A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis

Relapsing Multiple Sclerosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01247324
• Other study ID #: WA21092
• Secondary ID: 2010-020337-99
• Status: Completed
• Phase: Phase 3
• Start date: August 31, 2011
• Est. completion date: December 31, 2022

Study information

• Verified date: February 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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). Planned duration of double-blind treatment is 96 weeks. Participants who complete the 96-week double-blind treatment will have an option to enter a single-group, active-treatment, open-label extension period, providing they fulfill the eligibility criteria.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 821
• Est. completion date: December 31, 2022
• Est. primary completion date: April 2, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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 participants with EDSS 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 (e.g., 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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Relapsing Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Interferon beta-1a

• Ocrelizumab-matching placebo

• Ocrelizumab

• Interferon beta-1a-matching placebo

Locations

Country	Name	City	State
Argentina	Instituto centenario	Buenos Aires
Argentina	Hospital Español	Ciudad Autonoma Bs As
Argentina	Fundacion Rosarina de Neurorehabilitacion	Rosario
Australia	Royal North Shore Hospital; Department of Neurology	St Leonards	New South Wales
Austria	Barmherzige Brueder Konventspital	Linz
Belgium	AZ Sint Jan	Brugge
Belgium	Cliniques Universitaires Saint-Luc; Neurology	Bruxelles
Belgium	AZ Delta (Campus Rumbeke)	Roeselare
Brazil	Hospital das Clinicas - UFG;Reumatologia	Goiania	GO
Brazil	Clinica Neurologica; Neurocirurgica de Joinville	Joinville	SC
Brazil	IMV Pesquisa Neurológica	Porto Alegre	RS
Bulgaria	MHAT Avis Medica; Neurology Department	Pleven
Bulgaria	ACIBADEM CITY CLINIC TOKUDA HOSPITAL EAD; Clinic of Neurology and Sleep Medicine	Sofia
Bulgaria	First MHAT; Clinic of Neurology	Sofia
Bulgaria	MHATNP Sv.Naum EAD; Clinic in neurology diseases for movement disorders	Sofia
Bulgaria	Military Medical Academy; Neurology	Sofia
Chile	Hospital Carlos Van Buren	Valparaiso
Czechia	Fakultni nemocnice u sv. Anny; Neurologicka klinika	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Nemocnice Jihlava; NEU-Neurologicke oddeleni	Jihlava
Czechia	Krajska Nemocnice Pardubice Neurologicka Klinika	Pardubice
Czechia	VFN Praha Poliklinika Rs Centrum - Budova A	Prague
Czechia	Krajska zdravotni, a. s. ? Nemocnice Teplice, o. z.; Neurologicke oddeleni	Teplice
Estonia	West Tallinn Central Hospital	Tallinn
Estonia	Tartu University Hospital	Tartu
Finland	FinnMedi Oy	Tampere
France	Groupe Hospitalier Pellegrin	Bordeaux
France	CHU Hopital Gabriel Montpied; Service de Neurologie	Clermont Ferrand
France	Hopital Central; Neurologie	Nancy
France	CHU de Nîmes Hopital Caremeau; Service de Neurologie	Nimes
France	Hopital Hautepierre - CHU Strasbourg; Service de Neurologie	Strasbourg
Germany	Charité Universitaetsmedizin Berlin, Campus Charité Mitte	Berlin
Germany	Universitätsklinikum "Carl Gustav Carus"; MS Center Dresden	Dresden
Germany	Asklepiosklinik Barmbek; Abteilung Neurologie	Hamburg
Germany	Diakoniekrankenhaus Henriettenstiftung gGMBH; Klinik für Neurologie und klinische Neurophysiologie	Hannover
Germany	Universitaetsklinikum Mainz - PS; Klinik und Poliklinik fuer Neurologie	Mainz
Germany	Praxis Dr. med. Mathias Niedhammer, Facharzt für Neurologie	Oldenburg
Germany	Neurozentrum Prien Elisabeth Hans-Thümmler Stefan Braune	Prien
Germany	Universitätsklinikum Rostock, Zentrum für Nervenheilkunde; Klinik und Poliklinik für Neurologie	Rostock
Germany	Universitätsklinikum Tübingen, Zentrum für Neurologie	Tübingen
Germany	Studienzentrum Nordwest Dr med Joachim Springub Herr Wolfgang Schwarz	Westerstede
Hungary	Fovarosi Onkormanyzat Jahn Ferenc Del-Pesti	Budapest
Hungary	Semmelweis Egyetem AOK; Neurologiai Klinika	Budapest
Hungary	Szent Borbala Korhaz; Neurology	Tatabánya
Israel	Chaim Sheba Medical Center; Neurology Department	Ramat-Gan
Italy	Azienda Socio Sanitaria Territoriale della Valle Olona (pres	Gallarate	Valle D?Aosta
Italy	Irccs Ospedale San Raffaele	Milano	Lombardia
Italy	Azienda Ospedaliera di Padova; Clinica Neurologica	Padova	Veneto
Italy	Azienda Ospedaliera Sant'Andrea	Roma	Lazio
Latvia	Maritime Medicine Centre of Latvia Hospital of Vecmilgravis Department of Neurology	Riga
Latvia	P. Stradins Clinical University Hospital; Neurology	Riga
Lithuania	Kaunas Medical University Hospital	Kaunas
Lithuania	Klaipeda University Hospital Public Institution	Klaipeda
Lithuania	Vilnius University Hospital Santariskiu Clinic	Vilnius
Mexico	Grupo Médico Camino S.C.	Ciudad de México	Mexico CITY (federal District)
Mexico	Hospital Universitario Dr Jose Eleuterio Gonzalez; Universidad Autónoma de Nuevo León	Monterrey	Nuevo LEON
Netherlands	St. Antonius Ziekenhuis Nieuwegein	Nieuwegein
Peru	Policlinico Especializado en Neurologia	Callao
Peru	Clinica Anglo Americana	Lima
Peru	Hospital Nacional Dos de Mayo	Lima
Peru	Clinica Centenario Peruano Japonesa; Neurology	Pueblo Libre
Poland	COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika; Oddzia? Neurologiczny	Gdansk
Poland	MA-LEK Clinical Sp. Z o.o.	Katowice
Poland	Specjal. Praktyka Lekarska; Prof. Grzegorz Opala	Katowice
Poland	Neurologiczny NZOZ Centrum Leczenia SM; Osrodek Badan Klinicznych	Plewiska
Portugal	Hospital de Braga; Servico de Neurologia	Braga
Russian Federation	Kemerovo Regional Clinical Hospital	Kemerovo
Russian Federation	Central Clinical Hospital #2 N.A. Semashko OAO RJHD	Moskva	Moskovskaja Oblast
Russian Federation	FGBU FNKC FMBA of Russia	Moskva	Moskovskaja Oblast
Russian Federation	FSBIH Siberian Regional Medical Centre of FMBA of Russia	Novosibirsk
Russian Federation	MRC for Oncology and Neurology Biotherapy	Novosibirsk
Russian Federation	Samara State Medical University	Samara
Russian Federation	St.-Peterburg State institution of health care City multifield hospital #2	Sankt-peterburg	Sankt Petersburg
Russian Federation	Reg. SI of Health Care Smolensk Regional Clinical Hospital	Smolensk
Russian Federation	MMA of Ministry of Defense of Russia named after S.M. Kirov	St.Petersburg	Sankt Petersburg
Russian Federation	Regional Multiple Sclerosis Centre b/o CC ECM "Neftyanik"	Tyumen
Russian Federation	Regional Multiple Sclerosis Centre b/o CC ECM "Neftyanik"	Tyumen	Tjumen
Russian Federation	Sverdlovsk Regional Clinical Hospital 1	Yekaterinburg	Sverdlovsk
Serbia	Military Medical Academy	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Serbia	Clinical Center Nis	NIS
Slovakia	FNsP Bratislava - Nemocnica Stare mesto	Bratislava
Slovakia	FNsP Bratislava, Nemocnica Ruzinov	Bratislava
Slovakia	Univerzitna nemocnica Bratislava Nemocnica sv. Cyrila a Metoda; Nemocnicna lekaren	Bratislava
Slovakia	Fakultna nemocnica s poliklinikou Zilina	Zilina
South Africa	Dr CC Coetzee Inc	Durban
Spain	Hospital de Basurto	Bilbao	Vizcaya
Spain	Hospital Universitario Puerta De Hierro Majadahonda; Servicio de Neurología	Madrid
Spain	Complejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Neurologia	Santa Cruz De Tenerife	Tenerife
Spain	Hospital Universitario Virgen Macarena	Sevilla
Switzerland	Universitätsspital Basel Medizin Neurologie; Neurologische Poliklinik	Basel
Switzerland	Ospedale Regionale Lugano Civico Medizin Neurologie; Neurologia	Lugano
Tunisia	Hopital Razi	Mannouba
Tunisia	Hopital Universitaire Fattouma Bourguiba	Monastir
Tunisia	Hopital Charles Nicolle	Tunis
Ukraine	MMPIDon.Reg.Cl.&Ter.Med.Com.Neur.Dept.DNMU n.a.M.Gorkiy; Ch. of Nervous Diseases and Med. Genetics	Donetsk
Ukraine	St.In.Inst. of Neurol.Psych.and Narcol.of the AMSU; Dept. of Neuroinfection and Multiply Sclerosis	Kharkov
Ukraine	Kyiv City Cl.Hosp.#4 Depart.of Neurology #2NMU; Department of Neurology	Kyiv
Ukraine	Lviv Regional Clinical Hospital; Department of Neurology	Lviv
Ukraine	Vin.Reg.Psych.Hosp.N.A Yuschenko O.I., Vnmu N.A. Pyrogov; Department of Nervous Diseases	Vinnytsya
United Kingdom	Walton Centre NHS Foundation Trust, Neuroscience Research Centre; CLINICAL TRIALS UNIT	Liverpool
United Kingdom	Royal London Hospital; Neurology	London
United States	The MS Center; Advance Neurology and Pain	Advance	North Carolina
United States	University of New Mexico	Albuquerque	New Mexico
United States	Emory University; Department of Neurology	Atlanta	Georgia
United States	NeuroTrials Research, Inc.	Atlanta	Georgia
United States	Shepherd Center Inc.	Atlanta	Georgia
United States	American Health Network Institute, LLC	Avon	Indiana
United States	Massachusetts General Hospital.	Boston	Massachusetts
United States	Uni of Vermont Medical Center;	Burlington	Vermont
United States	Mercy Medical Group	Carmichael	California
United States	Atrium Health Neurosciences Institute ? Charlotte	Charlotte	North Carolina
United States	OnSite Clinical Solutions LLC	Charlotte	North Carolina
United States	Northwestern University; Dept. of Neurology	Chicago	Illinois
United States	University Neurology Inc.	Cincinnati	Ohio
United States	Michigan Neurology Associates P.C.	Clinton Township	Michigan
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Michigan Institute for Neurological Disorders	Farmington Hills	Michigan
United States	The Minneapolis Clinic of Neurology	Golden Valley	Minnesota
United States	Neurology Associates PA	Hickory	North Carolina
United States	Uni of Texas Health Science Center At Houston	Houston	Texas
United States	Scripps Clinic	La Jolla	California
United States	MS Center of California	Laguna Hills	California
United States	Southern California Permanente Medical Group	Los Angeles	California
United States	Bhupesh Dihenia M.D. P.A.	Lubbock	Texas
United States	Health First Physicians Inc.	Melbourne	Florida
United States	Mercy Research Institute	Miami	Florida
United States	Consultants in Neurology Ltd	Northbrook	Illinois
United States	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Neuro-Therapeutics Inc.	Pasadena	California
United States	Albert Einstein Medical Center; Depatment of Neurosensory sciences	Philadelphia	Pennsylvania
United States	21st Century Neurology	Phoenix	Arizona
United States	Magee-Woman's Hospital	Pittsburgh	Pennsylvania
United States	Providence Neurological Specialties	Portland	Oregon
United States	The MS Center for Innovations In Care	Saint Louis	Missouri
United States	Washington University; Wash Uni. Sch. Of Med	Saint Louis	Missouri
United States	University of California at San Francisco	San Francisco	California
United States	Miami Research Associates	South Miami	Florida
United States	Multicare Research Institute; Multicare Neuroscience Center of Washington	Tacoma	Washington
United States	Axiom Clinical Research of Florida	Tampa	Florida
United States	University of South Florida	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Chile,  Czechia,  Estonia,  Finland,  France,  Germany,  Hungary,  Israel,  Italy,  Latvia,  Lithuania,  Mexico,  Netherlands,  Peru,  Poland,  Portugal,  Russian Federation,  Serbia,  Slovakia,  South Africa,  Spain,  Switzerland,  Tunisia,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks	ARR was protocol-defined and calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of exposure to that treatment.	Week 96
Secondary	Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period	Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.	Week 108
Secondary	Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment	The total number of T1 gadolinium-enhancing lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.	Baseline up to Week 96
Secondary	Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment	The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.	Baseline up to Week 96
Secondary	Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks	Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined.	Week 96
Secondary	Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period	Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.	Week 108
Secondary	Number of T1 Hypointense Lesions During the Double-Blind Treatment	The total number of new T1-Hypo-Intense Lesions (Chronic Black Holes) for all participants in the treatment group was calculated as the sum of the individual number of new lesions at Weeks 24, 48, and 96.	Baseline up to Week 96
Secondary	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96	MSFC score consists of: A) Timed 25-Foot walk; B) 9-Hole Peg Test (9-HPT); and C) Paced Auditory Serial Addition Test (PASAT-3 version). The MSFCS is based on the concept that scores for these three dimensions (arm, leg, and cognitive function) are combined to create a single score (the MSFC) that can be used to detect change over time in a group of participants with MS. Since the three primary measures differ in what they actually measure, a common composite score for the three different measures i.e., Z- score was selected for the purpose. MSFC Score = {Z arm, average + Z leg, average + Z cognitive} / 3.0. The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each participant at each time point. A score of +1 indicates that, on average, an individual scored 1 standard deviation (SD) better than the reference population and a score of -1 indicates that an individual scored 1 SD worse than the reference population.	Baseline, Week 96
Secondary	Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96	Brain volume was recorded as an absolute "normalized" value at the baseline visit then recorded at subsequent visits as a percentage change relative to the absolute value at the baseline visit. Therefore, brain volume at Week 24 was calculated as the brain volume at the baseline visit multiplied by 1 + ([percentage change in brain volume from baseline visit to Week 24]/100). Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week.	From Week 24 up to Week 96
Secondary	Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96	The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t- scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status.	Baseline, Week 96
Secondary	Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96	NEDA was defined only for participants with a baseline EDSS score >=2.0. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Participants who completed the 96- week treatment period were considered as having evidence of disease activity if at least one protocol- defined relapse (PDR), a confirmed disability progression (CDP) event or at least one MRI scan showing MRI activity (defined as Gd-enhancing T1 lesions, or new or enlarging T2 lesions) was reported during the 96-week treatment period, otherwise the participant was considered as having NEDA.	Week 96
Secondary	Number of Participants With Adverse Events (AEs)	AEs included infusion related reactions (IRRs) and serious MS relapses, but excluded non-serious MS relapses. Serious Adverse Events (SAEs) included serious MS relapses and serious IRRs.	Baseline up to 588 weeks
Secondary	Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC)	AUC represents total drug exposure for one dosing interval after the 4th dose.	Pre-infusion at Weeks 1, 24, 48, 72; and 30 minutes post-infusion at Week 72; at any time during Weeks 84 and 96
Secondary	Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab	Number of participants positive for anti-drug antibodies (ADAs) to ocrelizumab is the number of post- baseline evaluable participants determined to have treatment-induced ADA or treatment-enhanced ADA during the study period.	Baseline up to week 96