Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study Two

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

— CARE-MS II  

Official title:

A Phase 3, Randomized, Rater- and Dose-Blinded Study Comparing Two Annual Cycles of Intravenous Low- and High-Dose Alemtuzumab to Three-Times Weekly Subcutaneous Interferon Beta 1a (Rebif®) in Patients With Relapsing Remitting Multiple Sclerosis Who Have Relapsed On Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00548405
• Other study ID #: CAMMS32400507
• Secondary ID: 2007-001162-32CA
• Status: Completed
• Phase: Phase 3
• First received: October 22, 2007
• Last updated: January 6, 2015
• Start date: October 2007
• Est. completion date: September 2011

Study information

• Verified date: January 2015
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: Department of Health and Ageing Therapeutic Goods AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustria: Federal Ministry for Health Family and YouthBelgium: Federal Agency for Medicinal Products and Health ProductsBrazil: National Health Surveillance AgencyCanada: Health CanadaCroatia: Agency for Medicinal Product and Medical DevicesCzech Republic: State Institute for Drug ControlDenmark: Danish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Paul-Ehrlich-InstitutIsrael: Ministry of HealthItaly: The Italian Medicines AgencyMexico: Federal Commission for Sanitary Risks ProtectionNetherlands: Medical Ethics Review Committee (METC)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Ministry of Health of the Russian FederationSerbia and Montenegro: Agency for Drugs and Medicinal DevicesSpain: Spanish Agency of MedicinesSweden: Medical Products AgencyUkraine: State Pharmacological Center - Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to establish the efficacy and safety of two different doses of alemtuzumab (Lemtrada™) as a treatment for relapsing-remitting multiple sclerosis (MS), in comparison with subcutaneous interferon beta-1a (Rebif®). The study enrolled participants who had received an adequate trial of disease-modifying therapies but experienced at least 1 relapse during prior treatment, and who met a minimum severity of disease as measured by magnetic resonance imaging (MRI). Participants had monthly laboratory tests and comprehensive testing every 3 months.

Description:

Every participant received active treatment; there was no placebo. After Amendment 2, the 24 mg alemtuzumab dose was closed to enrollment so newly enrolled participants were randomly assigned to treatment with either 12 mg alemtuzumab or interferon beta-1a in a 2:1 ratio (that is, 2 given 12 mg alemtuzumab for every 1 given interferon beta-1a). Alemtuzumab was administered in two annual courses, once at the beginning of the study and again 1 year later. Interferon beta-1a was self-injected 3 times per week for 2 years. All participants were required to return to their study site every 3 months for neurologic assessment. In addition, safety-related laboratory tests were performed at least monthly. Participation in this study ended 2 years after the start of treatment for each participant. Additionally, participants who received alemtuzumab might be followed in the CAMMS03409 Extension Study (NCT00930553) for safety and efficacy assessments. Participants who received interferon beta-1a and completed 2 years on study might be eligible to receive alemtuzumab in the Extension Study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 840
• Est. completion date: September 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Signed informed consent form (ICF)

• Age 18 to 55 years (inclusive) as of the date the ICF was signed

• Diagnosis of MS per update of McDonald criteria

• Onset of MS symptoms (as determined by a neurologist; could be retrospectively) within 10 years of the date the ICF was signed

• Expanded Disability Status Scale (EDSS) score 0.0 to 5.0 (inclusive) at Screening

• Greater than or equal to (>=) 2 MS attacks (first episode or relapse) occurring in the 24 months prior to the date the ICF was signed, with >=1 attack in the 12 months prior to the date the ICF was signed, with objective neurological signs confirmed by a physician, nurse practitioner, or other Genzyme-approved health-care provider and the objective signs could be identified retrospectively

• >=1 MS relapse during treatment with a beta interferon therapy or glatiramer acetate after having been on that therapy for >=6 months within 10 years of the date the ICF was signed

• MRI scan demonstrating white matter lesions attributable to MS and meeting at least 1 of the following criteria, as determined by the neurologist or a radiologist: >=9 time constant 2 (T2) lesions at least 3 millimeter (mm) in any axis; a gadolinium- (Gd-) enhancing lesion at least 3 mm in any axis plus >=1 brain T2 lesions; and a spinal cord lesion consistent with MS plus >=1 brain T2 lesion

Exclusion Criteria:

• Received prior therapy with alemtuzumab

• Current participation in another clinical study or previous participation in CAMMS323 (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, CARE-MS I)

• Treatment with natalizumab, methotrexate, azathioprine, or cyclosporine in the past 6 months. Participants who received one of these medications more than 6 months before the date the ICF was signed were eligible for study entry if approval was granted by Genzyme

• Any progressive form of MS

• History of malignancy (except basal skin cell carcinoma)

• CD4 +, CD8 +, CD19 + (that is, absolute CD3 + CD4 + , CD3 + CD8 + , or CD19 + /mm 3 ) count, absolute neutrophil count less than (<) lower limit of normal (LLN) at screening; if abnormal cell count(s) returned to within normal limits (WNL), eligibility could be reassessed

• Known bleeding disorder (for example, dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand's disease, disseminated intravascular coagulation, fibrinogen deficiency, or clotting factor deficiency)

• Significant autoimmune disease including but not limited to immune cytopenias, rheumatoid arthritis, systemic lupus erythematosus, other connective tissue disorders, vasculitis, inflammatory bowel disease, severe psoriasis

• Presence of anti-thyroid stimulating hormone (TSH) receptor (TSHR) antibodies (that is, above the LLN)

• Active infection or at high risk for infection

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Biological:
• Alemtuzumab 12 mg
Alemtuzumab 12 milligram (mg) per day intravenous (IV) infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
• Alemtuzumab 24 mg
Alemtuzumab 24 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 24 mg per day IV infusion on 3 consecutive days at Month 12.
• Interferon beta-1a
Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.

Locations

Country	Name	City	State
Argentina	DIABAID	Buenos Aires
Australia	The Wesley Research Institute	Auchenflower	Queensland
Australia	Concord Repatriation General Hospital, Neurosciences Department	Concord
Australia	St. Vincent's Hospital, MS Education & Research, Department of Clinical Neurosciences	Fitzroy	Victoria
Australia	Austin Health	Heidelberg	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Southern Neurology	Kogarah
Australia	Liverpool Hospital, Neurology Department	Liverpool
Australia	Royal Melbourne Hospital, Department of Neurology	Parkville	Victoria
Australia	Griffith School of Medicine, Gold Coast Campus, Griffith University	Southport	Queensland
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Clinical Cognitive Research Unit/Clinical Trials, The Queen Elizabeth Hospital, Neurology Department	Woodville South	South Australia
Austria	AKH Wien, Universitätsklinikum für Neurologie	Wien
Belgium	Cliniques Universitaires Saint-Luc, Neurology	Brussel
Belgium	CHU Ourthe Amblève, Neurology	Esneux
Belgium	University Hospital Leuven, Campus Gasthuisberg, Neurology	Leuven
Brazil	Hospital Sao Lucas PUC-RS	Porto Alegre	RS
Brazil	Hospital da Restauracao	Recife	PE
Brazil	Hospital de Clínicas USP	Sao Paulo
Brazil	Irmandade da Santa Casa de Misericordia de Sao Paulo	Sao Paulo
Canada	Centre de Sante et de Services Sociaux de Gatineau-Hull Hospital	Gatineau	Quebec
Canada	Clinique Neuro rive-sud, Recherche sepmus inc	Greenfield park	Quebec
Canada	Multiple Sclerosis Clinic, Connell 7, Kingston General Hospital	Kingston	Ontario
Canada	London Health Sciences Centre- University Hospital	London	Ontario
Canada	Hospital Maisonneuve-Rosemont	Montreal	Quebec
Canada	Montreal Neurological Institute and Hospital	Montreal	Quebec
Canada	The Ottawa Hospital, General Campus	Ottawa	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	UBC Hospital	Vancouver	British Columbia
Croatia	Clinical Hospital Centre Rijeka, Clinic for Neurology	Rijeka
Croatia	General Hospital Varazdin, Department of neurology	Varazdin
Croatia	Clinical Hospital Centre Zagreb	Zagreb
Croatia	Clinical Hospital Sestre Milosrdnice	Zagreb
Croatia	General Hospital " Sveti Duh", Department of neurology	Zagreb
Czech Republic	MS Center, Department of Neurology	Hradec Kralove
Czech Republic	St. Anne's University Hospital Brno	Pekarska
Czech Republic	Department of Neurology 1st Faculty of Medicine and General Teaching Hospital, MS Center	Praha 2
Czech Republic	Krajska zdravotni a.s. - Hospital Teplice	Teplice
Denmark	Århus Universitetshospital, Scleroseklinikken, Århus Sygehus	Aarhus
Denmark	Scleroseklinikken, Rigshospitalet	København
Denmark	Odense University Hospital	Odense
France	CHU Clermont-Ferrand, Hôpital Gabriel Montpied	Clermont-Ferrand
France	Hôpital General, Service de Neurologie	Dijon Cedex
France	Hospital Roger Salengro	Lille Cedex
France	Hôpital Pitié Salpétrière, Service de Neurologie	Paris
France	Sevice de Neurologie	Rennes Cedex
France	Hôpital Civil, Departement de Neurologie	Strasbourg Cedex
Germany	Krankenhaus Hohe Warte, Betriebsstätte der Bayreuth	Bayreuth
Germany	Judisches Krankenhaus Berlin	Berlin
Germany	Neurologisches Fachzentrum Berlin	Berlin
Germany	Neurologische Universitätsklinik Bonn	Bonn
Germany	Multiple Sklerose Zentrum am, Zentrum für klinische Neurowissenschaften, Neurologische Uniklinik Dresden	Dresden
Germany	Asklepios Klinic Barmbek	Hamburg
Germany	Medizinische Hochshule Hannover	Hannover
Germany	Oberhavelkliniken Hennigsdorf	Hennigsdorf
Germany	Klinikum Ingolstadt, Neurologische Klinik	Ingolstadt
Germany	Klinikum Rechts der Isar, Klinik für Neurologie	Muenchen
Germany	Klinik und Poliklinik fur Neurologie der Universitat Rockstock	Rostock
Germany	Universitatsklinik Ulm	Ulm
Germany	Fachkrankenhaus Hubertusburg	Wermsdorf
Israel	Hadassah Medical Center Ein Karem	Jerusalem
Israel	Tel Aviv Sourasky Medical Center, Department of Neurology	Tel Aviv
Israel	Sheba Medical Centre	Tel Hashomer
Italy	Ospedale Binaghi - Centro Sclerosi Multipla	Cagliari
Italy	Ospedale S. Antonio Abate di Gallarate	Gallarate
Italy	Università di Genova Dipartimento di Neuroscienze Oftalmologia e Genetica	Genova
Italy	Ospedale Civile di Brescia c/o Ospedale Richiedei, Centro di riferimento per la Sclerosi Multiple	Montichiari
Italy	Ospedale San Luigi di Orbassano	Orbassano
Italy	Azienda Ospedaliera Sant'Andrea Neurologia	Roma
Mexico	Unidad de Investigación en Salud de Chihuahua, S.C.	Chihuahua
Mexico	Hospital Medica Sur CIF-BIOTEC	Delegacion	Tlalpan
Mexico	Hospital Angeles del Pedregal; Camino a Santa Teresa	Mexico City
Netherlands	Jeroen Bosch Ziekenhuis	Hertogenbosch
Netherlands	Orbis Medisch Centrum, Department of Neurology	Sittard
Poland	Independent Public Healthcare Facility, Norbert Barlicki University Hospital No. 1 of the Medical University of Lodz	Lodz
Poland	Independent Public Teaching Hospital No. 4 in Lublin	Lublin
Poland	Heliodor Swiecicki Teaching Hospital of the Poznan, University of Medical Sciences	Poznan
Russian Federation	Research Medical Complex "Your Health" Ltd	Kazan
Russian Federation	Institution of the Russian Academy of Medical Sciences, "Neurology Scientific Center under RAMS"	Moscow
Russian Federation	Moscow State Medical Institution City Clinical Hospital #11, Moscow City Center for Multiple Sclerosis	Moscow
Russian Federation	Moscow State Public Medical Institution, City Clinical Hospital #11	Moscow
Russian Federation	Municipal Treatment and Prevention Institution, "City Hospital #33"	Nizhniy Novgorod
Russian Federation	Federal State Institution: Siberian District Medical Center	Novosibirsk
Russian Federation	State Medical Institution, "Samara Regional Clinical Hospital n.a. M.I. Kalinin"	Samara
Russian Federation	Institution of the Russian Academy of Sciences, "Institute of the Human Brain n.a. N.P. Bekhtereva within the Russian Academy of Sciences"	St. Petersburg
Russian Federation	St. Petersburg Pavlov State Medical University, Department of Neurology and Neurosurgery with a Clinic	St. Petersburg
Russian Federation	St.Petersburg State Medical Institution, "City Multispecialty Hospital #2"	St. Petersburg
Russian Federation	St.Petersburg State Medical Institution, "Nikolayevskaya Hospital"	St. Petersburg
Serbia	Clinic of Neurology, Clinical Centre of Serbia	Belgrade
Serbia	Military Medical Academy	Belgrade
Serbia	Clinical Centre of Kragujevac	Kragujevac
Serbia	Clinical Centre Vojvodina Institute of Neurology	Novi Sad
Spain	Servicio de Neurología Hospital Vall d'Hebron Paseo de Vall d'Hebron	Barcelona
Spain	Servicio de Neurología Hospital Clínico San Carlos	Madrid
Spain	Servicio de Neurología Hospital Carlos Haya	Malaga
Spain	Servicio de Neurología Hospital Virgen de la Macarena	Sevilla
Sweden	Sahlgrenska University Hospital, Neurologkliniken	Gothenburg
Sweden	Norrlands Universitets sjukhus	Umea
Ukraine	Institute of Neurology, Psychiatry and Narcology under the Academy of Medical Sciences of Ukraine	Kharkov
Ukraine	Kyiv Municipal Clinical Hospital #4, Department of Demyelinating Diseases of the Nervous System	Kyiv
Ukraine	Danylo Halytsky Lviv National Medical University, Department of Neurology	Lviv
United Kingdom	Frenchay Hospital	Bristol
United Kingdom	Department Of Neurosciences, Addenbrookes Hospital	Cambridge	England
United Kingdom	Centre for Neuroscience & Trauma, Blizard Institute of Cell and Molecular Science Barts and The London School of Medicine and Dentistry	London	England
United Kingdom	Salford Royal NHS Foundation Trust, Clinical Trials Unit	Salford
United Kingdom	Department of Neurology Glossop Road, Royal Hallamshire Hospital	Sheffield
United States	University of New Mexico, Health Sciences Center, MS Specialty Clinic	Alburquerque	New Mexico
United States	Lehigh Valley Hospital, Neuroscience and Pain Research	Allentown	Pennsylvania
United States	University of Michigan Department of Neurology	Ann Arbor	Michigan
United States	Emory University, Department of Neurology	Atlanta	Georgia
United States	Shepherd Center, Inc.	Atlanta	Georgia
United States	University of Colorado Hospital, Anschutz Outpatient Pavilioin	Aurora	Colorado
United States	East Bay Physicians Medical Group/Sutter East Bay Medical Foundation	Berkeley	California
United States	Caritas St. Elizabeth's Medical Center	Boston	Massachusetts
United States	Partners Multiple Sclerosis Center/Brigham and Women's Hospital	Boston	Massachusetts
United States	University of North Carolina-Chapel Hill, Department of Neurology	Chapel Hill	North Carolina
United States	University of Chicago Medical Center, Department of Neurology	Chicago	Illinois
United States	Cleveland Clinic Foundation, Mellen Center	Cleveland	Ohio
United States	Neurology Clinic, P.C.	Cordova	Tennessee
United States	North Central Neurology Associates, P.C.	Cullman	Alabama
United States	Clinical Center for Multiple Sclerosis	Dallas	Texas
United States	Neurology Specialists, Inc.	Dayton	Ohio
United States	Neurological Consultants	Denver	Colorado
United States	Iowa Health Physicians	Des Moines	Iowa
United States	Ruan Neurology Clinic and Research Center	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Wayne State University, School of Medicine, Department of Neurology	Detroit	Michigan
United States	Northshore Clinical Associates	Erie	Pennsylvania
United States	Advanced Neurosciences Research	Fort Collins	Colorado
United States	Fort Wayne Neurological Center	Fort Wayne	Indiana
United States	Advanced Neurosciences Institute	Franklin	Tennessee
United States	Biomedical Research Alliance of NY, LLC	Franklin	Tennessee
United States	Spectrum Health Medical Group, Neurology (Previously known as Michigan Medical P.C., Neurology)	Grand Rapids	Michigan
United States	Idaho Falls Multiple Sclerosis Center, PLLC	Idaho Falls	Idaho
United States	Indiana University School of Medicine, Department of Neurology	Indianapolis	Indiana
United States	Josephson Wallack Munshower Neurology P.C.	Indianapolis	Indiana
United States	University of Florida Neuroscience Institute	Jacksonville	Florida
United States	Neurology Consultants of Kansas City, Inc.	Kansas City	Missouri
United States	University of Kansas Medical Center, Department of Neurology	Kansas City	Kansas
United States	Hope Neurology PC	Knoxville	Tennessee
United States	Neurology Center of North Orange County	La Habra	California
United States	University of Nevada School of Medicine	Las Vegas	Nevada
United States	Empire Neurology, PC	Latham	New York
United States	Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center	Lebanon	New Hampshire
United States	MidAmerica Neuroscience Institute	Lenexa	Kansas
United States	Associates in Neurology, PSC	Lexington	Kentucky
United States	Department of Neurology, Keck School of Medicine, University of Southern California	Los Angeles	California
United States	University of Louisville Research Foundation	Louisville	Kentucky
United States	Neurology Associates, P.A.	Maitland	Florida
United States	Winthrop University Hospital, Clinical Trials Center	Mineola	New York
United States	Montana Neurobehavioral Specialists	Missoula	Montana
United States	Vanderbilt Multiple Sclerosis Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Mount Sinai School of Medicine, Corinne Goldsmith Dickinson Center for Multiple Sclerosis	New York	New York
United States	Consultants in Neurology, Ltd	Northbrook	Illinois
United States	MS Center of Oklahoma	Oklahoma City	Oklahoma
United States	Neuro-Therapeutics Inc.	Pasadena	California
United States	Neuro-Therapeutics, Inc	Pasadena	California
United States	Comprehensive Multiple Sclerosis Care Center at South Shore Neurologic Associates, P.C.	Patchogue	New York
United States	Barrow Neurological Institute, St. Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Hope Research Institute	Phoenix	Arizona
United States	University of Pittsburgh, Kaufmann Medical Building	Pittsburgh	Pennsylvania
United States	Neurological Associates	Pompano Beach	Florida
United States	The Neurology Foundation, Inc.	Providence	Rhode Island
United States	Renown Institute for Neurosciences / Renown regional Medical Center	Reno	Nevada
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Central Texas Neurology	Round Rock	Texas
United States	University of California, Davis Medical Center	Sacramento	California
United States	Integra Clinical Research	San Antonio	Texas
United States	Neurology Center of San Antonio	San Antonio	Texas
United States	Negroski, Stein, Sutherland and Hanes Neurology	Sarasota	Florida
United States	Mayo Clinic Arizona, Department of Neurology	Scottsdale	Arizona
United States	Swedish Neuroscience Institute	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Louisiana State University Health Sciences Center	Shreveport	Louisiana
United States	Rockwood Clinical Research Center	Spokane	Washington
United States	Springfield Neurology Associates, LLC	Springfield	Massachusetts
United States	Michigan Neurology Associates, P.C.	St. Clair Shores	Michigan
United States	Stanford University School of Medicine	Stanford	California
United States	SUNY Upstate Medical University, Department of Neurology	Syracuse	New York
United States	Axiom Clinical Research of Florida	Tampa	Florida
United States	University of South Florida, Department of Neurology	Tampa	Florida
United States	MS Center at Holy Name Hospital	Teaneck	New Jersey
United States	Northern Michigan Neurology	Traverse City	Michigan
United States	Northwest NeuroSpecialists, PLLC	Tucson	Arizona
United States	Oak Clinic for Multiple Sclerosis	Uniontown	Ohio
United States	MS Center of Greater Washington, P.C.	Vienna	Virginia
United States	George Washington University Medical Faculty Associates	Washington	District of Columbia
United States	Wake Forest University Health Science, Department of Neurology	Winston-Salem	North Carolina
United States	UMass Memorial Medical Center	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company	Bayer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Croatia,  Czech Republic,  Denmark,  France,  Germany,  Israel,  Italy,  Mexico,  Netherlands,  Poland,  Russian Federation,  Serbia,  Spain,  Sweden,  Ukraine,  United Kingdom, 

References & Publications (1)

Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA; CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1829-39. doi: 10.1016/S0140-6736(12)61768-1. Epub 2012 Nov 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Sustained Accumulation of Disability (SAD)	EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score: 0 (normal neurological examination) to 10 (death due to MS). As measured by EDSS score, SAD was defined as increase of at least 1.5 points for participants with Baseline score of 0 and increase of at least 1.0 point for participants with a Baseline score of 1.0 or more; and the increase persisted for at least the next 2 scheduled assessments, that is, 6 consecutive months. The onset date of SAD was date of first EDSS assessment that began 6 month consecutive period of SAD. Participants who did not reach SAD endpoint were censored at their last visit. Percentage of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported.	Up to 2 years	No
Primary	Annualized Relapse Rate	Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to multiple sclerosis that lasted for at least 48 hours, that were present at normal body temperature, and that were preceded by at least 30 days of clinical stability. Annualized relapse rate was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region using observed number of relapses as dependent variable, the log total amount of follow-up from date of first study treatment for each participant as an offset variable, and treatment group and geographic region as model covariates.	Up to 2 years	No
Secondary	Percentage of Participants Who Were Relapse Free at Year 2	Participants were considered relapse free at Year 2 if they did not experience a relapse from the date of first study treatment to study completion at 24 months. Percentage of participants who were relapse free at Year 2, estimated using the KM method, was reported.	Year 2	No
Secondary	Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Year 2	EDSS is an ordinal scale in half-point increments that qualifies disability in participants with multiple sclerosis (MS). It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Change was calculated by subtracting Baseline value from value at Year 2.	Baseline, Year 2	No
Secondary	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2	MSFC is a multidimensional measure consisting of quantitative tests of ambulation (Timed 25-Foot Walk), manual dexterity (9-Hole Peg Test; 9HPT), and cognitive function (Paced Auditory Serial Addition Test; PASAT). The MSFC score was calculated as the mean of the Z-scores of the 3 components. A Z-score was calculated by subtracting the mean of the reference population from the test result, then dividing by the standard deviation of the reference population. Higher Z-scores reflected better neurological function and a positive change from Baseline indicates improvement. An increase in score indicated an improvement (Z-score range: -3 to +3). Acquisition of disability was measured by change from Baseline in MSFC score at Year 2.	Baseline, Year 2	No
Secondary	Percent Change From Baseline in Magnetic Resonance Imaging Time Constant 2 (MRI-T2) Hyperintense Lesion Volume at Year 2	Percent change in MS lesion volume as measured by MRI-T2 scan was calculated from MRI-T2-weighted scans as the following: (lesion volume at 2 years - lesion volume at Baseline)*100/ (lesion volume at Baseline).	Baseline, Year 2	No

External Links

•   http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf