A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis (RMS)

Multiple Sclerosis Clinical Trial

Official title:

A Phase IIIb Multicenter, Randomized, Double-Blind, Controlled Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04544436
• Other study ID #: BN42082
• Secondary ID: 2020-000893-69
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 26, 2020
• Est. completion date: August 31, 2028

Study information

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

Clinical Trial Summary

This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks in participants with RMS, in comparison to the approved 600 mg dose of ocrelizumab.

Description:

Participants will be treated for a minimum of 120 weeks in the double-blind phase. Upon positive primary results after the double-blind phase, an optional higher dose extension treatment (OLE phase) is planned for eligible participants. The OLE will be carried out for approximately 96 weeks. Participants will be followed for safety for 48 weeks thereafter. Participants whose B-cell levels still did not replete to their baseline level or the low level of normal (LLN), whichever is lower, will move into the B-cell monitoring (BCM) phase following the safety follow-up phase. The study will end when all participants who were not treated with an alternative B-cell depleting therapy have repleted their B-cells to the baseline value or the lower limit of normal.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 864
• Est. completion date: August 31, 2028
• Est. primary completion date: December 19, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Diagnosis of relapsing multiple sclerosis (RMS) (i.e., RRMS or aSPMS where participants still experience relapses) in accordance with the revised McDonald Criteria 2017
• At least two documented clinical relapses within the last 2 years prior to screening, or one clinical relapse in the year prior to screening. No relapse 30 days prior to screening and at baseline.
• Participants must be neurologically stable for at least 30 days prior to randomization and baseline.
• Expanded disability status scale (EDSS) score, at screening and baseline, from 0 to 5.5 inclusive.
• Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds
• Average 9HPT score over four trials at screening and over four trials at baseline respectively, up to 250 (inclusive) seconds
• Documented MRI of brain with abnormalities consistent with MS at screening.
• Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization.
• Females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods.
• Female participants without reproductive potential may be enrolled e.g. if post-menopausal or if surgically sterile

Exclusion Criteria:

• History of primary progressive MS at screening.
• Any known or suspected active infection at screening or baseline (except nailbed infections), or any major episode of infection requiring hospitalization or treatment with IV antimicrobials within 8 weeks or treatment with oral antimicrobials within 2 weeks, prior to and during screening.
• History of confirmed or suspected progressive multifocal leukoencephalopathy.
• History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening.
• Immunocompromised state.
• Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization.
• Inability to complete an MRI or contraindication to gadolinium administration.
• Contraindications to mandatory pre-medications for IRRs.
• Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study
• Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study.
• Significant, uncontrolled disease that may preclude participant from participating in the study.
• History of or currently active primary or secondary, non-drug-related, immunodeficiency.
• Pregnant or breastfeeding or intending to become pregnant
• Lack of peripheral venous access.
• History of alcohol or other drug abuse within 12 months prior to screening.
• Treatment with any investigational agent within 24 weeks prior to screening or treatment with any experimental procedure for MS.
• Previous use of anti-CD20s (including ocrelizumab), unless the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy.
• Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline
• Previous treatment with natalizumab within 4.5 months of baseline
• Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline
• Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab
• Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label. If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication.
• Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation.
• Any previous history of transplantation or anti-rejection therapy.
• Treatment with intravenous (IV) immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to randomization.
• Systemic corticosteroid therapy within 4 weeks prior to screening.
• Positive screening tests for active, latent, or inadequately treated hepatitis B.
• Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab.
• Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Ocrelizumab
The actual higher dose of ocrelizumab will be assigned to participants based on their body weight at baseline: 1200 mg (participants's body weight <75 kg) or 1800 mg (participant's body weight >/=75 kg). The first dose of ocrelizumab will be administered as two 600 mg or 900 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 1200 mg or 1800 mg IV infusion every 24 weeks. During the optional open-label extension (OLE) phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total).
• Ocrelizumab
Ocrelizumab will be administered at a dose of 600 milligram (mg) every 24 weeks. The first dose of ocrelizumab will be administered as two 300 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 600 mg IV infusion every 24 weeks.
• Antihistamine
Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion.
• Methylprednisolone
Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.

Locations

Country	Name	City	State
Argentina	CEMIC	Buenos Aires
Argentina	Centro de Especialidades Neurológicas y Rehabilitación - CENyR	Buenos Aires
Argentina	Centro de Investigaciones Médicas Tucuman	San Miguel de Tucuman
Australia	Austin Hospital; Department of Neurology	Heidelberg	Victoria
Belgium	Hospital Erasme	Bruxelles
Belgium	Revalidatie en MS Centrum	Overpelt
Brazil	Instituto de Neurologia de Curitiba	Curitiba	PR
Brazil	Clinica Neurologica; Neurocirurgica de Joinville	Joinville	SC
Brazil	IMV Pesquisa Neurológica	Porto Alegre	RS
Brazil	CPQuali Pesquisa Clinica Ltda	Sao Paulo	SP
Canada	Recherche Sepmus Inc.	Greenfield Park	Quebec
Canada	Hotel-Dieu de Levis	Quebec
Denmark	Rigshospitalet Glostrup; Neurologisk Klinik	Glostrup
France	Groupe Hospitalier Pellegrin; Service de Neurologie - 3ème étage	Bordeaux
France	CHU Hopital Gabriel Montpied; Service de Neurologie	Clermont Ferrand
France	CH St Vincent de Paul	Lille
France	Hôpital Charles Nicolle; Service de Neurologie	Rouen
Germany	Charite - Universitätsmedizin Berlin	Berlin
Germany	St. Josef-Hospital, Klinik für Neurologie	Bochum
Germany	Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften	Dresden
Germany	Universitätsklinikum Schleswig-Holstein; Klinik für Neurologie	Kiel
Germany	PANAKEIA - Arzneimittelforschung Leipzig GmbH	Leipzig
Germany	Universität Leipzig; Innere Medizin, Neurologie, Dermatologie	Leipzig
Germany	Universitätsklinikum Tübingen, Zentrum für Neurologie	Tübingen
Germany	Universitätsklinikum Ulm; Klinik für Neurologie	Ulm
Germany	Deutsche Klinik für Diagnostik; DKD Helios Klinik Wiesbaden, Abt. Neurologie	Wiesbaden
Greece	401 Military Hospital of Athens; Neurology Department	Athens
Greece	AHEPA Univ. General Hospital of Thessaloniki; B' Neurology Dept.	Thessaloniki
Hungary	S-Medicon Egeszsegugyi Szolgaltato Kft.	Budapest
Hungary	UNO Medical Trials Kft.	Budapest
Hungary	Somogy Vármegyei Kaposi Mór Oktató Kórház	Kaposvar
Italy	Universita? G. D'Annunzio; Dipartimento di Neuroscienze, Imaging e Scienze Cliniche	Chieti	Abruzzo
Italy	Fond. Istituto Neurologico C.Besta; UO Neurologia IV - Neuroimmunologia Malattie Neuromuscolari	Milano	Lombardia
Italy	AOU Seconda Università degli Studi; Dip. Assistenziale Integrato Medicina Int-II Clinica Neurologica	Napoli	Campania
Italy	AOU Seconda Università degli Studi; Dip.Assistenziale Integrato Medicina Int-I Clinica Neurologica	Napoli	Campania
Italy	IRCCS Istituto Neurologico Neuromed; Centro per lo Studio e la Cura della Sclerosi Multipla	Pozzilli	Molise
Italy	NCL Institute Neuroscience	Roma	Lazio
Italy	Policlinico Tor Vergata Dip. Neuroscienze-Clinica Neurologica-UOSD Sclerosi Multipla	Roma	Lazio
Italy	Policlinico Umberto I; Centro Sclerosi Multipla DAI Neuroscienze e Salute Mentale	Roma	Lazio
Peru	Hospital IV Alberto Sabogal Sologuren; Unidad de Investigacion	Bellavista
Peru	Clinica Internacional; Unidad De Investigacion	Lima
Peru	Hospital Maria Auxiliadora	Lima
Peru	Hospital Nacional Dos de Mayo; Unidad de Investigacion de Neurologia	Lima
Peru	Instituto Nacional de Ciencias Neurológicas - Hospital Mogrovejo; Peru	Lima
Peru	Clinica Sanchez Ferrer	Trujillo
Poland	Neurocentrum Bydgoszcz sp. z o.o	Bydgoszcz
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	Centrum Neurologii Krzysztof Selmaj	Lodz
Poland	SPZOZ Uniwersytecki Szp. Klin. nr1 im.N.Barlickiego UM;Oddzial Kliniczny Neurologii	Lodz
Poland	Indywidualna Praktyka Lekarska Prof. Dr Hab. N. Med. Konrad Rejdak.	Lublin
Poland	Neurologiczny Niepubliczny ZOZ Centrum Leczenia SM Osrodek Bada? Klinicznych	Plewiska
Poland	EMC Instytut Medyczny SA	Pozna?
Poland	Nmedis sp. z o.o.	Rzeszów
Poland	Osrodek Badan Klinicznych Euromedis	Szczecin
Poland	Centrum Medyczne NeuroProtect	Warszawa
Poland	Instytut Psychiatrii i Neurologii II Klinika Neurologiczna	Warszawa
Poland	Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie	Warszawa
Poland	Wojskowy Instytut Medyczny - Pa?Stwowy Instytut Badawczy	Warszawa
Portugal	Hospital de Braga; Centro Clínico Académico (Piso 1, Ala E)	Braga
Portugal	Centro Hospitalar de Lisboa Ocidental - Hospital Egas Moniz; Neurologia	Lisboa
Portugal	Hospital de Santa Maria; Servico de Neurologia	Lisboa
Russian Federation	KSMU Interregional Clinical Diagnostic Centre	Kazan	Tatarstan
Russian Federation	Vertebronevrologiya LLC	Kazan	Tatarstan
Russian Federation	FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency	Krasnoyarsk	Krasnojarsk
Russian Federation	Neiro Clinica LLC	Moscow	Moskovskaja Oblast
Russian Federation	Research Center of Neurology of RAMS	Moscow	Moskovskaja Oblast
Russian Federation	City Clinical Hospital #24; Multipal Sclerosis department	Moskva	Moskovskaja Oblast
Russian Federation	Federal center of brain research and neurotechnologies	Moskva	Moskovskaja Oblast
Russian Federation	National Center of Social Significant Disease	Sankt-peterburg	Leningrad
Russian Federation	N.P. Bechtereva Institute of the Human Brain	Sankt-petersburg	Sankt Petersburg
Russian Federation	Saratov State Medical University of RosZdrav; Neurology	Saratov
Russian Federation	City Hospital #40 of Kurortniy Administrative District	St. Petersburg	Sankt Petersburg
Russian Federation	Nebbiolo Center for Clinical Trials	Tomsk
Russian Federation	Ulyanovsk Regional Clinical Hospital	Ulyanovsk	Uljanovsk
Russian Federation	SHI Sverdlovsk Regional Clinical Hospital #1;Neurology	Yekaterinburg	Sverdlovsk
Spain	Hospital Universitari Vall d'Hebron; Servicio de Neumo-Inmunologia	Barcelona
Spain	Hospital Puerta del Mar; Sevicio de Neurologia	Cadiz
Spain	Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Neurologia	Coruña	LA Coruña
Spain	Hospital Regional Universitario de Malaga ? Hospital General; Servicio de Neurologia	Malaga
Spain	Hospital Quiron de Madrid; Servicio de Neurologia	Pozuelo de Alarcon	Madrid
Spain	Hospital Alvaro Cunqueiro; Servicio de Neurologia	Vigo	Pontevedra
Switzerland	Universitätsspital Basel Medizin Neurologie; Neurologische Poliklinik	Basel
Switzerland	Inselspital Bern Medizin Neurologie; Neurologische Poliklinik	Bern
Switzerland	Ospedale Regionale di Lugano - Civico; Neurologia	Lugano
Turkey	Kocaeli University Hospital; Department of Neurology	Kocaeli
Ukraine	5th Cherkasy City Center of Primary Health Care	Cherkasy	KIEV Governorate
Ukraine	Mun.Med.Proph.Inst.?Chernihiv Reg.Hosp.?; Neurology Department	Chernihiv
Ukraine	Bukovinsky SMU RMI Chernivtsi RCH	Chernivtsi
Ukraine	SI USSRI of Medical and Social Problems of Disabilities of MOHU	Dnipro	KIEV Governorate
Ukraine	Regional Clinical Hospital; Neurology Department	Ivano-Frankivsk
Ukraine	Municipal Nonprofit Enterprise of Kharkiv Regional Council Regional Clinical Hospital	Kharkiv	Kharkiv Governorate
Ukraine	St.In.Inst. of Neurol.Psych.and Narcol.of the AMSU; Dept. of Neuroinfection and Multiply Sclerosis	Kharkov
Ukraine	Medical Center Dopomoga Plus	Kyiv	Chernihiv Governorate
Ukraine	Medical Center of Private Execution First Private Clinic	Kyiv	KIEV Governorate
Ukraine	Lvivska oblasna tsentralna likarnia	Lviv	KIEV Governorate
Ukraine	Municipal Non-profit Enterprise Zaporizhzhya Regional Hospital Zaporizhzhya Regional Council	Zaporizhzhia	Katerynoslav Governorate
Ukraine	Zaporizhia City Multispecialty Clinical Hospital #9	Zaporizhzhye	Katerynoslav Governorate
United Kingdom	Derriford Hospital	Plymouth
United States	Abington Neurological Associates	Abington	Pennsylvania
United States	The NeuroMedical Clinic of Central Louisiana	Alexandria	Louisiana
United States	Dent Neurological Institute	Amherst	New York
United States	American Health Network Institute, LLC	Avon	Indiana
United States	Mountain Neurological Research Center; Roaring Fork Neurologt, P.C.	Basalt	Colorado
United States	Profound Research, LLC	Carlsbad	California
United States	North Central Neurology Associates	Cullman	Alabama
United States	UC Health Neurology	Dayton	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	Advanced Neurology of Colorado, LLC	Fort Collins	Colorado
United States	Alabama Neurology Associates	Homewood	Alabama
United States	Tri-State Mountain Neurology	Johnson City	Tennessee
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Evergreen MS Center	Kirkland	Washington
United States	Hope Neurology	Knoxville	Tennessee
United States	Cleveland Clinic Lou Ruvo; Center for Brain Research	Las Vegas	Nevada
United States	Bhupesh Dihenia M.D. P.A.	Lubbock	Texas
United States	Neurology Associates, PA; Research Department	Maitland	Florida
United States	Oklahoma Medical Research Foundation; MS Center of Excellence	Oklahoma City	Oklahoma
United States	21st Century Neurology	Phoenix	Arizona
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Neurology Center of San Antonio	San Antonio	Texas
United States	Maine Medical Center	Scarborough	Maine
United States	Stanford University Medical Center; Stanford Neuroscience Health Center	Stanford	California
United States	University of South Florida	Tampa	Florida
United States	Collaborative Neuroscience Network Inc.	Torrance	California
United States	Dragonfly Research, LLC	Wellesley	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  Denmark,  France,  Germany,  Greece,  Hungary,  Italy,  Peru,  Poland,  Portugal,  Russian Federation,  Spain,  Switzerland,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Onset of 12-week cCDP (cCDP12)	Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.	Baseline up to approximately 4.3 years
Secondary	Time to Onset of 24-week cCDP (cCDP24)	Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.	Baseline up to approximately 4.3 years
Secondary	Time to Onset of 48-week cCDP (cCDP48)	Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.	Baseline up to approximately 4.3 years
Secondary	Time to onset of cCDP12 independent of protocol-defined relapses (PDR)	Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT independent of protocol defined relapses.	Baseline up to approximately 4.3 years
Secondary	Time to onset of 12-week CDP (CDP12)	CDP, defined as a sustained increase from baseline in EDSS score of >/=1.0 point in participants with a baseline EDSS score of	Baseline up to approximately 4.3 years
Secondary	Time to >/= 20% Increase in 12-week Confirmed by Timed 25-Foot Walk Test (T25FWT)	The T25FWT is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant is directed to start at one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible.	Baseline up to approximately 4.3 years
Secondary	Annual rate of percent change from baseline in total brain volume		Baseline up to approximately 4.3 years
Secondary	Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT)	The SDMT is a performance measure that has demonstrated sensitivity in detecting not only the presence of cognitive impairment but also changes in cognitive functioning over time and in response to treatment. Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses will be collected orally. A four-point change from baseline is typically considered clinically meaningful.	Baseline up to approximately 4.3 years
Secondary	Time to 12-week confirmed 8-point increase in 12-Item Multiple Sclerosis Walking Scale (MSWS-12)	Self-reported measure of the impact of MS on the individual's ability to walk	Baseline up to approximately 4.3 years
Secondary	Change in NfL at Week 48 for patients assigned to the higher dose ocrelizumab group	Biomarker for neurodegneration NfL	Baseline up to approximately 4.3 years
Secondary	Change in NfL at Week 48 for patients assigned to the approved dose ocrelizumab group	Biomarker for neurodegneration NfL	Baseline up to approximately 4.3 years
Secondary	Serum Concentration of Ocrelizumab at Specified Time points		Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
Secondary	B-cell levels in blood	Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood	Baseline up to approximately 4.3 years
Secondary	Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood	Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood	Baseline up to approximately 4.3 years
Secondary	Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood in Participants with the High versus Low Affinity Fcgamma Receptor 3A (FcgR3A) Genotype per Arm	Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood	Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
Secondary	Change from Baseline in the Anti-Drug Antibody (ADA) Levels		Week 0, 24, 48, 72, 96, 120
Secondary	Levels of Neurofilament Light Chain (NfL) in Blood	Biomarker for neurodegneration NfL	Baseline up to approximately 4.3 years
Secondary	Levels of Interleukin-6 (IL-6) in Blood		Baseline up to approximately 4.3 years
Secondary	Levels of Blood B-cells	Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood	Baseline up to approximately 4.3 years
Secondary	Levels of Lymphocytes in Blood		Baseline up to approximately 4.3 years
Secondary	Proportion of Participants with Different DNA Genotypes		Week 0