.Proph.Inst."Chernihiv Reg.Hosp."; Neurology Department	Chernihiv		Ukraine	14029
197	Bukovinsky SMU RMI Chernivtsi RCH	Chernivtsi		Ukraine	58013
198	Regional Clinical Hospital; Neurology Department	Ivano-Frankivsk		Ukraine	76008
199	St.In.Inst. of Neurol.Psych.and Narcol.of the AMSU; Dept. of Neuroinfection and Multiply Sclerosis	Kharkov		Ukraine	61068
200	The Royal London Hospital	London		United Kingdom	E1 1FR
201	National Hospital for Neurology and Neurosurgery,; MRC Centre for Neuromuscular Diseases	London		United Kingdom	WC1 3BG
202	University of Nottingham	Nottingham		United Kingdom	NG7 2UH
203	Derriford Hospital	Plymouth		United Kingdom	PL6 8DH