Clinical trial NCT04548999: A Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS)
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 Primary Progressive Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: Primary Progressive Multiple Sclerosis; Higher Dose of CD20 Antibody Ocrelizumab; Efficacy, Safety and Pharmacokinetics
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2020-09-16
Enrollment: 769
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 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 PPMS, 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 lower limit 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.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of PPMS
* EDSS score at screening and baseline, from 3 to 6.5 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 (two trials with each hand) at screening and over four trials (two trials with each hand) at baseline respectively, up to 250 (inclusive) seconds
* Score of ≥ to 2.0 on the Functional Systems (FS) scale for the pyramidal system that was due to lower extremity findings at screening and baseline
* Documented magnetic resonance imaging (MRI) of brain with abnormalities consistent with MS
* 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
* Participants must be neurologically stable for at least 30 days prior to randomization and baseline
* Disease duration from the onset of MS symptoms; if EDSS score at screening is ≤ 5, disease duration must be less than 10 years; If EDSS score at screening is \> 5, disease duration must be less than 15 years
* Documented evidence of the presence of at least one cerebrospinal fluid-specific oligoclonal bands
* 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 relapsing remitting or secondary 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 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
* Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab
* 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
* 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

Primary outcomes:
measure: Time to Onset of Composite Confirmed Disability Progression (cCDP) Sustained for at least 12 Weeks
timeFrame: Baseline up to approximately 4.3 years
Secondary outcomes:
measure: Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12) Independent of Protocol-defined Relapses (PDR)
timeFrame: Baseline up to approximately 4.3 years
measure: Time to Onset of 12-week Confirmed Disability Progression (CDP12)
timeFrame: Baseline up to approximately 4.3 years
measure: Time to ≥ 20% Increase in 12-week Confirmed by T25FWT
timeFrame: Baseline up to approximately 4.3 years
measure: Change in Neurofilament Light (NfL) at Week 96
timeFrame: Baseline up to Week 96
measure: Time to 12-week Confirmed 8-point Increase in 12-item Multiple Sclerosis Walking Scale (MSWS12)
timeFrame: Baseline up to approximately 4.3 years
measure: Annual Rate of Percent Change From Baseline in Total Brain Volume
timeFrame: Baseline up to approximately 4.3 years
measure: Annual Rate of Percent Change From Baseline in Thalamic Volume
timeFrame: Baseline up to approximately 4.3 years
measure: Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT)
timeFrame: Baseline up to approximately 4.3 years
measure: Change in NfL (i.e. Ratio to Baseline) at Week 96 for Participants in the Approved Dose Ocrelizumab Group
timeFrame: Baseline up to Week 96
measure: Change in NfL (i.e. Ratio to Baseline) at Week 96 for Participants in the Higher Dose Ocrelizumab Group
timeFrame: Baseline up to Week 96
measure: Time to Onset of 24-week Composite Confirmed Disability Progression (cCDP24) Independent of PDR
timeFrame: Baseline up to approximately 4.3 years
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Baseline up to approximately 8 years
measure: Serum Concentrations of Ocrelizumab at Specified Timepoints
timeFrame: Weeks 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
measure: Change in B-cell Levels in Blood
timeFrame: Baseline up to approximately 4.3 years
measure: Percentage of Participants Achieving 5 or Less B-cells per Microliter of Blood
timeFrame: Baseline up to approximately 4.3 years
measure: Change From Baseline in the Anti-drug Antibody (ADA) Levels
timeFrame: Week 0, 24, 48, 72, 96, 120
Other outcomes:
Locations:
city: Homewood
country: United States
facility: Alabama Neurology Associates
state: Alabama
city: Phoenix
country: United States
facility: 21st Century Neurology
state: Arizona
city: Irvine
country: United States
facility: University of California Irvine
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Fort Collins
country: United States
facility: Advanced Neurosciences Research LLC
state: Colorado
city: Clearwater
country: United States
facility: MS and Neuromuscular Center of Excellence
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Nicholasville
country: United States
facility: Baptist Health Lexington
state: Kentucky
city: Lutherville
country: United States
facility: International Neurorehabilitation Institute
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital.
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: Farmington Hills
country: United States
facility: Michigan Institute for Neurological Disorders
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Neptune
country: United States
facility: Jersey Shore University Medical Centre
state: New Jersey
city: Great Neck
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Cordova
country: United States
facility: Neurology Clinic 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: San Antonio
country: United States
facility: Lone Star Neurology of San Antonio
state: Texas
city: Sherman
country: United States
facility: Texas Institute for Neurological Disorders
state: Texas
city: Milwaukee
country: United States
facility: Wheaton Franciscan Healthcare - St. Francis Outpatient Center
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: CEMIC Saavedra
city: Buenos Aires
country: Argentina
facility: Centro de Especialidades Neurológicas y Rehabilitación - CENyR
city: Rosario
country: Argentina
facility: INECO
city: Overpelt
country: Belgium
facility: Revalidatie en MS Centrum
city: Brasilia
country: Brazil
facility: L2 Ip Instituto de Pesquisas Clinicas Ltda ME
state: Distrito Federal
city: Goiania
country: Brazil
facility: Hospital das Clinicas - UFG
state: Goiás
city: Curitiba
country: Brazil
facility: Instituto de Neurologia de Curitiba
state: Paraná
city: Passo Fundo
country: Brazil
facility: Instituto Méderi de Pesquisa e Saúde
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: IMV Pesquisa Neurológica
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas - PUCRS
state: Rio Grande Do Sul
city: Joinville
country: Brazil
facility: Clinica Neurologica
state: Santa Catarina
city: Campinas
country: Brazil
facility: Hospital das Clinicas - UNICAMP
state: São Paulo
city: Santo Andre
country: Brazil
facility: Praxis Pesquisa Médica
state: São Paulo
city: Sao Paulo
country: Brazil
facility: CPQuali Pesquisa Clinica Ltda
state: São Paulo
city: Pleven
country: Bulgaria
facility: UMHAT Dr. Georgi Stranski
city: Sofia
country: Bulgaria
facility: MHATNP Sveti Naum EAD
city: Montreal
country: Canada
facility: Chum Campus Notre Dame
state: Quebec
city: Montreal
country: Canada
facility: MUCH - Montreal Neurological Institute & Hospital
state: Quebec
city: Quebec
country: Canada
facility: Hotel-Dieu de Levis
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital
city: Glostrup
country: Denmark
facility: Rigshospitalet Glostrup
city: Besançon
country: France
facility: CHU de Besancon Hopital Jean Minjoz
city: Brest
country: France
facility: CHU Brest Hopital La Cavale Blanche
city: Caen
country: France
facility: Hopital Cote De Nacre
city: Clermont Ferrand
country: France
facility: CHU Hopital Gabriel Montpied
city: Lille
country: France
facility: CH St Vincent de Paul
city: Nancy
country: France
facility: Hopital Central - CHU de Nancy
city: Strasbourg
country: France
facility: Hopital Hautepierre - CHU Strasbourg
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Neurologie
city: Leipzig
country: Germany
facility: Universität Leipzig
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Zentrum für Neurologie
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Wiesbaden
country: Germany
facility: Deutsche Klinik für Diagnostik
city: Athens
country: Greece
facility: Hospital Eginition
city: Athens
country: Greece
facility: 401 Military Hospital of Athens
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Idegsebeszeti és Neurointervencios Klinika
city: Budapest
country: Hungary
facility: UNO Medical Trials Kft.
city: Gyor
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz
city: Kaposvár
country: Hungary
facility: Somogy Megyei Kaposi Mor Oktato Korhaz
city: Kistarcsa
country: Hungary
facility: Kistarcsai Flor Ferenc Korhaz
city: Napoli
country: Italy
facility: A. O. U. Federico II
state: Campania
city: Napoli
country: Italy
facility: AOU Seconda Università degli Studi
state: Campania
city: Roma
country: Italy
facility: Azienda Ospedaliera Sant'Andrea
state: Lazio
city: Gallarate
country: Italy
facility: Ospedale S.Antonio Abate
state: Lombardia
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
state: Lombardia
city: Pavia
country: Italy
facility: IRCCS Istituto Neurologico C. Mondino?Dip. Neurologia Neuroriabilitazione S.S. Sclerosi Multipla
state: Lombardia
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza
state: Piemonte
city: Guadalajara
country: Mexico
facility: Centro de Investigacion Medico Biologico y Terapia Avanzada, S.C.
state: Jalisco
city: Mexico City
country: Mexico
facility: Clinstile S.A de C.V.
state: Mexico CITY (federal District)
city: San Luis Potosí
country: Mexico
facility: Neurociencias Prisma, A.C
state: SAN LUIS Potosi
city: Mexico
country: Mexico
facility: Grupo Médico Camino S.C.
city: La Victoria, Lima
country: Peru
facility: Hospital Nacional Guillermo Almenara Irigoyen
city: Lima
country: Peru
facility: Instituto Nacional de Ciencias Neurológicas - Hospital Mogrovejo
city: Lima
country: Peru
facility: Hospital Nacional Dos de Mayo
city: Bydgoszcz
country: Poland
facility: Neurocentrum Bydgoszcz sp. z o.o
city: Gdansk
country: Poland
facility: COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika
city: Katowice
country: Poland
facility: MA-LEK Clinical Sp. Z o.o.
city: Krakow
country: Poland
facility: Szpital Specjalistyczny im. Rydygiera w Krakowie
city: Lodz
country: Poland
facility: Centrum Neurologii Krzysztof Selmaj
city: Lublin
country: Poland
facility: Indywidualna Praktyka Lekarska Prof. Dr Hab. N. Med. Konrad Rejdak.
city: Oswiecim
country: Poland
facility: Instytut Zdrowia Dr Boczarska-Jedynak Sp. z o.o. Sp. k.
city: Plewiska
country: Poland
facility: Neurologiczny Niepubliczny ZOZ Centrum Leczenia SM Osrodek Bada? Klinicznych
city: Pozna?
country: Poland
facility: EMC Instytut Medyczny SA
city: Rybnik
country: Poland
facility: Wojewódzki Szpital Specjalistyczny Nr 3
city: Rzeszów
country: Poland
facility: Nmedis sp. z o.o.
city: Szczecin
country: Poland
facility: Osrodek Badan Klinicznych Euromedis
city: Warszawa
country: Poland
facility: Centrum Medyczne NeuroProtect
city: Warszawa
country: Poland
facility: Instytut Psychiatrii i Neurologii II Klinika Neurologiczna
city: Braga
country: Portugal
facility: Hospital de Braga
city: Lisboa
country: Portugal
facility: Hospital Santo Antonio dos Capuchos
city: Lisboa
country: Portugal
facility: Centro Hospitalar de Lisboa Ocidental - Hospital Egas Moniz
city: Porto
country: Portugal
facility: Hospital Geral de Santo Antonio
city: Krasnoyarsk
country: Russian Federation
facility: Krasnoyarsk State Medical Academy
state: Krasnojarsk
city: Krasnoyarsk
country: Russian Federation
facility: FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency
state: Krasnojarsk
city: Sankt-peterburg
country: Russian Federation
facility: National Center of Social Significant Disease
state: Leningrad
city: Moscow
country: Russian Federation
facility: Research Center of Neurology of RAMS
state: Moskovskaja Oblast
city: Moskva
country: Russian Federation
facility: Federal center of brain research and neurotechnologies
state: Moskovskaja Oblast
city: Moskva
country: Russian Federation
facility: City Clinical Hospital #24
state: Moskovskaja Oblast
city: Sankt-petersburg
country: Russian Federation
facility: N.P. Bechtereva Institute of the Human Brain
state: Sankt Petersburg
city: St Petersburg
country: Russian Federation
facility: Leningrad Regional Clinical Hospital
state: Sankt Petersburg
city: St. Petersburg
country: Russian Federation
facility: City Hospital #40 of Kurortniy Administrative District
state: Sankt Petersburg
city: Yekaterinburg
country: Russian Federation
facility: SHI Sverdlovsk Regional Clinical Hospital #1
state: Sverdlovsk
city: Kazan
country: Russian Federation
facility: Vertebronevrologiya LLC
state: Tatarstan
city: Ulyanovsk
country: Russian Federation
facility: Ulyanovsk Regional Clinical Hospital
state: Uljanovsk
city: Kirov
country: Russian Federation
facility: Center of Cardiology and Neurology
city: Krasnodar
country: Russian Federation
facility: Regional clinical hospital named after prof. S.V. Ochapovsky
city: Novosibirsk
country: Russian Federation
facility: FSBIH Siberian Regional Medical Centre of FMBA of Russia
city: Perm
country: Russian Federation
facility: Perm SMA n.a. academ. E.A. Vagner
city: Pozuelo de Alarcon
country: Spain
facility: Hospital Quiron de Madrid
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario Puerta De Hierro Majadahonda
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de Arrixaca
city: Bern
country: Switzerland
facility: Inselspital Bern Medizin Neurologie
city: Ankara
country: Turkey
facility: Gazi University Medical Faculty
city: Istanbul
country: Turkey
facility: Haseki Training and Research Hospital
city: Istanbul
country: Turkey
facility: Istanbul Universitesi - Cerrahpasa Cerrahpasa Tip Fakultesi
city: Istanbul
country: Turkey
facility: Sancaktepe Training and Research Hospital
city: Istanbul
country: Turkey
facility: Selcuk University Medical Faculty
city: Kayseri
country: Turkey
facility: Erciyes Universitesi
city: Kocaeli
country: Turkey
facility: Kocaeli University Hospital
city: Lzmir
country: Turkey
facility: Ege Üniversitesi Tip Fakültesi
city: Merkez
country: Turkey
facility: Cumhuriyet Universitesi Tip Fakultesi
city: Mersin
country: Turkey
facility: Mersin University Medical Faculty
city: Samsun
country: Turkey
facility: Ondokuz Mayis University School of Medicine
city: Çankaya
country: Turkey
facility: Baskent Universitesi Ankara Hastanesi
city: Cherkasy
country: Ukraine
facility: 5th Cherkasy City Center of Primary Health Care
city: Dnipro
country: Ukraine
facility: SI USSRI of Medical and Social Problems of Disabilities of MOHU
city: Ivano-Frankivsk
country: Ukraine
facility: Regional Clinical Hospital
city: Kharkiv
country: Ukraine
facility: State Institution Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine
city: Kharkov
country: Ukraine
facility: St.In.Inst. of Neurol.Psych.and Narcol.of the AMSU
city: Kyiv
country: Ukraine
facility: Medical Center of Private Execution First Private Clinic
city: Kyiv
country: Ukraine
facility: Medical Center Dopomoga Plus
city: Lutsk
country: Ukraine
facility: Volyn Regional Clinical Hospital
city: Lviv
country: Ukraine
facility: Lvivska oblasna tsentralna likarnia
city: Sumy
country: Ukraine
facility: Sumy Regional Clinical Hospital
city: Vinnytsi
country: Ukraine
facility: Medical Clinical Research Center of Medical Center LLC Health Clinic
city: Zaporizhzhia
country: Ukraine
facility: Municipal Non-profit Enterprise Zaporizhzhya Regional Hospital Zaporizhzhya Regional Council
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: National Hospital for Neurology and Neurosurgery,
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: