Clinical trial NCT01412333: A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis
Official title: A Randomized, Double-Blind, Double-Dummy, Parallel-Group Study To Evaluate the Efficacy and Safety of Ocrelizumab in Comparison to Interferon Beta-1a (Rebif) in Patients With Relapsing Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsing Multiple Sclerosis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2011-08-09
Enrollment: 835
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized, double-blind, double-dummy, parallel-group study will evaluate the efficacy and safety of ocrelizumab in comparison with interferon beta-1a (Rebif) in participants with relapsing multiple sclerosis. Participants will be randomized to receive either ocrelizumab 600 mg or matching placebo intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week; or interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).


Eligibility criteria: Inclusion Criteria:

* Diagnosis of multiple sclerosis, in accordance with the revised McDonald criteria (2010)
* At least 2 documented clinical attacks within the last 2 years prior to screening or one clinical attack in the years prior to screening (but not within 30 days prior to screening)
* Neurologic stability for greater than or equal to (\>/=) 30 days prior to both screening and baseline
* Expanded Disability Status Scale (EDSS) score 0 to 5.5 inclusive

Exclusion Criteria:

* Primary progressive multiple sclerosis
* Disease duration of more than 10 years in patients with EDSS score less than or equal to (\</=) 2.0 at screening
* Contraindications for MRI
* Known presence of other neurological disorders which may mimic multiple sclerosis
* Pregnancy or lactation
* Requirement for chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
* History of or currently active primary or secondary immunodeficiency
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
* Active infection, or history of or known presence of recurrent or chronic infection (for example, hepatitis B or C, Human Immunodeficiency Virus \[HIV\], syphilis, tuberculosis)
* History of progressive multifocal leukoencephalopathy
* Contraindications to or intolerance of oral or IV corticosteroids
* Contraindications to Rebif or incompatibility with Rebif use

Primary outcomes:
measure: Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks In Double Blind Period
timeFrame: Week 96
Secondary outcomes:
measure: Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period
timeFrame: Week 104
measure: Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment
timeFrame: Baseline up to week 96
measure: Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment
timeFrame: Baseline up to week 96
measure: Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks In Double Blind Period
timeFrame: Week 96
measure: Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period
timeFrame: Week 104
measure: Number of T1 Hypointense Lesions During the Double-Blind Treatment
timeFrame: Baseline up to week 96
measure: Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96 In Double Blind Period
timeFrame: Baseline, Week 96
measure: Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96 In Double Blind Period
timeFrame: From week 24 up to week 96
measure: Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 In Double Blind Period
timeFrame: Baseline, Week 96
measure: Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96 In Double Blind Period
timeFrame: Week 96
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Baseline up to Week 96
measure: Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC) In Double Blind Period
timeFrame: Pre-infusion at Weeks 1, 24, 48, 72; and 30 minutes post-infusion at Week 72; at any time during Weeks 84 and 96
measure: Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab In Double Blind Period
timeFrame: Baseline up to Week 96
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Hope Research Institute
state: Arizona
city: Scottsdale
country: United States
facility: HonorHealth Neurology
state: Arizona
city: Tucson
country: United States
facility: Territory Neurology and Research Institute
state: Arizona
city: Long Beach
country: United States
facility: Collaborative Neuroscience Research, LLC
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Fort Collins
country: United States
facility: Advanced Neurosciences Research LLC
state: Colorado
city: Fairfield
country: United States
facility: Associated Neurologists of Southern CT PC
state: Connecticut
city: Hollywood
country: United States
facility: Infinity Clinical Research
state: Florida
city: Miami
country: United States
facility: University of Miami; Dept. of Neurology MS Center
state: Florida
city: Orlando
country: United States
facility: Neurological Services of Orlando
state: Florida
city: Sarasota
country: United States
facility: Lovelace Scientific Resources
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Atlanta Neuroscience Institute
state: Georgia
city: Indianapolis
country: United States
facility: Josephson Wallack Munshower Neurology PC
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Prairie Village
country: United States
facility: MidAmerica Neuroscience Institute
state: Kansas
city: Lexington
country: United States
facility: Associates in Neurology PSC
state: Kentucky
city: Wellesley
country: United States
facility: Dragonfly Research, LLC
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Detroit
country: United States
facility: Wayne State University; Department of Neurology
state: Michigan
city: Golden Valley
country: United States
facility: The Minneapolis Clinic of Neurology
state: Minnesota
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: Teaneck
country: United States
facility: Holy Name Hospital
state: New Jersey
city: Teaneck
country: United States
facility: MS Comprehensive Care Center
state: New Jersey
city: Toms River
country: United States
facility: Shore Neurology
state: New Jersey
city: Latham
country: United States
facility: Empire Neurology, PC
state: New York
city: New York
country: United States
facility: Weill Cornell MC-NY Presbyter; Dept. of Neurology/Neuroscience, Judith Jaffe Multiple Sclerosis Ctr
state: New York
city: Patchogue
country: United States
facility: South Shore Neurologic Associates P.C.
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Stony Brook
country: United States
facility: SUNY at Stony Brook
state: New York
city: Charlotte
country: United States
facility: The Neurological Institute PA
state: North Carolina
city: Hickory
country: United States
facility: Neurology Associates PA
state: North Carolina
city: Raleigh
country: United States
facility: Raleigh Neurology Associates
state: North Carolina
city: Columbus
country: United States
facility: Columbus Neuroscience
state: Ohio
city: Abington
country: United States
facility: Abington Neurological Associates
state: Pennsylvania
city: Greenville
country: United States
facility: Absher Neurology PA
state: South Carolina
city: Cordova
country: United States
facility: Neurology Clinic PC
state: Tennessee
city: Knoxville
country: United States
facility: Sibyl Wray MD Neurology PC
state: Tennessee
city: Nashville
country: United States
facility: Advanced Neurosciences Institute
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Lubbock
country: United States
facility: Bhupesh Dihenia M.D. P.A.
state: Texas
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants
state: Texas
city: San Antonio
country: United States
facility: Integra Clinical Research, Llc
state: Texas
city: San Antonio
country: United States
facility: Neurology Center of San Antonio
state: Texas
city: Seattle
country: United States
facility: Swedish Neuroscience Institute
state: Washington
city: Buenos Aires
country: Argentina
facility: ALPI-Inst. de Rehabilitacion Marcelo Fitte
city: Ciudad de Buenos Airesa
country: Argentina
facility: STAT Research S.A.
city: Grodno
country: Belarus
facility: Grodno State Medical University
state: Hrodzyenskaya Voblasts'
city: Vitebsk
country: Belarus
facility: Vitebsk; Regional Diagnostic Center
state: Vitsyebskaya Voblasts'
city: Vitebsk
country: Belarus
facility: Vitebsk Regional Clinical Hospital
state: Vitsyebskaya Voblasts'
city: Minsk
country: Belarus
facility: City Clinical Hospital #9
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Sarajevo
country: Bosnia and Herzegovina
facility: University Clinic Ctr Sarajevo
city: Tuzla
country: Bosnia and Herzegovina
facility: Uni Hospital Center Tuzla
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia; de Belo Horizonte
state: MG
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitario Gaffree e Guinle
state: RJ
city: Campinas
country: Brazil
facility: Hospital das Clinicas - UNICAMP
state: SP
city: Sofia
country: Bulgaria
facility: MHATNP Sv.Naum EAD; Clinic for intensive treatment of neurology diseases
city: Sofia
country: Bulgaria
facility: Fifth MHAT-Sofia AD; Neuro Dept with Vascular Unit
city: Sofia
country: Bulgaria
facility: MHAT National Cardiology Hospital, EAD; Neurology
city: Sofia
country: Bulgaria
facility: UMHAT Alexandrovska, EAD; Neurology
city: Calgary
country: Canada
facility: Multiple Sclerosis Clinic
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta; Northern Alberta Trials & Research Centre
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver Hospital - UBC Hospital Site
state: British Columbia
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
state: Ontario
city: Gatineau
country: Canada
facility: Clinique NeuroOutaouais
state: Quebec
city: Greenfield Park
country: Canada
facility: Recherche Sepmus Inc.
state: Quebec
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Montréal
country: Canada
facility: Hôpital Maisonneuve - Rosemont; Recherche Clinique de Neurologie
state: Quebec
city: Pula
country: Croatia
facility: General Hospital Pula
city: Varazdin
country: Croatia
facility: General Hospital Varazdin
city: Zagreb
country: Croatia
facility: Clinical Hospital Centre Zagreb;Clinic for Neurology
city: Zagreb
country: Croatia
facility: Uni Hospital Centre Dubrava
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Havirov
country: Czechia
facility: Neurospol s.r.o.
city: Pardubice
country: Czechia
facility: Pardubicka Krajska Nemocnice; Department of Neurology
city: Teplice
country: Czechia
facility: Krajska zdravotni, a. s. ? Nemocnice Teplice, o. z.; Neurologicke oddeleni
city: Bron
country: France
facility: Hopital Neurologique Pierre Wertheimer
city: Dijon Cedex
country: France
facility: Hôpital General - Service de neurologie; Service de neurologie
city: Lommé
country: France
facility: Hôpital Saint Philibert
city: Paris
country: France
facility: Groupe Hospitalier Pitie-Salpetriere
city: Reims
country: France
facility: Hôpital Maison Blanche; Service de Neurologie
city: Toulouse
country: France
facility: CHU toulouse - Hôpital Purpan; Departement de Neurologie
city: Berlin
country: Germany
facility: Sankt Gertrauden Krankenhaus; Neurologisches Facharztzentrum
city: Bonn
country: Germany
facility: Neurologische Praxis Bonn
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf; Klinik für Neurologie
city: Essen
country: Germany
facility: Zentrum fuer ambulante Neurologie
city: Frankfurt
country: Germany
facility: Universitaetsklinikum Frankfurt; Klinik für Neurologie
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
city: Mittweida
country: Germany
facility: Ratsapotheke Mittweida
city: Muenchen
country: Germany
facility: Klinikum Grosshadern der LMU
city: München
country: Germany
facility: Klinikum rechts der Isar der TU Muenchen; Neurologische Klinik und Poliklinik im Neuro-Kopf-Zentrum
city: Ulm
country: Germany
facility: Neurologische Gemeinschaftspraxis Dr. Lang, Prof. Schreiber, Dr. Krauß, Dr. Kornhuber
city: Dublin 4
country: Ireland
facility: St Vincents University Hospital
city: Roma
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Tor Vergata
state: Lazio
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
state: Lazio
city: Genova
country: Italy
facility: A.O. Universitaria S. Martino Di Genova
state: Liguria
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta; Farmacia Interna
state: Lombardia
city: Montichiari
country: Italy
facility: Ospedale Civile di Montichiari; Centro Sclerosi Multipla
state: Lombardia
city: Torrette - Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I-G.M. Lancisi-G. Salesi Di Ancona
state: Marche
city: Ponderano
country: Italy
facility: Ospedale degli Infermi
state: Piemonte
city: Acquaviva delle Fonti
country: Italy
facility: Ospedale Generale Regionale F. Miulli
state: Puglia
city: San Giovanni Rotondo
country: Italy
facility: Ospedale Casa Sollievo Della Sofferenza IRCCS
state: Puglia
city: Cefalu
country: Italy
facility: Fond. Ist. S. Raffaele - giglio
state: Sicilia
city: Guadalajara
country: Mexico
facility: Hospital Mexico Americano SC; Departamento de Electroencefalografía
state: Jalisco
city: Ciudad de México
country: Mexico
facility: Mexico Centre for Clinical Research
state: Mexico CITY (federal District)
city: Tlalnepantla de Baz
country: Mexico
facility: Clinical Research Institute
state: Mexico CITY (federal District)
city: Culiacán Rosales
country: Mexico
facility: Hospital Angeles Culiacan; Neurociencias
state: Sinaloa
city: Aguascalientes
country: Mexico
facility: Instituto Biomedico De Investigacion A.C.
city: Chihuahua
country: Mexico
facility: Hospital CIMA Chihuahua; Centro de Investigación Clínicatorre de Consultoriospiso 4
city: Bergen
country: Norway
facility: Haukeland Universitetssykehus
city: Bydgoszcz
country: Poland
facility: Vitamed
city: Katowice
country: Poland
facility: MA-LEK Clinical Sp. Z o.o.
city: Krakow
country: Poland
facility: Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii K
city: Lodz
country: Poland
facility: SPZOZ Uniwersytecki Szp. Klin. nr1 im.N.Barlickiego UM;Oddzial Kliniczny Neurologii
city: Lodz
country: Poland
facility: Centrum Neurologii Krzysztof Selmaj
city: Lublin
country: Poland
facility: Samodz.Publi.Szpital Kliniczny; nr 4 w Lublinie
city: Olsztyn
country: Poland
facility: Wojewodzki Specjalistyczny Szpital w Olsztynie; Oddzial Neurologiczny z Pododdzialem Udarowym
city: Siemianowice ?l?skie
country: Poland
facility: Neuro-Care Gabriela Klodowska
city: Warszawa
country: Poland
facility: mMED Maciej Czarnecki
city: Barnaul
country: Russian Federation
facility: State institution of health care - Territorial Clinical Hospital
state: Altaj
city: Sankt-peterburg
country: Russian Federation
facility: St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta
state: Sankt Petersburg
city: Pyatigorsk
country: Russian Federation
facility: City Clinical Hospital#2
state: Stavropol
city: Kazan
country: Russian Federation
facility: State autonomous institution of healthcare Inter-regional clinical and diagnostic center
state: Tatarstan
city: Kirov
country: Russian Federation
facility: Kirov City Clinical Hospital #1; Neurology Department
city: Nizniy Novgorod
country: Russian Federation
facility: SBHI of Nizhny Novgorod region City Clinical Hospital #3; neurology department
city: Perm
country: Russian Federation
facility: Perm SMA n.a. academ. E.A. Vagner
city: Saratov
country: Russian Federation
facility: Saratov State Medical University of RosZdrav; Neurology
city: Banska Bystrica
country: Slovakia
facility: MUDr. Beata Dupejova Neurologicka ambulancia s.r.o
city: Banska Bystrica
country: Slovakia
facility: Fakultna Nemocnica Roosevelta
city: Levoca
country: Slovakia
facility: Vseobecna nemocnica s poliklinikou Levoca a.s.
city: Badalona
country: Spain
facility: Institut Catala d?Oncologia Hospital Germans Trias i Pujol
state: Barcelona
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge; Servicio de Neurologia
state: Barcelona
city: Alicante
country: Spain
facility: Hospital General Univ. de Alicante
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Girona
country: Spain
facility: Hospital Universitari de Girona Dr Josep Trueta
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon; Servicio de Neurologia
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia; Servicio de Neurologia
city: Göteborg
country: Sweden
facility: Sahlgrenska Sjukhuset; Neurology
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna Neurology
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Huddinge
city: Umeå
country: Sweden
facility: Norrlands Universitetssjukhus
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty; Neurology
city: Istanbul
country: Turkey
facility: Haseki Training and Research Hospital
city: Istanbul
country: Turkey
facility: Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi; Noroloji Anabilim Dali
city: Istanbul
country: Turkey
facility: Istanbul Bilim Universty Medical Fac.
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Kocaeli
country: Turkey
facility: Kocaeli University Medical Faculty
city: Samsun
country: Turkey
facility: Ondokuz Mayis Univ. Med. Fac.; Neurology
city: Trabzon
country: Turkey
facility: Karadeniz Tecnical Uni. Med. Fac.; Neurology
city: Chernihiv
country: Ukraine
facility: Mun.Med.Proph.Inst.?Chernihiv Reg.Hosp.?; Neurology Department
city: Dnipropetrovsk
country: Ukraine
facility: City Clinical Hospital #4
city: Donetsk
country: Ukraine
facility: State Institution V.K. Gusak Institute of Urgent and Recover; Dep of Reconstructive Angioneurology a
city: Donetsk
country: Ukraine
facility: Road Clinical Hospital of Donetsk Station; Neurology Department
city: Ivano-Frankivsk
country: Ukraine
facility: Regional Clinical Hospital; Neurology Department
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital (Wonford)
city: London
country: United Kingdom
facility: Kings College Hospital; Neurosciences Clinical Trials Office
city: Stoke on Trent
country: United Kingdom
facility: City General Hospital; Department of Neurology
city: Swansea
country: United Kingdom
facility: Morriston Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Arnold DL, Sprenger T, Bar-Or A, Wolinsky JS, Kappos L, Kolind S, Bonati U, Magon S, van Beek J, Koendgen H, Bortolami O, Bernasconi C, Gaetano L, Traboulsee A. Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS. Mult Scler. 2022 Oct;28(12):1927-1936. doi: 10.1177/13524585221097561. Epub 2022 Jun 7.
citation: Krishnan AP, Song Z, Clayton D, Gaetano L, Jia X, de Crespigny A, Bengtsson T, Carano RAD. Joint MRI T1 Unenhancing and Contrast-enhancing Multiple Sclerosis Lesion Segmentation with Deep Learning in OPERA Trials. Radiology. 2022 Mar;302(3):662-673. doi: 10.1148/radiol.211528. Epub 2021 Dec 14.
citation: Giovannoni G, Kappos L, de Seze J, Hauser SL, Overell J, Koendgen H, Manfrini M, Wang Q, Wolinsky JS. Risk of requiring a walking aid after 6.5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis: Data from the OPERA I and OPERA II trials. Eur J Neurol. 2022 Apr;29(4):1238-1242. doi: 10.1111/ene.14823. Epub 2021 May 5.
citation: Hauser SL, Kappos L, Arnold DL, Bar-Or A, Brochet B, Naismith RT, Traboulsee A, Wolinsky JS, Belachew S, Koendgen H, Levesque V, Manfrini M, Model F, Hubeaux S, Mehta L, Montalban X. Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology. 2020 Sep 29;95(13):e1854-e1867. doi: 10.1212/WNL.0000000000010376. Epub 2020 Jul 20.
citation: Kappos L, Wolinsky JS, Giovannoni G, Arnold DL, Wang Q, Bernasconi C, Model F, Koendgen H, Manfrini M, Belachew S, Hauser SL. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. 2020 Sep 1;77(9):1132-1140. doi: 10.1001/jamaneurol.2020.1568.
citation: Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234. doi: 10.1056/NEJMoa1601277. Epub 2016 Dec 21.