Oral Cladribine in Early Multiple Sclerosis (MS)

Multiple Sclerosis Clinical Trial

— ORACLE MS  

Official title:

A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Trial of Oral Cladribine in Subjects With a First Clinical Event at High Risk of Converting to MS

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00725985
• Other study ID #: 28821
• Status: Completed
• Phase: Phase 3
• Start date: December 31, 2008
• Est. completion date: April 30, 2012

Study information

• Verified date: February 2021
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 617
• Est. completion date: April 30, 2012
• Est. primary completion date: July 31, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Cladribine
Cladribine tablets were administered until CDMS conversion, whichever occur first.
• Placebo
Placebo matched to cladribine tablets were administered.
• Rebif® new formulation (RNF)
Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.

Locations

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

Sponsors (1)

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

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Bosnia and Herzegovina,  Bulgaria,  Canada,  Croatia,  Czechia,  Estonia,  Finland,  France,  Georgia,  Germany,  India,  Italy,  Korea, Republic of,  Lebanon,  North Macedonia,  Norway,  Poland,  Portugal,  Romania,  Russian Federation,  Serbia,  Singapore,  Spain,  Sweden,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Arab Emirates,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ITP: Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS	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.	ITP: Baseline up to Week 96
Secondary	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	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.	ITP: Baseline up to Week 96
Secondary	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	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: Baseline up to Week 96
Secondary	OLMP: Time to 3 Month Confirmed Expanded Disability Status Scale (EDSS) Progression From Randomization Represented by Kaplan-Meier Estimates of Probability of Disability Progression	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.	OLMP: Day 1, 90, 180, 270, 360, 450, 540, 630, 720 and 810
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Time to Conversion to Multiple Sclerosis (MS) According to the 2005 McDonald Criteria	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.	Time from Randomization up to 1217 days
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) According to Poser Criteria	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.	Time from Randomization up to 1217 days
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) According to Poser Criteria	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.	Time from Randomization up to 1217 days
Secondary	ITP: Percentage of Participants Converting to Clinically Definite Multiple Sclerosis (CDMS) as Per Poser Criteria	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.	ITP: Baseline up to week 96
Secondary	ITP: Percentage of Participants Converting to McDonald Multiple Sclerosis (MS) (2005)	Percentage of participants converting to mcDonald multiple sclerosis (2005) were reported.	ITP: Baseline up to week 96
Secondary	ITP: Number of New or Persisting Gd-enhanced Lesions	Number of new or persisting Gd-enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96
Secondary	OLMP: Number of New or Persisting Gd-enhanced Lesions	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 24, 48, 72 and 96
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of New or Persisting Gd-enhanced Lesions	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24 and 36
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of New or Persisting Gd-enhanced Lesions	Number of new or persisting Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24, 36 and 48
Secondary	ITP: Number of New or Enlarging T2 Lesions	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96
Secondary	OLMP: Number of New or Enlarging T2 Lesions	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 24, 48, 72 and 96
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of New or Enlarging T2 Lesions	Number of new or enlarging T2 Lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24 and 36
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of New or Enlarging T2 Lesions	Number of new or enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24, 36 and 48
Secondary	ITP: Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	Number of CUA lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Week 13, 24, 36, 48, 60, 72, 84 and 96
Secondary	OLMP: Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	Number of combined unique active (CUA) lesions were measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 24, 48, 72 and 96
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	Number of CUA MRI lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24 and 36
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions	Number of CUA lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24, 36 and 48
Secondary	ITP: Change From Baseline in Volume of T1 Gd-Enhanced Lesions	Change in volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.	ITP: Baseline, Week 96
Secondary	OLMP: Mean Volume of T1 Gd-Enhanced Lesions and Changes From Baseline in Volume of T1 Gd-Enhanced Lesions	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 24, 48, 72 and 96
Secondary	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	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24 and 36
Secondary	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	Volume of T1 Gd-Enhanced lesions was measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 13, 24, 36 and 48
Secondary	ITP: Changes From Baseline in Volume of T2 Lesions	Change in volume of T2 lesions from baseline was measured by using magnetic resonance imaging (MRI) scans.	ITP: Baseline, Week 48 and 96
Secondary	OLMP: Mean Volume of T2 Lesions and Changes From Baseline in Volume of T2 Lesions	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 48 and 96
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Mean Volume of T2 Lesions	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline (Day 1)
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Mean Volume of T2 Lesions and Changes From Baseline in Volume of T2 Lesions	Volume of T2 lesions was measured by using magnetic resonance imaging (MRI) scans.	Baseline, Week 48
Secondary	ITP: Number of T1 Hypointense Lesions	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.	ITP: Baseline, Week 48 and 96
Secondary	OLMP: Number of T1 Hypointense Lesions	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.	OLMP: Baseline, Week 48 and 96
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of T1 Hypointense Lesions	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline (Day 1)
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of T1 Hypointense Lesions	Number of T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.	LTFU: Baseline, Week 48
Secondary	ITP: Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	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: Baseline up to Week 96
Secondary	OLMP: Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	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.	OLMP: Baseline up to Week 96
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	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: Baseline up to Week 48
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Percentage of Participants With no New or Persisting T1 Gd-Enhanced Lesions	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.	Baseline up to Week 48
Secondary	ITP: Percentage of Participants With no New or Enlarging T2 Lesions	T2 lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no new or enlarging T2 lesions were reported.	ITP: Baseline up to Week 96
Secondary	OLMP: Percentage of Participants With no New or Enlarging T2 Lesions	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.	OLMP: Baseline up to 96
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Percentage of Participants With no New or Enlarging T2 Lesions	Enlarging T2 Lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no New or Enlarging T2 Lesions were reported.	Baseline up to Week 48
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Percentage of Participants With no New or Enlarging T2 Lesions	Enlarging T2 lesions were measured by using magnetic resonance imaging (MRI) scans. Percentage of participants with no New or Enlarging T2 lesions were reported.	LTFU: Baseline up to Week 48
Secondary	ITP: Percent Change From Baseline in Brain Volume	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.	ITP: Baseline, Week 48 and 96
Secondary	OLMP: Percent Change From Baseline in Brain Volume	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: Baseline, Week 48 and 96
Secondary	OLMP: Number of Relapses	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.	Baseline up to Week 96
Secondary	LTFU (LTFU Analysis Set [Treated at LTFU Entry]): Number of Relapses	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.	Baseline up to Week 48
Secondary	LTFU (LTFU Analysis Set [No Treatment at LTFU Entry]): Number of Relapses	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.	Baseline up to Week 48
Secondary	OLMP: Annualized Relapse Rate	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.	Baseline up to Week 96
Secondary	OLMP: Percentage of Relapse-Free Participants	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.	Baseline up to Week 96
Secondary	ITP: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	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.	ITP: Baseline up to Week 96

External Links

•   Trial Awareness and Transparency website
•   US Medical Information website, Medical Resources