Clinical trial NCT03523858: A Study to Evaluate Ocrelizumab Treatment in Participants With Progressive Multiple Sclerosis
Official title: An Open-Label, Single-Arm 4-Year Study to Evaluate Effectiveness and Safety of Ocrelizumab Treatment in Patients With Progressive Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Progressive Multiple Sclerosis (PMS)
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-05-14
Enrollment: 927
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is a prospective, multicenter, open-label, single-arm effectiveness and safety study in participants with progressive multiple sclerosis (PMS).


Eligibility criteria: Inclusion Criteria:

* Have a definite diagnosis of PMS (as per the revised McDonald 2010 criteria for PPMS or Lublin et al. 2014 criteria for PMS)
* EDSS (Expanded Disability Status Scale) \</ =6.5 at screening
* Have a documented evidence of disability progression independent of relapse at any point over the 2 years prior to the screening visit. In case relapse(s) have occurred in the last 2 years, disability progression will have to be considered as independent of relapse activity as per treating physician's judgment
* Fulfill at least one of the 21 criteria assessing the evidence of disability progression independent of relapse activity in the last 2 years using the pre-baseline disability progression rating system checklist
* Have experience of having used a smartphone and connecting a smartphone to Wi-Fi network providers
* For women of childbearing potential: agreement to remain abstinent or use acceptable contraceptive methods during the treatment period and for at least 6 months, or longer if the local label is more stringent after the last dose of study drug

Exclusion Criteria:

* Relapsing-remitting multiple sclerosis (RRMS) at screening
* Inability to complete an MRI
* Gadolinium (Gd) intolerance
* Known presence of other neurological disorders

Exclusions Related to General Health:

* Pregnancy confirmed by positive serum β human chorionic gonadotropin (hCG) measured at screening
* Lactation
* Any concomitant disease that may require chronic treatment of systemic corticosteroids or immunosuppressants during the course of the study
* History or currently active primary or secondary immunodeficiency
* Lack of peripheral venous access
* Significant or uncontrolled somatic disease or any other significant disease that may preclude participant from participating in the study.
* Active infections must be treated and resolved prior to the first infusion of ocrelizumab
* Participants in a severely immunocompromised state until the condition resolves
* Participants with known active malignancies or being actively monitored for recurrence of malignancy
* Participants who have or have had confirmed progressive multifocal leukoencephalopathy (PML)

Exclusions Related to Laboratory Findings:

* Positive screening tests for hepatitis B
* CD4 count \<250/μL
* ANC \<1.0 × 103/μL
* AST/SGOT or ALT/SGPT ≥3.0 × ULN in combination with either an elevated total bilirubin (\>2 X ULN) or clinical jaundice

Exclusions Related to Medications:

* Hypersensitivity to ocrelizumab or to any of its excipients
* Previous treatment with ocrelizumab
* Previous treatment with B-cell targeted therapies (i.e., atacicept, tabalumab, belimumab, ofatumumab, or obinutuzumab). Note: previous treatment with rituximab is allowed as long as the last dose was administered more than 6 months before the ocrelizumab infusion AND if discontinuation was due to adverse events or immunogenicity AND if Bcell levels are above the lower limit of normal (LLN) prior to screening.
* Any previous treatment with alemtuzumab (Campath/Mabcampath/Lemtrada), total body irradiation, or bone marrow transplantation
* Previous treatment with natalizumab where PML has not been excluded according to specific algorithm
* Contraindications to or intolerance of oral or intravenous (IV) corticosteroids, including methylprednisolone administered IV, according to the country label
* Systemic corticosteroid therapy within 4 weeks prior to screening
* All vaccines should be given at least 6 weeks before the first infusion of ocrelizumab, unless the local regulations allow for a shorter interval. Live/live attenuated vaccines should be avoided during treatment and safety follow-up period until B cells are peripherally repleted
* Previous treatment with daclizumab, ozanimod or figolimod in the last 8 weeks
* Previous treatment with siponimod in the last 2 weeks
* Treatment with fampridine/dalfampridine (Fampyra)/Ampyra) or other symptomatic MS treatment unless on stable dose for ≥30 days prior to screening
* Previous treatment with natalizumab in the last 12 weeks.
* Previous treatment with teriflunomide in the last 12 weeks. This washout period can be shortened if an accelerated elimination procedure is implemented before screening visit. One of the following elimination procedures can be used:
* Cholestyramine 8 g administered 3 times daily for a period of at least 7 days (cholestyramine 4 g three times a day can be used, if cholestyramine 8 g three times a day is not well tolerated)
* Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for a period of at least 7 days.
* Previous treatment with azathioprine, cyclophosphamide, mycophenolate mofetil or methotrexate in the last 12 weeks
* Treatment with any investigational agent within 24 weeks of screening (Visit 1) or five half-lives of the investigational drug (whichever is longer) or treatment with any experimental procedures for MS
* Previous treatment with mitoxantrone, cyclosporine or cladribine in the last 96 weeks
* Participants previously treated with teriflunomide within the last two years, unless measured plasma concentrations are less than 0.02 mg/l. If above or not known, an accelerated elimination procedure should be implemented before screening visit

Primary outcomes:
measure: Proportion of Participants with No Evidence of Progression (NEP)
timeFrame: From Baseline to Week 96, Week 96 to Week 192 and Baseline to Week 192
measure: Proportion of Participants with no evidence of progression and no active disease (NEPAD)
timeFrame: From Baseline to Week 96, Week 96 to Week 192 and Baseline to Week 192
Secondary outcomes:
measure: Change from Baseline in Cognitive Function, as Measured by the Symbol Digit Modalities Test (SDMT)
timeFrame: Baseline to end of study (Week 192)
measure: Change from Baseline in Cognitive Function, as Measured by Brief Visuospatial Memory Test - Revised (BVMT-R)
timeFrame: Baseline to end of study (Week 192)
measure: Mean Change from Baseline in the Expanded Disability Status Scale (EDSS) score over the course of the study
timeFrame: Baseline to end of study (Week 192)
measure: Time to Onset of First Confirmed Disability Progression (CDP) Sustained for at least 24 and 48 Weeks
timeFrame: Baseline to onset of first CDP (as measured by EDSS) sustained for at least 24 and 48 weeks
measure: Time to Onset of First >=20% Increase in Timed 25-foot Walk Test (T25FWT) Sustained for at least 24 Weeks
timeFrame: Baseline to onset of first >=20% increase in T25FWT sustained for at least 24 weeks
measure: Time to Onset of First >=20% Increase in 9 Hole Peg Test (9HPT) Sustained For At Least 24 Weeks
timeFrame: Baseline to onset of first >=20% increase in 9HPT sustained for at least 24 weeks
measure: Proportion of Participants with NEP
timeFrame: Week 24 to Week 96, Week 24 to Week 192, and Week 48 to Week 192
measure: Proportion of Participants with NEPAD
timeFrame: Week 24 to Week 96, Week 24 to Week 192, Week 48 to Week 192
measure: Change from Baseline in Patient-Reported Outcomes (PROs)
timeFrame: Baseline to end of study (Week 192)
measure: Change from Baseline in the number of falls and near-falls
timeFrame: Baseline to end of study (Week 192)
measure: Change in Whole Brain Volume (Whole, Cerebral White Matter, Cortical Grey Matter, Deep grey matter)
timeFrame: Baseline to end of study (Week 192)
measure: Change in thalamic volumes
timeFrame: Baseline to end of study (Week 192)
measure: Change in whole and regional cerebellar volume (cervical cord grey and white matter area)
timeFrame: Baseline to end of study (Week 192)
measure: Change in cervical cord cross-sectional area (total, white matter and grey matter)
timeFrame: Baseline to end of study (Week 192)
measure: Change in number of new/enlarging T2 lesions and total T2 Lesion Volume
timeFrame: Baseline to end of study (Week 192)
measure: Change in number of T1 Gadolinium (Gd)+ Lesions and total volume
timeFrame: 'Baseline to end of study (Week 192)
measure: Change in number of T1 lesions
timeFrame: Baseline to end of study (Week 192)
measure: Number in total volume of T1 lesions
timeFrame: Baseline to end of study (Week 192)
measure: Change in Slowly Evolving Lesions (SEL)
timeFrame: Baseline to end of study (Week 192)
measure: Change in normalised T1 intensity/T1 Gd+ enhancement in New Focal T2 Lesions, SELs, Persistent Areas of Non-SEL T2 Lesions, and Normal-Appearing Brain Tissue
timeFrame: Baseline to end of study (Week 192)
measure: Change in Gd-enhancing late-Fluid-Attenuated Inversion-Recovery (FLAIR) Meningeal Lesions
timeFrame: Baseline to end of study (Week 192)
measure: Change in the number/ spatial distribution of lesions in the cervical spinal cord
timeFrame: Baseline to end of study (Week 192)
measure: Spectroscopic MR: Measure of the Relative Signal Amplitude of N-Acetyl Aspartate (NAA), and Choline to Creatine
timeFrame: Baseline to end of study (Week 192)
measure: Measure of phase rim lesions using a Susceptibility-Weighted Imaging [SWI]/T2 sequence
timeFrame: Baseline to end of study (Week 192)
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Baseline to end of study (Week 192)
measure: Rates of study treatment discontinuation due to adverse events
timeFrame: Baseline to Week 192
Other outcomes:
Locations:
city: Laguna Hills
country: United States
facility: MS Center of California
state: California
city: Pasadena
country: United States
facility: SC3 Research Group, Inc
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: North Haven
country: United States
facility: Yale University
state: Connecticut
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Wellesley
country: United States
facility: Dragonfly Research, LLC
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University School of Medicine
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Latham
country: United States
facility: The MS Center of Northeastern New York
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Mellen Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Cordova
country: United States
facility: Neurology Clinic PC
state: Tennessee
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants
state: Texas
city: San Antonio
country: United States
facility: Lone Star Neurology of San Antonio
state: Texas
city: Seattle
country: United States
facility: Swedish Multiple Sclerosis Center
state: Washington
city: Banja Luka
country: Bosnia and Herzegovina
facility: University Clinical Center of the Republic of Srpska
city: Mostar
country: Bosnia and Herzegovina
facility: University Hospital Mostar
city: Sarajevo
country: Bosnia and Herzegovina
facility: Clinical Center University of Sarajevo
city: Tuzla
country: Bosnia and Herzegovina
facility: University Clinical Center Tuzla
city: Curitiba
country: Brazil
facility: Instituto de Neurologia de Curitiba
state: Paraná
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas - PUCRS
state: Rio Grande Do Sul
city: Ribeirao Preto
country: Brazil
facility: Hospital das Clínicas Faculdades Médicas de Ribeirão Preto
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP_X
state: São Paulo
city: Burnaby
country: Canada
facility: Fraser Health Authority - Fraser Health Multiple Sclerosis
state: British Columbia
city: Vancouver
country: Canada
facility: University of British Columbia Hospital
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre Uni Campus
state: Ontario
city: Toronto
country: Canada
facility: St. Michael'S Hospital
state: Ontario
city: Greenfield Park
country: Canada
facility: Recherche Sepmus Inc.
state: Quebec
city: Montreal
country: Canada
facility: Hospital Notre-Dame du Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Saskatoon
country: Canada
facility: Saskatoon City Hospital
state: Saskatchewan
city: Bogota
country: Colombia
facility: Organizacion Sanitas Internacional
city: Cali
country: Colombia
facility: Fundacion Clinica Valle del Lili
city: San José
country: Costa Rica
facility: Hospital Clínica Biblica
city: Jihlava
country: Czechia
facility: Nemocnice Jihlava
city: Olomouc
country: Czechia
facility: Fakultní Nemocnice Olomouc
city: Ostrava-Poruba
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital
city: Glostrup
country: Denmark
facility: Rigshospitalet
city: Sønderborg
country: Denmark
facility: Hjerne- og nervesygdomme, Ambulatorium, Skleroseklinikken
city: Alexandria
country: Egypt
facility: Clinical Research Center-Alex university
city: Cairo
country: Egypt
facility: Ain Shams University Hospital
city: Bayonne Cedex
country: France
facility: CHIC Cote Basque Bayonne
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin
city: Bron
country: France
facility: Hopital neurologique Pierre Wertheimer - CHU Lyon
city: Caen
country: France
facility: CHU De Caen
city: Clermont-Ferrand
country: France
facility: Hopital Gabriel Montpied CHU de Clermont-Ferrand
city: Lille
country: France
facility: Hopital B Roger Salengro
city: Marseille
country: France
facility: CHU de la Timone - Hopital d Adultes
city: Montpellier
country: France
facility: Hopital Gui de Chauliac
city: Nancy
country: France
facility: CHRU Nancy
city: Nantes
country: France
facility: Hopital Nord Laennec
city: Nice
country: France
facility: Hôpital Pasteur
city: Nimes
country: France
facility: GroupeHospitalo-Universitaire Caremeau
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes
city: Salouel
country: France
facility: CHU Amiens Hopital Sud
city: Strasbourg
country: France
facility: Hopitaux Universitaires de Strasbourg
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus", Zentrum für Klinische Neurowissenschaften
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Stuttgart
country: Germany
facility: NeuroConcept AG C/O mind mvz GmbH
city: Ulm
country: Germany
facility: NeuroPoint Gesellschaft fur vorbeugende Gesundheitspflege mbH
city: Westerstede
country: Germany
facility: Studienzentrum Nordwest Dr med Joachim Springub Herr Wolfgang Schwarz
city: Wiesbaden
country: Germany
facility: Deutsche Klinik für Diagnostik
city: Ciudad Guatemala
country: Guatemala
facility: Nucare
city: Budapest
country: Hungary
facility: Semmelweis Egyetem AOK
city: Esztergom
country: Hungary
facility: VALEOMED Diagnosztikai Központ
city: Nyíregyháza
country: Hungary
facility: Jósa András Oktatókórház
city: Pécs
country: Hungary
facility: Pécsi Tudományegyetem, Klinikai Központ Neurológiai Klinika
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Dublin
country: Ireland
facility: St Vincents University Hospital
city: Napoli
country: Italy
facility: A. O. U. Federico II
state: Campania
city: Napoli
country: Italy
facility: Università degli Studi della Campania Luigi Vanvitelli
state: Campania
city: Napoli
country: Italy
facility: Università degli studi della Campania Luigi Vanvitelli
state: Campania
city: Trieste
country: Italy
facility: Ospedale Cattinara
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: Policlinico Tor Vergata Dip. Neuroscienze-Clinica Neurologica-UOSD Sclerosi Multipla
state: Lazio
city: Roma
country: Italy
facility: Policlinico Universitario A. Gemelli
state: Lazio
city: Roma
country: Italy
facility: A.O. Sant'Andrea
state: Lazio
city: Roma
country: Italy
facility: Azienda Ospedaliera Sant'Andrea
state: Lazio
city: Genova
country: Italy
facility: Irccs A.O.U.San Martino Ist
state: Liguria
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
state: Lombardia
city: Milano
country: Italy
facility: Fond. Istituto Neurologico C.Besta
state: Lombardia
city: Pavia
country: Italy
facility: IRCCS Istituto Neurologico C. Mondino?Dip. Neurologia Neuroriabilitazione S.S. Sclerosi Multipla
state: Lombardia
city: Pozzilli
country: Italy
facility: IRCCS Istituto Neurologico Neuromed
state: Molise
city: Orbassano
country: Italy
facility: Azienda Sanitaria Ospedaliera S. Luigi Gonzaga
state: Piemonte
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza
state: Piemonte
city: Bari
country: Italy
facility: Azienda Ospedaliero Universitaria Consorziale Policlinico di
state: Puglia
city: Cagliari
country: Italy
facility: Ospedale Binaghi
state: Sardegna
city: Catania
country: Italy
facility: AOU Policlinico V. Emanuele - P.O G. Rodolico
state: Sicilia
city: Firenze
country: Italy
facility: AOUC Azienda Ospedaliero-Universitaria Careggi
state: Toscana
city: Verona
country: Italy
facility: Policlinico G.B. Rossi
state: Veneto
city: Beirut
country: Lebanon
facility: American University of Beirut - Medical Center
city: Beirut
country: Lebanon
facility: Lebanese American University Medical Center- Rizk Hospial
city: Mexico City
country: Mexico
facility: Grupo Medico de Investigacion Clinica Multidisciplinaria
state: Mexico CITY (federal District)
city: Mexico City
country: Mexico
facility: Clinstile S.A de C.V.
state: Mexico CITY (federal District)
city: Mexico
country: Mexico
facility: Hospital General de Mexico
state: Tlaxcala
city: Ciudad de México
country: Mexico
facility: Unidad de investigacion en salud (UIS)
city: FES
country: Morocco
facility: Centre Hospitalier Universitaire Hassan II
city: Rabat
country: Morocco
facility: Hopital Cheikh Zaid
city: Rabat
country: Morocco
facility: Hopital Militaire d'Instruction Mohamed V
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Catharina ziekenhuis
city: NL -rotterdam
country: Netherlands
facility: Maasstadziekenhuis
city: Sittard-Geleen
country: Netherlands
facility: Zuyderland Medisch Centrum - Sittard Geleen
city: Panama City
country: Panama
facility: Consultorios Médicos PaItilla
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Bialymstoku
city: Kraków
country: Poland
facility: Szpital Uniwersytecki w Krakowie
city: Lodz
country: Poland
facility: Centrum Neurologii Krzysztof Selmaj
city: Pozna?
country: Poland
facility: SP Swiecickiego UM Marcinkowskiego
city: Rzeszow
country: Poland
facility: Centrum Medyczne "MEDYK"
city: Warszawa
country: Poland
facility: Wojskowy Instytut Medyczny - Pa?Stwowy Instytut Badawczy
city: Zabrze
country: Poland
facility: SPSK nr 1
city: Sankt-peterburg
country: Russian Federation
facility: National Center of Social Significant Disease
state: Leningrad
city: Moscow
country: Russian Federation
facility: Jusupovskaya Hospital
state: Moskovskaja Oblast
city: Moscow
country: Russian Federation
facility: Scientific Neurology Center
state: Moskovskaja Oblast
city: Moscow
country: Russian Federation
facility: Vladimirskiy Regional Scientific Research Inst.
state: Moskovskaja Oblast
city: Moskva
country: Russian Federation
facility: City Clinical Hospital #24
state: Moskovskaja Oblast
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de Arrixaca
city: Valencia
country: Spain
facility: Hospital Universitario la Fe
city: Abu Dhabi
country: United Arab Emirates
facility: Cleveland Clinic Abu Dhabi
city: Dubai
country: United Arab Emirates
facility: Rashid hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: