A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis (RMS)
- Conditions
- Multiple Sclerosis
- Interventions
- Registration Number
- NCT04544436
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This is a randomized, double-blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and PK of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks (Q24W) in participants with RMS, in comparison to the approved 600 milligrams (mg) dose of ocrelizumab.
- Detailed Description
Participants will be treated for a minimum of 120 weeks in the double-blind treatment (DBT) phase. Upon positive primary results after the DBT phase, an optional higher dose extension treatment, open-label extension (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 LLN.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 864
- Diagnosis of RMS
- 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
- 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 magnetic resonance imaging (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
- 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 infusion-related reaction (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- cluster of differentiation 20 (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 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ocrelizumab Approved Dose Ocrelizumab Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Higher Dose Ocrelizumab Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Higher Dose Antihistamine Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Approved Dose Antihistamine Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Higher Dose Methylprednisolone Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight \<75 kilograms \[kg\]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion. Ocrelizumab Approved Dose Methylprednisolone Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
- Primary Outcome Measures
Name Time Method Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12) Baseline up to approximately 4.3 years Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by Expanded Disability Status Scale (EDSS), Timed 25-foot Walk Test (T25FWT) or 9-hole Peg Test (9-HPT).
- Secondary Outcome Measures
Name Time Method Time to Onset of 24-week cCDP (cCDP24) Baseline up to approximately 4.3 years Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.
Time to Onset of 48-week cCDP (cCDP48) Baseline up to approximately 4.3 years Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.
Time to Onset of cCDP12 Independent of Protocol-defined Relapses (PDR) Baseline up to approximately 4.3 years 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 PDR.
Time to Onset of 12-week Confirmed Disability Progression (CDP12) Baseline up to approximately 4.3 years CDP, defined as a sustained increase from baseline in EDSS score of ≥1.0 point in participants with a baseline EDSS score of ≤5.5 or a sustained increase of ≥0.5 points in participants with a baseline EDSS score of \>5.5.
Time to ≥ 20% Increase in 12-week Confirmed by T25FWT Baseline up to approximately 4.3 years 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.
Annual Rate of Percent Change From Baseline in Total Brain Volume Baseline up to approximately 4.3 years Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) Baseline up to approximately 4.3 years 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.
Time to 12-week Confirmed 8-point Increase in 12-item Multiple Sclerosis Walking Scale (MSWS-12) Baseline up to approximately 4.3 years Self-reported measure of the impact of multiple sclerosis (MS) on the individual's ability to walk
Change in Neurofilament Light (NfL) at Week 48 for Participants Assigned to the Higher Dose Ocrelizumab Group Baseline (Week 0), Week 48 Biomarker for neurodegeneration NfL
Change in NfL at Week 48 for Participants Assigned to the Approved Dose Ocrelizumab Group Baseline (Week 0), Week 48 Biomarker for neurodegeneration NfL
Percentage of Participants With Adverse Events (AEs) Baseline up to approximately 7.5 years Serum Concentration of Ocrelizumab at Specified Time Points Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120 B-cell Levels in Blood Baseline up to approximately 4.3 years Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
Percentage of Participants Achieving 5 or Less B-cells per Microliter of Blood Baseline up to approximately 4.3 years Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
Change From Baseline in the Anti-drug Antibody (ADA) Levels Week 0, 24, 48, 72, 96, 120
Trial Locations
- Locations (121)
Osrodek Badan Klinicznych Euromedis
🇵🇱Szczecin, Poland
Centrum Medyczne NeuroProtect
🇵🇱Warszawa, Poland
Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie
🇵🇱Warszawa, Poland
Instytut Psychiatrii i Neurologii II Klinika Neurologiczna
🇵🇱Warszawa, Poland
Wojskowy Instytut Medyczny - Pa?Stwowy Instytut Badawczy
🇵🇱Warszawa, Poland
Hospital de Braga
🇵🇹Braga, Portugal
Centro Hospitalar de Lisboa Ocidental - Hospital Egas Moniz
🇵🇹Lisboa, Portugal
Hospital de Santa Maria
🇵🇹Lisboa, Portugal
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Puerta del Mar
🇪🇸Cadiz, Spain
Hospital Regional Universitario de Malaga ? Hospital General
🇪🇸Malaga, Spain
Universitätsspital Basel Medizin Neurologie
🇨🇭Basel, Switzerland
Inselspital Bern Medizin Neurologie
🇨🇭Bern, Switzerland
Ospedale Regionale di Lugano - Civico
🇨🇭Lugano, Switzerland
Kocaeli University Hospital
🇹🇷Kocaeli, Turkey
5th Cherkasy City Center of Primary Health Care
🇺🇦Cherkasy, Ukraine
Mun.Med.Proph.Inst.?Chernihiv Reg.Hosp.?
🇺🇦Chernihiv, Ukraine
Bukovinsky SMU RMI Chernivtsi RCH
🇺🇦Chernivtsi, Ukraine
Somogy Vármegyei Kaposi Mór Oktató Kórház
🇭🇺Kaposvar, Hungary
Universita? G. D'Annunzio
🇮🇹Chieti, Abruzzo, Italy
Policlinico Tor Vergata Dip. Neuroscienze-Clinica Neurologica-UOSD Sclerosi Multipla
🇮🇹Roma, Lazio, Italy
NCL Institute Neuroscience
🇮🇹Roma, Lazio, Italy
Policlinico Umberto I
🇮🇹Roma, Lazio, Italy
Fond. Istituto Neurologico C.Besta
🇮🇹Milano, Lombardia, Italy
IRCCS Istituto Neurologico Neuromed
🇮🇹Pozzilli, Molise, Italy
Hospital IV Alberto Sabogal Sologuren
🇵🇪Bellavista, Peru
Clinica Internacional
🇵🇪Lima, Peru
Instituto Nacional de Ciencias Neurológicas - Hospital Mogrovejo
🇵🇪Lima, Peru
Hospital Maria Auxiliadora
🇵🇪Lima, Peru
Hospital Nacional Dos de Mayo
🇵🇪Lima, Peru
Clinica Sanchez Ferrer
🇵🇪Trujillo, Peru
Neurocentrum Bydgoszcz sp. z o.o
🇵🇱Bydgoszcz, Poland
FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency
🇷🇺Krasnoyarsk, Krasnojarsk, Russian Federation
National Center of Social Significant Disease
🇷🇺Sankt-peterburg, Leningrad, Russian Federation
Neiro Clinica LLC
🇷🇺Moscow, Moskovskaja Oblast, Russian Federation
Research Center of Neurology of RAMS
🇷🇺Moscow, Moskovskaja Oblast, Russian Federation
Federal center of brain research and neurotechnologies
🇷🇺Moskva, Moskovskaja Oblast, Russian Federation
City Clinical Hospital #24
🇷🇺Moskva, Moskovskaja Oblast, Russian Federation
EMC Instytut Medyczny SA
🇵🇱Pozna?, Poland
Nmedis sp. z o.o.
🇵🇱Rzeszów, Poland
North Central Neurology Associates
🇺🇸Cullman, Alabama, United States
Alabama Neurology Associates
🇺🇸Homewood, Alabama, United States
21st Century Neurology
🇺🇸Phoenix, Arizona, United States
Profound Research, LLC
🇺🇸Carlsbad, California, United States
Instituto de Neurologia de Curitiba
🇧🇷Curitiba, Paraná, Brazil
CPQuali Pesquisa Clinica Ltda
🇧🇷Sao Paulo, São Paulo, Brazil
Recherche Sepmus Inc.
🇨🇦Greenfield Park, Quebec, Canada
Hotel-Dieu de Levis
🇨🇦Levis, Quebec, Canada
Rigshospitalet Glostrup
🇩🇰Glostrup, Denmark
Groupe Hospitalier Pellegrin
🇫🇷Bordeaux, France
CHU Hopital Gabriel Montpied
🇫🇷Clermont Ferrand, France
CH St Vincent de Paul
🇫🇷Lille, France
Hôpital Charles Nicolle
🇫🇷Rouen, France
Charite - Universitätsmedizin Berlin
🇩🇪Berlin, Germany
St. Josef-Hospital, Klinik für Neurologie
🇩🇪Bochum, Germany
AOU Seconda Università degli Studi
🇮🇹Napoli, Campania, Italy
COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika
🇵🇱Gdansk, Poland
MA-LEK Clinical Sp. Z o.o.
🇵🇱Katowice, Poland
SPZOZ Uniwersytecki Szp. Klin. nr1 im.N.Barlickiego UM
🇵🇱Lodz, Poland
Centrum Neurologii Krzysztof Selmaj
🇵🇱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
SI USSRI of Medical and Social Problems of Disabilities of MOHU
🇺🇦Dnipro, Ukraine
Regional Clinical Hospital
🇺🇦Ivano-Frankivsk, Ukraine
St.In.Inst. of Neurol.Psych.and Narcol.of the AMSU
🇺🇦Kharkov, Ukraine
Medical Center of Private Execution First Private Clinic
🇺🇦Kyiv, Ukraine
Medical Center Dopomoga Plus
🇺🇦Kyiv, Ukraine
Lvivska oblasna tsentralna likarnia
🇺🇦Lviv, Ukraine
LCC "Medical center "Unimed"
🇺🇦Zaporizhzhia, Ukraine
Municipal Non-profit Enterprise Zaporizhzhya Regional Hospital Zaporizhzhya Regional Council
🇺🇦Zaporizhzhia, Ukraine
Derriford Hospital
🇬🇧Plymouth, United Kingdom
UNO Medical Trials Kft.
🇭🇺Budapest, Hungary
Stanford University Medical Center
🇺🇸Stanford, California, United States
Advanced Neurology of Colorado, LLC
🇺🇸Fort Collins, Colorado, United States
Neurology Associates, PA
🇺🇸Maitland, Florida, United States
University of South Florida
🇺🇸Tampa, Florida, United States
American Health Network Institute, LLC
🇺🇸Avon, Indiana, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
The NeuroMedical Clinic of Central Louisiana
🇺🇸Alexandria, Louisiana, United States
Maine Medical Center
🇺🇸Scarborough, Maine, United States
Dragonfly Research, LLC
🇺🇸Wellesley, Massachusetts, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Cleveland Clinic Lou Ruvo
🇺🇸Las Vegas, Nevada, United States
Dent Neurological Institute
🇺🇸Amherst, New York, United States
UC Health Neurology
🇺🇸Dayton, Ohio, United States
Oklahoma Medical Research Foundation
🇺🇸Oklahoma City, Oklahoma, United States
Abington Neurological Associates
🇺🇸Willow Grove, Pennsylvania, United States
Tri-State Mountain Neurology
🇺🇸Johnson City, Tennessee, United States
Hope Neurology
🇺🇸Knoxville, Tennessee, United States
Bhupesh Dihenia M.D. P.A.
🇺🇸Lubbock, Texas, United States
Lone Star Neurology of San Antonio
🇺🇸San Antonio, Texas, United States
Evergreen MS Center
🇺🇸Kirkland, Washington, United States
Centro de Especialidades Neurológicas y Rehabilitación - CENyR
🇦🇷Buenos Aires, Argentina
CEMIC
🇦🇷Buenos Aires, Argentina
Centro de Investigaciones Médicas Tucuman
🇦🇷San Miguel de Tucuman, Argentina
Austin Hospital
🇦🇺Heidelberg, Victoria, Australia
Hospital Erasme
🇧🇪Bruxelles, Belgium
Revalidatie en MS Centrum
🇧🇪Overpelt, Belgium
IMV Pesquisa Neurológica
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Clinica Neurologica
🇧🇷Joinville, Santa Catarina, Brazil
Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften
🇩🇪Dresden, Germany
Universitätsklinikum Schleswig-Holstein
🇩🇪Kiel, Germany
Universität Leipzig
🇩🇪Leipzig, Germany
Universitätsklinikum Tübingen, Zentrum für Neurologie
🇩🇪Tübingen, Germany
Universitätsklinikum Ulm
🇩🇪Ulm, Germany
Deutsche Klinik für Diagnostik
🇩🇪Wiesbaden, Germany
401 Military Hospital of Athens
🇬🇷Athens, Greece
S-Medicon Egeszsegugyi Szolgaltato Kft.
🇭🇺Budapest, Hungary
N.P. Bechtereva Institute of the Human Brain
🇷🇺Sankt-petersburg, Sankt Petersburg, Russian Federation
City Hospital #40 of Kurortniy Administrative District
🇷🇺St. Petersburg, Sankt Petersburg, Russian Federation
SHI Sverdlovsk Regional Clinical Hospital #1
🇷🇺Yekaterinburg, Sverdlovsk, Russian Federation
Vertebronevrologiya LLC
🇷🇺Kazan, Tatarstan, Russian Federation
KSMU Interregional Clinical Diagnostic Centre
🇷🇺Kazan, Tatarstan, Russian Federation
Ulyanovsk Regional Clinical Hospital
🇷🇺Ulyanovsk, Uljanovsk, Russian Federation
Saratov State Medical University of RosZdrav
🇷🇺Saratov, Russian Federation
Nebbiolo Center for Clinical Trials
🇷🇺Tomsk, Russian Federation
Complejo Hospitalario Universitario A Coruña (CHUAC)
🇪🇸Coruña, LA Coruna, Spain
Hospital Quiron de Madrid
🇪🇸Pozuelo de Alarcon, Madrid, Spain
Hospital Alvaro Cunqueiro
🇪🇸Vigo, Pontevedra, Spain
Municipal Nonprofit Enterprise of Kharkiv Regional Council Regional Clinical Hospital
🇺🇦Kharkiv, Ukraine