Oral Cladribine in Early Multiple Sclerosis (MS)

Phase 3

Completed

Conditions: Multiple Sclerosis

Interventions: Drug: Cladribine
Drug: Placebo
Drug: Rebif® new formulation (RNF)

Registration Number: NCT00725985

Lead Sponsor: EMD Serono Research & Development Institute, Inc.

Brief Summary: A randomized, double-blind, clinical trial to assess the safety and efficacy of two doses of oral cladribine versus placebo in participants who had a first clinical demyelinating event (clinically isolated syndrome). Participants in either the cladribine or placebo group may also enter treatment periods with open-label interferon-beta or open-label cladribine depending upon the disease status. The primary objective of this study is to evaluate the effect of two dosage regimens of oral cladribine versus placebo on the time to conversion to multiple sclerosis (MS) (from randomization) according to the Poser criteria in participants with first clinical demyelinating event at high risk of converting to MS.

Detailed Description: This will be a randomized, double blind, three-arm, placebo-controlled, multi-center trial to evaluate the safety and efficacy of oral cladribine versus placebo in the treatment of participants who have sustained a first clinical demyelinating event within 75 days prior to the Screening. Participants must have a minimum of 2 clinically silent lesions on the Screening magnetic resonance imaging (MRI).

The study will include a pre-study evaluation period (Screening period: between 10 and 28 days prior to the start of treatment with blinded study medication (oral cladribine or placebo).

Depending upon the clinical course of their MS, participants will then proceed from the ITP to either the Maintenance Treatment Period (with open-label interferon-beta treatment) or LTFU period (with either open-label low-dose cladribine or no additional treatment (if no progression to MS has been noted after the initial treatment period). The single primary endpoint for the overall study, which will be determined during the ITP, is time to conversion to MS (from randomization), according to the Poser criteria.

For every participants, eligibility for study enrollment and entry into each of the study periods, and diagnosis of conversion to either McDonald MS or CDMS must be confirmed and approved by a Sponsor appointed study Adjudication Committee.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 617

Inclusion Criteria

Male or female between 18 and 55 years old, inclusive
Weighed between 40 to 120 kilogram (kg), inclusive
Participant has experienced a single, first clinical event suggestive of MS within 75 days prior to the Screening visit, (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic
Participant has at least two clinically silent lesions on the T2-weighted MRI scan, at screening, with a size of at least 3 millimeter (mm), at least one of which is ovoid or periventricular or infratentorial on screening MRI
Participant has EDSS 0 - 5.0 at Screening
Participant has no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease, as evidenced by the Mantoux tuberculosis (TB) skin test or a comparable sensitive test according to local regulations/guidelines (if the Mantoux test is not available), and/or a chest X-ray
Participant has normal hematological parameters at Screening, as defined by the central laboratory that performed all the assessments
If female, she must:
- be neither pregnant nor breast-feeding, nor attempting to conceive and
- use a highly effective method of contraception throughout the entire duration of the study and for 90 days following completion of the last dose of study medication. A highly effective method of contraception is defined as those which result in a low failure rate (that is less than 1 percent per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner, or
- be post-menopausal or surgically sterilized (Note: for Danish sites only, participants should use a hormonal contraceptive or intrauterine device for the duration of the trial)
Male participants must be willing to use contraception to avoid impregnating partners throughout the study, and for 90 days following the last dose of study medication
Be willing and able to comply with study procedures for the duration of the study
Participant has to provide written informed consent voluntarily, including, for United states of America (USA), participant authorization under Health Insurance Portability and Accountability Act (HIPAA), prior to any study-related procedure that is not part of normal medical care
Participant has refused any treatment already available for clinically isolated syndrome (CIS) such as interferons or glatiramer acetate, at the time of entry into the Initial Treatment Period of this study

Exclusion Criteria

Participant has a diagnosis of MS (per McDonald criteria, 2005)
Participant has any other disease that could better explain the participant's signs and symptoms
Participant has complete transverse myelitis or bilateral optic neuritis
Participant using or has used any other approved MS disease modifying drug (DMD)
Participant has used any investigational drug or undergone an experimental procedure within 12 weeks prior to Study day 1
Participant received oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days prior to screening MRI. The MRI had to be performed 30 days after the oral or systemic corticosteroids or ACTH treatment. In case this interfered with MRI timing the screening period could be extended accordingly.
Participant has abnormal total bilirubin, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the upper limit of normal
Participant suffered from current autoimmune disease other than MS
Participant suffered from psychiatric illness (including history of, or concurrent, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the participant or could affect compliance with the study protocol
Participant suffered from major medical illness such as cardiac (for example angina, congestive heart failure or arrhythmia), endocrinologic, hepatic, immunologic, metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine
Participant has a history of seizures not adequately controlled by medications
Participant has a known allergy to cladribine, interferon-beta, the excipient(s) of the study medications, or to gadolinium- diethylenetriamine penta-acetic acid (DTPA)
Participant has any renal condition that would preclude the administration of gadolinium (for example acute or chronic severe renal insufficiency (glomerular filtration rate [GFR] less than 30 milliliter per minute per 1.73 square meter [mL/min/1.73 m^2])
Participant has a history of chronic or clinically significant hematological abnormalities
Participant has a history of active or chronic infectious disease or any disease that compromises immune function (for example human immunodeficiency virus positive [HIV+], human T-lymphotrophic virus [HTLV-1], Lyme disease, latent tuberculosis infection [LTBI] or TB, insulin-dependent diabetes).
Participant has previously been screened in this study (signed an informed consent) and then withdrawn
Participant has received any immunomodulatory or immunosuppressive therapy) at any time prior to Study Day 1, including, but not limited to, the following products: any interferon, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (for example natalizumab, alemtuzumab/Campath, anti-cluster of differentiation 4 [CD4]), intravenous immunoglobulin G (IVIG), cytokines or anti-cytokine therapy
Participant has received experimental MS treatment
Participant has a history of alcohol or drug abuse
Participant has intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
Participant has inability to administer subcutaneous injections either by self or by caregiver
Participant has prior or current malignancy (with the exception of in situ basal or squamous cell skin cancer surgically removed without recurrence for at least five years)
Participant has a positive stool hemoccult test at Screening

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cladribine 3.5 mg/kg (ITP)	Cladribine	Cladribine tablets administered as cumulative dose of 0.875 mg/kg over a course of 5 consecutive days at Weeks 1, 5, 48, 52 and placebo matched to cladribine tablets was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the ITP of 96 weeks or until CDMS conversion, whichever occurred first.
Placebo (ITP)	Placebo	Placebo matched to cladribine tablets administered over a course of 5 consecutive days at Weeks 1, 5, 9, 13, 48 and 52 during the ITP of 96 weeks or until CDMS conversion, whichever occurred first.
Cladribine 5.25 mg/kg, Rebif (OLMP)	Cladribine	Participants who received cladribine 5.25 mg/kg and converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received Rebif® new formulation (RNF) subcutaneously at a dose of 44 microgram (mcg) three times a week for up to 96 weeks. Due to trial termination, the OLMP duration was reduced for some participants.
Cladribine 3.5 mg/kg, Rebif (OLMP)	Cladribine	Participants who received cladribine 3.5 mg/kg and converted to CDMS during ITP entered in OLMP and received RNF subcutaneously at a dose of 44 mcg three times a week for up to 96 weeks. Due to trial termination, the OLMP duration was reduced for some participants.
Placebo, Rebif (OLMP)	Placebo	Participants who received placebo and converted to CDMS during ITP entered in OLMP and received RNF subcutaneously at a dose of 44 mcg three times a week for up to 96 weeks. Due to trial termination, the OLMP duration was reduced for some participants.
Cladribine 5.25 mg/kg, Rebif, Cladribine 3.5 mg/kg (LTFU)	Cladribine	Participants who received cladribine 5.25 mg/kg and did not convert to CDMS during ITP, entered in long-term follow-up (LTFU) period. Participants who converted to McDonald multiple sclerosis (MS) during ITP or during LTFU period received open-label cladribine tablets (3.5 mg/kg) during LTFU period. Participants who converted to CDMS during LTFU received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Placebo, Rebif, Cladribine 3.5 mg/kg (LTFU)	Placebo	Participants who received placebo and did not convert to CDMS during ITP, entered in long-term follow-up (LTFU) period. Participants who converted to McDonald multiple sclerosis (MS) during ITP or during LTFU period received open-label cladribine tablets (3.5 mg/kg) during LTFU period. Participants who converted to CDMS during LTFU received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Cladribine 5.25 mg/kg, Rebif (LTFU)	Cladribine	Participants who received cladribine 5.25 mg/kg and did not convert to CDMS during ITP, entered in LTFU period. Participants who did not convert to McDonald MS during ITP did not receive any treatment during LTFU period. Participants who converted to CDMS during LTFU period received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Placebo, Rebif (LTFU)	Placebo	Participants who received placebo and did not convert to CDMS during ITP, entered in LTFU period. Participants who did not convert to McDonald MS during ITP did not receive any treatment during LTFU period. Participants who convert to CDMS during LTFU period received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Placebo (ITP)	Rebif® new formulation (RNF)	Placebo matched to cladribine tablets administered over a course of 5 consecutive days at Weeks 1, 5, 9, 13, 48 and 52 during the ITP of 96 weeks or until CDMS conversion, whichever occurred first.
Cladribine 5.25 mg/kg (ITP)	Rebif® new formulation (RNF)	Cladribine tablets administered as cumulative dose of 0.875 mg/kg over a course of 5 consecutive days at Weeks 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 milligrams per kilograms (mg/kg) during the ITP of 96 weeks or until clinically definite multiple sclerosis (CDMS) conversion, whichever occurred first.
Cladribine 3.5 mg/kg (ITP)	Rebif® new formulation (RNF)	Cladribine tablets administered as cumulative dose of 0.875 mg/kg over a course of 5 consecutive days at Weeks 1, 5, 48, 52 and placebo matched to cladribine tablets was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the ITP of 96 weeks or until CDMS conversion, whichever occurred first.
Cladribine 3.5 mg/kg, Rebif (OLMP)	Rebif® new formulation (RNF)	Participants who received cladribine 3.5 mg/kg and converted to CDMS during ITP entered in OLMP and received RNF subcutaneously at a dose of 44 mcg three times a week for up to 96 weeks. Due to trial termination, the OLMP duration was reduced for some participants.
Cladribine 5.25 mg/kg, Rebif (OLMP)	Rebif® new formulation (RNF)	Participants who received cladribine 5.25 mg/kg and converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received Rebif® new formulation (RNF) subcutaneously at a dose of 44 microgram (mcg) three times a week for up to 96 weeks. Due to trial termination, the OLMP duration was reduced for some participants.
Cladribine 5.25 mg/kg, Rebif, Cladribine 3.5 mg/kg (LTFU)	Rebif® new formulation (RNF)	Participants who received cladribine 5.25 mg/kg and did not convert to CDMS during ITP, entered in long-term follow-up (LTFU) period. Participants who converted to McDonald multiple sclerosis (MS) during ITP or during LTFU period received open-label cladribine tablets (3.5 mg/kg) during LTFU period. Participants who converted to CDMS during LTFU received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Cladribine 3.5 mg/kg, Rebif, Cladribine 3.5 mg/kg (LTFU)	Rebif® new formulation (RNF)	Participants who received cladribine 3.5 mg/kg and did not convert to CDMS during ITP, entered in long-term follow-up (LTFU) period. Participants who converted to McDonald multiple sclerosis (MS) during ITP or during LTFU period received open-label cladribine tablets (3.5 mg/kg) during LTFU period. Participants who converted to CDMS during LTFU received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Cladribine 5.25 mg/kg, Rebif (LTFU)	Rebif® new formulation (RNF)	Participants who received cladribine 5.25 mg/kg and did not convert to CDMS during ITP, entered in LTFU period. Participants who did not convert to McDonald MS during ITP did not receive any treatment during LTFU period. Participants who converted to CDMS during LTFU period received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Cladribine 3.5 mg/kg, Rebif (LTFU)	Rebif® new formulation (RNF)	Participants who received cladribine 3.5 mg/kg and did not convert to CDMS during ITP, entered in LTFU period. Participants who did not convert to McDonald MS during ITP did not receive any treatment during LTFU period. Participants who converted to CDMS during LTFU period received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Cladribine 5.25 mg/kg (ITP)	Cladribine	Cladribine tablets administered as cumulative dose of 0.875 mg/kg over a course of 5 consecutive days at Weeks 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 milligrams per kilograms (mg/kg) during the ITP of 96 weeks or until clinically definite multiple sclerosis (CDMS) conversion, whichever occurred first.
Cladribine 3.5 mg/kg, Rebif, Cladribine 3.5 mg/kg (LTFU)	Cladribine	Participants who received cladribine 3.5 mg/kg and did not convert to CDMS during ITP, entered in long-term follow-up (LTFU) period. Participants who converted to McDonald multiple sclerosis (MS) during ITP or during LTFU period received open-label cladribine tablets (3.5 mg/kg) during LTFU period. Participants who converted to CDMS during LTFU received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.
Cladribine 3.5 mg/kg, Rebif (LTFU)	Cladribine	Participants who received cladribine 3.5 mg/kg and did not convert to CDMS during ITP, entered in LTFU period. Participants who did not convert to McDonald MS during ITP did not receive any treatment during LTFU period. Participants who converted to CDMS during LTFU period received RNF subcutaneously at a dose of 44 mcg three times a week for the remaining LTFU period. Under the original study design, total duration of LTFU period was up to 96 weeks. The LTFU duration was reduced due to trial termination. Following the notice of trial termination, no further open label cladribine treatment was administered during the LTFU.

Primary Outcome Measures

Name	Time	Method
ITP: Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS	ITP: Baseline up to Week 96	CDMS according to the Poser criteria is defined as the occurrence of a second attack or a sustained increase in the expanded disability status scale (EDSS) Score. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to Multiple Sclerosis \[MS\]) was calculated. Sustained EDSS progression was defined as an increase in the EDSS score of greater than or equal to (\>=) 1 point if baseline EDSS was between \>= 1.0 and less than or equal to (=\<) 4.5; or \>= 1.5 points if baseline EDSS was 0, or \>= 0.5 if baseline EDSS \>= 5.0 over a period of at least 3 months. Kaplan-Meier estimates were provided for of the cumulative (cum.) percentage (%) of participants with CDMS over time. The probability of patients remaining event-free over time (from randomization) in each of the three treatment groups was displayed in the form of survival curves estimated using the non-parametric Kaplan-Meier method.

Secondary Outcome Measures

Name	Time	Method
ITP: Number of New or Persisting Gd-enhanced Lesions	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96	Number of new or persisting Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of New or Persisting Gd-enhanced Lesions	LTFU: Baseline, Week 13, 24 and 36	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.
ITP: Number of New or Enlarging T2 Lesions	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.
OLMP: Time to 3 Month Confirmed Expanded Disability Status Scale (EDSS) Progression From Randomization Represented by Kaplan-Meier Estimates of Probability of Disability Progression	OLMP: Day 1, 90, 180, 270, 360, 450, 540, 630, 720 and 810	EDSS progression is based on a standardized neurological exam and focuses on symptoms that commonly occur in Multiple Sclerosis (MS). Overall scores ranges from 0.0 (normal) to 10.0 (death due to MS). A sustained progression on EDSS score was defined as an EDSS progression confirmed into two consecutive assessment. Probability of disability progression at different time points was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first EDSS increase.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Time to Conversion to Multiple Sclerosis (MS) According to the 2005 McDonald Criteria	Time from Randomization up to 1217 days	The McDonald criteria use dissemination in time and space established by magnetic resonance imaging (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium enhanced (Gd+) lesion found on a repeat MRI.
ITP: Number of Combined Unique Active (CUA) Lesions, New or Enlarging Time Constant 2 (T2) Lesions, and New or Persisting Time Constant 1 (T1) Gadolinium Enhanced (Gd+) Lesions Per Participant Per Scan	ITP: Baseline up to Week 96	Number of CUA lesions, new or enlarging T2 lesions, and new or persisting T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.
ITP: Percentage of Participants Converting to McDonald Multiple Sclerosis (MS) (2005)	ITP: Baseline up to week 96	Percentage of participants converting to mcDonald multiple sclerosis (2005) were reported.
OLMP: Number of New or Enlarging T2 Lesions	OLMP: Baseline, Week 24, 48, 72 and 96	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.
OLMP: Mean Volume of T1 Gd-Enhanced Lesions and Changes From Baseline in Volume of T1 Gd-Enhanced Lesions	OLMP: Baseline, Week 24, 48, 72 and 96	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.
ITP: Number of T1 Hypointense Lesions	ITP: Baseline, Week 48 and 96	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.
ITP: Percentage of Participants Converting to Clinically Definite Multiple Sclerosis (CDMS) as Per Poser Criteria	ITP: Baseline up to week 96	Clinically definite multiple sclerosis (CDMS) according to the Poser criteria is defined as the occurrence of a second attack or a sustained increase in the expanded disability status scale (EDSS) Score. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Sustained EDSS progression was defined as an increase in the EDSS score of greater than or equal to (\>=) 1 point if baseline EDSS was between \>= 1.0 and less than or equal to (=\<) 4.5; or \>= 1.5 points if baseline EDSS was 0, or \>= 0.5 if baseline EDSS \>= 5.0 over a period of at least 3 months. The percentage of participants who converted to CDMS are reported here.
OLMP: Number of New or Persisting Gd-enhanced Lesions	OLMP: Baseline, Week 24, 48, 72 and 96	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.
ITP: Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96	Number of CUA lesions were measured by using magnetic resonance imaging (MRI) scans.
OLMP: Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	OLMP: Baseline, Week 24, 48, 72 and 96	Number of combined unique active (CUA) lesions were measured by using magnetic resonance imaging (MRI) scans.
ITP: Changes From Baseline in Volume of T2 Lesions	ITP: Baseline, Week 48 and 96	Change in volume of T2 lesions from baseline was measured by using magnetic resonance imaging (MRI) scans.
OLMP: Mean Volume of T2 Lesions and Changes From Baseline in Volume of T2 Lesions	OLMP: Baseline, Week 48 and 96	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Mean Volume of T2 Lesions	LTFU: Baseline (Day 1)	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Mean Volume of T2 Lesions and Changes From Baseline in Volume of T2 Lesions	Baseline, Week 48	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.
OLMP: Number of T1 Hypointense Lesions	OLMP: Baseline, Week 48 and 96	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.
ITP: Time to Develop Multiple Sclerosis (MS) Conversion According to the Revised McDonald Criteria (2005) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With McDonald MS	ITP: Baseline up to Week 96	The McDonald criteria use dissemination in time and space established by magnetic resonance imaging (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium enhanced (Gd+) lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions. Kaplan-Meier estimates were provided for the cum. percentage (%) of participants with McDonald MS over time.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of New or Persisting Gd-enhanced Lesions	LTFU: Baseline, Week 13, 24, 36 and 48	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of New or Enlarging T2 Lesions	LTFU: Baseline, Week 13, 24 and 36	Number of new or enlarging T2 Lesions were measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of New or Enlarging T2 Lesions	LTFU: Baseline, Week 13, 24, 36 and 48	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	LTFU: Baseline, Week 13, 24 and 36	Number of CUA MRI lesions were measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	LTFU: Baseline, Week 13, 24, 36 and 48	Number of CUA lesions were measured by using magnetic resonance imaging (MRI) scans.
ITP: Change From Baseline in Volume of T1 Gd-Enhanced Lesions	ITP: Baseline, Week 96	Change in volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.
OLMP: Percentage of Participants With no New or Enlarging T2 Lesions	OLMP: Baseline up to 96	T2 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or enlarging T2 Lesions were reported.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) According to Poser Criteria	Time from Randomization up to 1217 days	CDMS according to the Poser criteria is defined as the occurrence of a second attack or a sustained increase in the expanded disability status scale (EDSS) Score. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Sustained EDSS progression was defined as an increase in the EDSS score of greater than or equal to (\>=) 1 point if baseline EDSS was between \>= 1.0 and less than or equal to (=\<) 4.5; or \>= 1.5 points if baseline EDSS was 0, or \>= 0.5 if baseline EDSS \>= 5.0 over a period of at least 3 months.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) According to Poser Criteria	Time from Randomization up to 1217 days	CDMS according to the Poser criteria is defined as the occurrence of a second attack or a sustained increase in the expanded disability status scale (EDSS) Score. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Sustained EDSS progression was defined as an increase in the EDSS score of greater than or equal to (\>=) 1 point if baseline EDSS was between \>= 1.0 and less than or equal to (=\<) 4.5; or \>= 1.5 points if baseline EDSS was 0, or \>= 0.5 if baseline EDSS \>= 5.0 over a period of at least 3 months.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Mean Volume of T1 Gd-Enhanced Lesions and Changes From Baseline in Volume of T1 Gd-Enhanced Lesions	LTFU: Baseline, Week 13, 24 and 36	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Mean Volume of T1 Gd-Enhanced Lesions and Changes From Baseline in Volume of T1 Gd-Enhanced Lesions	LTFU: Baseline, Week 13, 24, 36 and 48	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of T1 Hypointense Lesions	LTFU: Baseline (Day 1)	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of T1 Hypointense Lesions	LTFU: Baseline, Week 48	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.
OLMP: Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	OLMP: Baseline up to Week 96	T1 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or persisting T1 Gd-enhanced lesions were reported.
ITP: Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	ITP: Baseline up to Week 96	T1 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or persisting T1 Gd-enhanced lesions were reported.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	LTFU: Baseline up to Week 48	T1 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or persisting T1 Gd-enhanced lesions were reported.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	Baseline up to Week 48	T1 Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or persisting T1 Gd-enhanced lesions were reported.
ITP: Percentage of Participants With no New or Enlarging T2 Lesions	ITP: Baseline up to Week 96	T2 lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or enlarging T2 lesions were reported.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of Relapses	Baseline up to Week 48	Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Percentage of Participants With no New or Enlarging T2 Lesions	Baseline up to Week 48	Enlarging T2 Lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no New or Enlarging T2 Lesions were reported.
ITP: Percent Change From Baseline in Brain Volume	ITP: Baseline, Week 48 and 96	Brain volume was measured by using magnetic resonance imaging (MRI) scans. Percent change from baseline in brain volume at Week 48 and 96 was reported.
OLMP: Percent Change From Baseline in Brain Volume	OLMP: Baseline, Week 48 and 96	Brain volume was measured by using magnetic resonance imaging (MRI) scans. Percent change from baseline in brain volume at Week 48 and 96 was reported.
OLMP: Number of Relapses	Baseline up to Week 96	Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.
LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of Relapses	Baseline up to Week 48	Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.
OLMP: Annualized Relapse Rate	Baseline up to Week 96	The annualized relapse rate for each treatment group was the mean of the annualized relapse rates for all the participants in the group, calculated as the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25. Where, Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.
OLMP: Percentage of Relapse-Free Participants	Baseline up to Week 96	Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of relapse-free participants were reported.
LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Percentage of Participants With no New or Enlarging T2 Lesions	LTFU: Baseline up to Week 48	Enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no New or Enlarging T2 lesions were reported.
ITP: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	ITP: Baseline up to Week 96	An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of Participants with TEAEs and serious TEAEs were reported.

Trial Locations

Locations (157): Multiple Sclerosis Center Drive, Neurology Suite 701
🇺🇸
Newport Beach, California, United States
MS Center of Brevard MIMA Centry Research Associates
🇺🇸
Melbourne, Florida, United States
University of Cincinnati
🇺🇸
Cincinnati, Ohio, United States
Turun Yliopistollinen Keskussairaala Rakennus 3 1
🇫🇮
Turku, Finland
Dennis Dietrich
🇺🇸
Great Falls, Montana, United States
Centrul Medical SANA
🇷🇴
Bucharest, Romania
Spitalul Clinic Judetean Mures
🇷🇴
Targu-Mures, Romania
County Hospital Timisoara
🇷🇴
Timisoara, Romania
Hospital for Prevention and Treatment of Cerebro-Vascular Diseases
🇷🇸
Belgrade, Serbia
University Hospital St Naum
🇧🇬
Sofia, Bulgaria
Medical Centre Centromed 2000
🇧🇬
Veliko Tarnovo, Bulgaria
Hospital de Santa Maria
🇵🇹
Lisboa, Portugal
Medical Academy
🇵🇱
Warsaw, Poland
Clinical Centre Niš
🇷🇸
Niš, Serbia
National Neuroscience Institute (TTSH Campus)
🇸🇬
Singapore, Singapore
S. Khechinashvili Tbilisi State Medical University
🇬🇪
Tbilisi, Georgia
M S Ramaiah Medical College Hospital
🇮🇳
Bangalore, Karnataka, India
Amrita Institute of Medical Sciences and Research
🇮🇳
Kochi, Kerala, India
Helse Bergen HF Kvinneklinikken Haukeland Universitetssykehus Jonas
🇳🇴
Bergen, Norway
University of Colorado at Denver Health Sciences
🇺🇸
Denver, Colorado, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
MS Center of Oklahoma
🇺🇸
Oklahoma City, Oklahoma, United States
International Clinic and Hospital, Neurology
🇷🇺
St Petersburg, Russian Federation
State Educational Institution of Higher Professional Education "Siberian State Medical University of Roszdrav"
🇷🇺
Tomsk, Russian Federation
Neurology and Sleep Medicine
🇺🇸
Bethlehem, Pennsylvania, United States
Bruce Hughes West Building
🇺🇸
Des Moines, Iowa, United States
Michigan Neurology Associates
🇺🇸
Clinton Township, Michigan, United States
Henry Ford Hospital
🇺🇸
Detroit, Michigan, United States
Fundacion Rosarina de Neurorehabilitacion
🇦🇷
Rosario, Argentina
Instituto Medico Rodriguez Alfici
🇦🇷
Godoy Cruz, Argentina
Hopital Erasme
🇧🇪
Bruxelles, Belgium
Krankenhaus der Barmherzigen Brüder
🇦🇹
Linz, Austria
MBAL Rousse AD 1st
🇧🇬
Rousse, Bulgaria
Second MHAT
🇧🇬
Sofia, Bulgaria
Tokuda Hospital
🇧🇬
Sofia, Bulgaria
General Hospital Varazdin
🇭🇷
Varazdin, Croatia
Faculty Hospital Brno
🇨🇿
Brno, Czechia
Faculty Hospital Motol
🇨🇿
Prague, Czechia
Klinika Vseobecne
🇨🇿
Prague, Czechia
Nemocnice Teplice
🇨🇿
Teplice, Czechia
David Tatishvili Medical Center
🇬🇪
Tbilisi, Georgia
Universitaetsklinikum und Medizinische Fakultaet Heidelberg
🇩🇪
Heidelberg, Germany
Medical Center Health
🇬🇪
Tbilisi, Georgia
St.John's Medical College and Hospital
🇮🇳
Bangalore, Karnataka, India
Philipps-Universitaet Marburg
🇩🇪
Marburg, Germany
Kovai Medical Centre and Hospital
🇮🇳
Coimbatore, India
Università de Bari
🇮🇹
Bari, Italy
Mallikatta Neuro and Research Centre
🇮🇳
Mangalore, India
Ospedale Regionale Torrette
🇮🇹
Ancona, Italy
Ospedale San Antonio Abate
🇮🇹
Gallarate, Italy
Dipartimento di Neuroscienze
🇮🇹
Catania, Italy
Università G. D'Annunzio
🇮🇹
Chieti, Italy
Universita degli Studi di Genova
🇮🇹
Genova, Italy
Ospedale e casa di riposo P. Richiedei
🇮🇹
Gussago, Italy
Ospedale San Raffaele
🇮🇹
Milano, Italy
Azienda Sanitaria Ospedaliera San Luigi Gonzaga
🇮🇹
Orbassano, Italy
Dipartimento di Scienze Neurologiche
🇮🇹
Napoli, Italy
Villa Sofia Hospital Azienda Ospedaliera Villa Sofia P.zza Salerno e Resuttana 1
🇮🇹
Palermo, Italy
Istituto Neurologico C. Mondino
🇮🇹
Pavia, Italy
Department of Neurology, 50 Ilwon-dong, Gangnam-gu
🇰🇷
Seoul, Korea, Republic of
Seoul National University Hospital, Department of Neurology
🇰🇷
Seoul, Korea, Republic of
Yonsei University Medical Center, Department of Neurology, Yonsei University Medical Center
🇰🇷
Seoul, Korea, Republic of
10 Wojskowy Szpital Kliniczny
🇵🇱
Bydgoszcz, Poland
Clinic of Neurology "Klinicki Centar"
🇲🇰
Skopje, North Macedonia
Wojewodzki Szpital Specjalistyczny im. M. Kopernika
🇵🇱
Gdansk, Poland
Panstwowy Szpital Kliniczny
🇵🇱
Lublin, Poland
Medical Academy II
🇵🇱
Warsaw, Poland
Hospital Fernando da Fonseca
🇵🇹
Amadora, Portugal
Centro Hospitalar de Coimbra
🇵🇹
S. Martinho Do Bispo, Portugal
Hospitais da Universidade de Coimbra
🇵🇹
Coimbra, Portugal
"Dr. Carol Davilla" Military Clinical Hospital
🇷🇴
Bucharest, Romania
State Medical Institution " Jursk Regional Clinical Hospital"
🇷🇺
Kursk, Russian Federation
Municipal Healthcare Institution "City Clinical Hospital #3"
🇷🇺
Chelyabinsk, Russian Federation
State Healthcare Institution "Kaluga Regional Hospital"
🇷🇺
Kaluga, Russian Federation
State Healthcare Institution "Sverdlovsk Regional Clinical Hospital #1"
🇷🇺
Ekaterinburg, Russian Federation
State Healthcare Institution "Kemerovo Regional Clinical Hospital"
🇷🇺
Kemerovo, Russian Federation
State Medical Institution "Republican Rehabilitation Clinic of Tatarstan Ministry of Health"
🇷🇺
Kazan, Russian Federation
Non-State Healthcare Institution "Central Clinical Hospital #2 named after N.A. Semasko of Russian Railways"
🇷🇺
Moscow, Russian Federation
Municipal Treatment Prophylactic Institution "City Hospital #33"
🇷🇺
Nizhny Novgorod, Russian Federation
Federal State Institution " Siberian Reginal Medical Center of Roszdarv"
🇷🇺
Novosibirsk, Russian Federation
State Educational Institute of Higher Professional Education "Rostov State Medical University of Roszdrav"
🇷🇺
Rostov-on-Don, Russian Federation
State Healthcare Institution "Rostov Region Clinical Hospital"
🇷🇺
Rostov-on-Don, Russian Federation
State Educational Institution of Higher Professional Education "Military Medical Academy named after S. M. Korov of Dept of Defense of Russian Federation based on Clinic of Neurology of State Institution
🇷🇺
Saint-Petersburg, Russian Federation
State Educational Institution of Higher Professional Education "Samara State Medical University of Roszdrav" on State Healthcare Institution "Samara Regional Clinical Hospital named after M. I. Kalinin"
🇷🇺
Samara, Russian Federation
State Educational Institution of Higher Professional Education "Saratov State Medical University of Roszdrav" based on Clincial Hosptial #3 of Saratov State Medical University
🇷🇺
Saratov, Russian Federation
St. Petersburg State Healthcare Institution "Multifield City Hospital #2"
🇷🇺
St. Petersburg, Russian Federation
Regional State Healthcare Institution "State Smolensk Region Clinical Hospital"
🇷🇺
Smolensk, Russian Federation
Closed joint-stock society Medical sanitary unit "Nephtaynik" based the hospital
🇷🇺
Tyumen, Russian Federation
Clinical Centre of Serbia
🇷🇸
Belgrade, Serbia
Vladimir Regional State Healthcare Institution "Regional Clinical Hospital"
🇷🇺
Vladimir, Russian Federation
Municipal Healthcare Institution "Yaroslavi Clinical Hospital #8"
🇷🇺
Yaroslavl, Russian Federation
Hospital Reina Sofia Cordoba
🇪🇸
Cordoba, Spain
Sahlgrenskasjukhuset
🇸🇪
Goteborg, Sweden
Karolinska University Hospital
🇸🇪
Stockholm, Sweden
Umea University Hospital
🇸🇪
Umea, Sweden
Srinagarind Hospital
🇹🇭
Khon Kaen, Thailand
Chang Gung Medical Foundation- Linkou Branch No5
🇨🇳
Taoyuan, Taiwan
Ondokuz Mayis Universitesi
🇹🇷
Samsun, Turkey
Rashid Hospital
🇦🇪
Dubai, United Arab Emirates
Kings College London
🇬🇧
London, United Kingdom
State Educational Institute of Higher Professional Education "I.M. Sechenov Moscow Medical Academy of Roszdrav" Russia based on A. Ya. Kozhevnikov Nervous Disease Clinic
🇷🇺
Moscow, Russian Federation
Hope Research Institute Medical Plaza LLC Desert Hills
🇺🇸
Phoenix, Arizona, United States
Fort Collins Neurology
🇺🇸
Fort Collins, Colorado, United States
University of South Florida
🇺🇸
Tampa, Florida, United States
MS Center of Atlanta
🇺🇸
Atlanta, Georgia, United States
University of Medicine and Dentistry of New Jersey School of Neurology
🇺🇸
Stratford, New Jersey, United States
Upstate Clinical Research LLC 3
🇺🇸
Albany, New York, United States
Neurological Specialists of Long Island
🇺🇸
Great Neck, New York, United States
Comprehensive MS Care Clinic at South Shore Multiple Sclerosis
🇺🇸
Patchogue, New York, United States
Multiple Sclerosis Center of Northeastern NY
🇺🇸
New York, New York, United States
Carolinas Medical Center
🇺🇸
Charlotte, North Carolina, United States
Meritcare Neuroscience Center Neurology
🇺🇸
Fargo, North Dakota, United States
Swedish Medical Center Cherry Hill
🇺🇸
Seattle, Washington, United States
Neurology & Neurological Association of Tacoma
🇺🇸
Tacoma, Washington, United States
Cliniques Universitaires St-Luc
🇧🇪
Brussels, Belgium
Algemeen Ziekenhuis St Jan
🇧🇪
Brugge, Belgium
CHU de Liege - Domaine Universitaire du Sart Tilman,
🇧🇪
Liège, Belgium
Military Medical Academy- Sofia (MMA)
🇧🇬
Pleven, Bulgaria
Clinical Center University of Sarajevo
🇧🇦
Sarajevo, Bosnia and Herzegovina
Central Clinic Hospital
🇧🇬
Sofia, Bulgaria
Military Medical Academy
🇧🇬
Sofia, Bulgaria
National Heart Hospital
🇧🇬
Sofia, Bulgaria
Ottawa General Hospital
🇨🇦
Ottawa, Canada
University Hospital Zagreb
🇭🇷
Zagreb, Croatia
Neurological dept of Faculty
🇨🇿
Hradec Kralove, Czechia
Fakultní nemocnice s poliklinikou Ostrava
🇨🇿
Ostrava, Czechia
HUS Hyvinkaa Central Hospital
🇫🇮
Hyvinkaa, Finland
East Tallinn Central Hospital
🇪🇪
Tallinn, Estonia
West Tallinn Central Hospital
🇪🇪
Tallinn, Estonia
OYKS Neurologian Klinikka
🇫🇮
Oulu, Finland
Tampere University Hospital
🇫🇮
Tampere, Finland
Neurologian Klinikka Seinajoen Keskussairaala
🇫🇮
Seinajoki, Finland
CHU de Nantes
🇫🇷
Nantes, France
American Memorial Hospital
🇫🇷
Reims Cedex, France
CHU de Lille
🇫🇷
Lille Cedex, France
Sanjay Gandhi Post Graduate Institute of Medical Sciences
🇮🇳
Lucknow, India
Ospedale Binaghi Centro Sclerosi Multipla
🇮🇹
Cagliari, Italy
Azienda Ospedaliera Garibaldi
🇮🇹
Catania, Italy
Università di Roma La Sapienza
🇮🇹
Roma, Italy
Azienda Ospedaliera S. Camillo Forlanini
🇮🇹
Roma, Italy
Azienda Ospedaliera Universitaria Policlinico Tor Vergata
🇮🇹
Roma, Italy
National Cancer Center, Department of Neurology,
🇰🇷
Gyeonggi-do, Korea, Republic of
Department of Neurology, Asan Medical Center, 388-1 Pungnap 2-dong, Songpa-gu
🇰🇷
Seoul, Korea, Republic of
American University of Beirut
🇱🇧
Beirut, Lebanon
Regionsykehuset I Trondheim, Nevrologisk avd.
🇳🇴
Trondheim, Norway
Niepubliczny Zespol Opieki Zdrowotnej
🇵🇱
Krakow, Poland
Medical Academy of Lodz
🇵🇱
Lodz, Poland
Wojewodzki Szpital Specjalistyczny Oddział Neurologii z Pododdziałem Udarowym
🇵🇱
Olsztyn, Poland
Moscow State Healthcare Institution City Clinical Hospital #11
🇷🇺
Moscow, Russian Federation
State institution Science Research Institute Clinical and Experimental Lymphology of Russian Academy of Medical Sciences
🇷🇺
Novosibirsk, Russian Federation
Institute of Human Brain of Russian Academy of Science Dept. of Multiple Sclerosis
🇷🇺
St Petersburg, Russian Federation
Taipei Veterans
🇨🇳
Taipei, Taiwan
State Established "Institute of Neurology, Psychiatry and Narcology of the AMS of Ukraine", Depart of Neurinfections and Multiple Sclorosis
🇺🇦
Kharkiv, Ukraine
Dokuz Eylul University
🇹🇷
Izmir, Turkey
Hospital Universitario Nuestra Senora de la Candelaria
🇪🇸
Sta. Cruz de Tenerife, Spain
Vinnylsia Regional Psychoneurological Hosptial Named After O. I Yushchenko, Neurological Depart, Vinnytsia National Medical University Named After M. I. Pirogov, Chair of Neurology
🇺🇦
Vinnitsa, Ukraine
Institue for Clinical Radiology of the State Establishment "Research Centre for Radiation Medicine of the AMS of Ukraino" Depart of Radiation Psychoneurology
🇺🇦
Kiev, Ukraine