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

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

Sponsors

Lead Sponsor: Hoffmann-La Roche

Source Hoffmann-La Roche
Brief 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 PPMS, in comparison to the approved 600 mg dose of ocrelizumab.

Detailed 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 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 lower limit of normal.

Overall Status Not yet recruiting
Start Date November 17, 2020
Completion Date August 8, 2028
Primary Completion Date February 23, 2025
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Time to Onset of Composite Confirmed Disability Progression (cCDP) Sustained for at least 12 Weeks Baseline up to approximately 4.3 years
Secondary Outcome
Measure Time Frame
Time to Onset of 24-week cCDP (cCDP24) Baseline up to approximately 4.3 years
Time to Onset of 12-week CDP (CDP12) Baseline up to approximately 4.3 years
Time to Onset of 24-week CDP (CDP24) Baseline up to approximately 4.3 years
Time to >/= 20% Increase in 12-week Confirmed by Timed 25-Foot Walk Test (T25FWT) Baseline up to approximately 4.3 years
Time to >/= 20% Increase in 24-week Confirmed T25FWT Baseline up to approximately 4.3 years
Time to >/= 20% Increase in 12-week Confirmed by 9-Hole Peg Test (9-HPT) Baseline up to approximately 4.3 years
Time to >/= 20% Increase in 24-week Confirmed by 9-HPT Baseline up to approximately 4.3 years
Change from Baseline in the Multiple Sclerosis Impact Scale (MSIS 29) Score at Week 120 Baseline to Week 120
Percent Change in Total Brain Volume from Week 24 to Week 120 Week 24 to Week 120
Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) Baseline up to approximately 4.3 years
Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) Baseline up to approximately 4.3 years
Serum Concentration of Ocrelizumab at Specified Timepoints Baseline up to approximately 4.3 years
Change in B-cell Levels in Blood Baseline up to approximately 4.3 years
Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood Baseline up to approximately 4.3 years
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 Baseline up to approximately 4.3 years
Change from Baseline in the Anti-Drug Antibody (ADA) Levels Baseline up to approximately 4.3 yearsv
Levels of Neurofilament Light Chain (NfL) in Blood Baseline up to approximately 4.3 years
Levels of Interleukin-6 (IL-6) in Blood Baseline up to approximately 4.3 years
Levels of Blood B-cells Baseline up to approximately 4.3 years
Levels of Lymphocytes in Blood Baseline up to approximately 4.3 years
Proportion of Participants with Different DNA Genotypes Baseline up to approximately 4.3 years
Enrollment 699
Condition
Intervention

Intervention Type: Drug

Intervention Name: Ocrelizumab

Description: 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.

Arm Group Label: Ocrelizumab Higher Dose

Other Name: Ocrevus

Intervention Type: Drug

Intervention Name: Ocrelizumab

Description: 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.

Arm Group Label: Ocrelizumab Approved Dose

Other Name: Ocrevus

Intervention Type: Drug

Intervention Name: Antihistamine

Description: 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.

Other Name: Non-Investigational Medicinal Product

Intervention Type: Drug

Intervention Name: Methylprednisolone

Description: Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.

Other Name: Non-Investigational Medicinal Product

Eligibility

Criteria:

Inclusion Criteria:

- Diagnosis of primary progressive multiple sclerosis (PPMS).

- Expanded disability status scale (EDSS) score at screening and baseline, from 3 to 6.5 inclusive.

- Score of >/= to 2.0 on the Functional Systems scale for the pyramidal system that was due to lower extremity findings.

- 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, less than 15 years in participants with an EDSS score at screening >5.0, less than 10 years in participants with an EDSS score at screening

- Documented evidence of the presence of cerebrospinal fluid-specific oligoclonal bands.

- For females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods.

- For female participants without reproductive potential, may be enrolled if post-menopausal unless receiving a hormonal therapy for her menopause 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.

- 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.

- 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-CD20s if in the last 2 years before screening, or if B-cell count is not normal, or if treatment was stopped due to safety reasons or lack of efficacy.

- Previous use of mitoxantrone, cladribine, atacicept, and alemtuzumab.

- 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 of ocrelizumab.

- Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above.

Gender: All

Minimum Age: 18 Years

Maximum Age: 55 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Clinical Trials Study Director Hoffmann-La Roche
Overall Contact

Last Name: Reference Study ID Number: BN42083 www.roche.com/about_roche/roche_worldwide.htm

Phone: 888-662-6728 (U.S. and Canada)

Email: [email protected]

Location
Facility:
Alabama Neurology Associates | Homewood, Alabama, 35209, United States
21st Century Neurology | Phoenix, Arizona, 85004, United States
Center for Neurosciences | Tucson, Arizona, 85718, United States
University of California Irvine | Irvine, California, 92697, United States
University of California Davis Medical Center | Sacramento, California, 95817, United States
University of California San Francisco | San Francisco, California, 94117, United States
Stanford University Medical Center; Stanford Neuroscience Health Center | Stanford, California, 94305, United States
Los Angeles Biomedical Research Institute at Harbor-UCLA | Torrance, California, 90502, United States
University of Colorado Denver | Aurora, Colorado, 80045, United States
Mountain Neurological Research Center; Roaring Fork Neurologt, P.C. | Basalt, Colorado, 81621, United States
Colorado Neurological Institute | Englewood, Colorado, 80113, United States
KI Health Partners, LLC; New England Institute for Clinical Research | Stamford, Connecticut, 06905, United States
SFM Clinical Research, LLC | Boca Raton, Florida, 33487, United States
MS and Neuromuscular Center of Excellence | Clearwater, Florida, 33761, United States
Infinity Clinical Research, LLC | Sunrise, Florida, 33351, United States
Axiom Clinical Research of Florida | Tampa, Florida, 33609, United States
University of South Florida | Tampa, Florida, 33612, United States
Rush University | Chicago, Illinois, 60612, United States
Maine Medical Center | Scarborough, Maine, 04074, United States
International Neurorehabilitation Institute | Lutherville, Maryland, 21093, United States
Massachusetts General Hospital. | Boston, Massachusetts, 02114, United States
Neuro Institute of New England P.C.; Research | Foxboro, Massachusetts, 02035, United States
Dragonfly Research, LLC | Wellesley, Massachusetts, 02481, United States
University of Massachusetts Medical School | Worcester, Massachusetts, 01655, United States
Michigan Institute for Neurological Disorders | Farmington Hills, Michigan, 48334, United States
Memorial Healthcare Institute for Neurosciences and Multiple Sclerosis | Owosso, Michigan, 48867, United States
Washington University School of Medicine | Saint Louis, Missouri, 63110, United States
Lenox Hill Hospital | New York, New York, 10075, United States
Carolinas Medical Center; Department of Neurology | Charlotte, North Carolina, 28207, United States
University of Cincinnati; Department of Neurology | Cincinnati, Ohio, 45267, United States
Cleveland Clinic Mellen Center; U10; Investigational Drug Pharmacy | Cleveland, Ohio, 44195, United States
Ohio Health Research Institute Grant Medical Center | Columbus, Ohio, 43215, United States
UC Health Neurology | Dayton, Ohio, 45417, United States
Premier Neurology | Greer, South Carolina, 29650, United States
Neurology Clinic PC | Cordova, Tennessee, 38018, United States
Wesley Neurology Clinic | Cordova, Tennessee, 38018, United States
New Orleans Center for Clinical Research | Knoxville, Tennessee, 37920, United States
Advanced Neurosciences Institute | Nashville, Tennessee, 37205, United States
University of Texas Southwestern Medical Center | Dallas, Texas, 75390, United States
Baylor College of Medicine | Houston, Texas, 77030, United States
Neurology Center of San Antonio | San Antonio, Texas, 78212, United States
Meridian Clinical Research | Norfolk, Virginia, 23502, United States
Wheaton Franciscan Healthcare - St. Francis Outpatient Center; Center for Neurological Disorders | Milwaukee, Wisconsin, 53215, United States
CEMIC Saavedra | Buenos Aires, 1431, Argentina
Instituto DIABAID | Ciudad Autónoma de Buenos Aires, C1061ABD, Argentina
INECO; Neurociencias | Rosario, 1921, Argentina
CH EpiCURA Site Ath | Ath, 7800, Belgium
Revalidatie en MS Centrum | Overpelt, 3900, Belgium
Instituto de Neurologia de Curitiba | Curitiba, PR, 81210-310, Brazil
IMV Pesquisa Neurológica | Porto Alegre, RS, 90110-000, Brazil
Hospital Sao Lucas - PUCRS | Porto Alegre, RS, 90610-000, Brazil
Clinica Neurologica; Neurocirurgica de Joinville | Joinville, SC, 89201-165, Brazil
Hospital das Clinicas - UNICAMP | Campinas, SP, 13083-888, Brazil
CPQuali Pesquisa Clinica Ltda | Sao Paulo, SP, 01228-000, Brazil
Hospital das Clinicas - FMUSP | Sao Paulo, SP, 05403-000, Brazil
University of British Columbia | Vancouver, British Columbia, V6T 1Z4, Canada
Clinique Neuro Outaouais | Gatineau, Quebec, J8Y 1W2, Canada
Recherche Sepmus, Inc. | Greenfield Park, Quebec, J4V 2J2, Canada
Chum Campus Notre Dame | Montreal, Quebec, H2X 0A9, Canada
MUCH - Montreal Neurological Institute & Hospital | Montreal, Quebec, H3A 2B4, Canada
Institut Universitaire de gériatrie de Sherbrooke | Sherbrooke, Quebec, J1J 3H5, Canada
Fakultni nemocnice u sv. Anny; Neurologicka klinika | Brno, 656 91, Czechia
Fakultni nemocnice Ostrava; MS centrum | Ostrava-Poruba, 708 52, Czechia
Vseobecna fakultni nemocnice v Praze | Praha 2, 12808, Czechia
Aalborg Universitetshospital; Neurologisk Afdeling og Neurofysiologisk Afdeling; Skleroseamb. | Aalborg, 9000, Denmark
Rigshospitalet Glostrup; Neurologisk Klinik | Glostrup, 2600, Denmark
Odense Universitetshospital, Neurologisk Afdeling N; Neurologisk Ambulatorium N5; Skleroseklinikken | Odense C, 5000, Denmark
401 Military Hospital of Athens; Neurology Department | Athens, 11525, Greece
University General Hospital of Larisa; Neurology Clinic | Larisa, 411 10, Greece
AHEPA Univ. General Hospital of Thessaloniki; B' Neurology Dept. | Thessaloniki, 54636, Greece
Hospital Eginition; First Department of Neurology | Αθηνα, 115 28, Greece
UNO Medical Trials Kft. | Budapest, 1135, Hungary
Petz Aladar Megyei Oktato Korhaz; Neurologiai Osztaly | Gyor, 9024, Hungary
Somogy Megyei Kaposi Mor Oktato Korhaz; Department of Neurology | Kaposvár, 7400, Hungary
A. O. U. Federico II; Dip Neuroscienze, Scienze Riproduttive ed Odontostomatologiche | Napoli, Campania, 80131, Italy
Ospedale S.Camillo Forlanini; UOSD Day Hospital Neurologico e Neurochirurgico | Roma, Lazio, 00152, Italy
Azienda Ospedaliera Sant'Andrea; UOC Neurologia | Roma, Lazio, 00189, Italy
ASST PAPA GIOVANNI XXIII Neurologia USS Malattie Autoimmuni Centro Sclerosi Multipla | Bergamo, Lombardia, 24127, Italy
Ospedale S.Antonio Abate; Neurologia 2 - Sclerosi Multipla e Recupero Neurologico | Gallarate, Lombardia, 21013, Italy
IRCCS Ospedale San Raffaele; Neurologia Neurofisiologia Neuroriabilitazione-Centro Sclerosi Multipla | Milano, Lombardia, 20132, Italy
IRCCS Istituto Neurologico C. Mondino-Dip. Neurologia Neuroriabilitazione S.S. Sclerosi Multipla | Pavia, Lombardia, 27100, Italy
AOU Città della Salute e della Scienza; Neurologia 1 | Torino, Piemonte, 10126, Italy
Ospedale Binaghi; Centro Sclerosi Multipla | Cagliari, Sardegna, 09126, Italy
AOU Senese - Presidio Ospedaliero Le Scotte; UOSA Neurologia Sperimentale | Siena, Toscana, 53100, Italy
Clinstile S.A de C.V. | Mexico City, Mexico CITY (federal District), 06700, Mexico
Neurociencias Prisma, A.C | San Luis Potosí, SAN LUIS Potosi, 78216, Mexico
Centro de Investigacion Medico Biologico y Terapia Avanzada, S.C. | Guadalajara, 44130, Mexico
Grupo Médico Camino S.C. | Mexico, 03600, Mexico
Hospital Nacional Guillermo Almenara Irigoyen | La Victoria, Lima, Lima 13, Peru
Hospital Nacional Dos de Mayo; Unidad de Investigacion de Neurologia | Lima, 15003, Peru
Instituto Nacional de Ciencias Neurológicas - Hospital Mogrovejo; Peru | Lima, Lima 01, Peru
Neurocentrum Bydgoszcz sp. z o.o | Bydgoszcz, 85-796, Poland
COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika; Oddział Neurologiczny | Gdansk, 80-803, Poland
M.A. - LEK A.M.Maciejowscy SC. | Katowice, 40-595, Poland
Specjalistyczny Szpital Sw. Lukasza | Konskie, 26-200, Poland
Szpital Specjalistyczny im. Rydygiera w Krakowie; Oddzial Neurologii i Udarow Mozgu | Krakow, 31-637, Poland
Centrum Neurologii Krzysztof Selmaj | Lodz, 90-324, Poland
Indywidualna Praktyka Lekarska Prof. Dr Hab. N. Med. Konrad Rejdak. | Lublin, 20-016, Poland
Wojewodzki Szpital Specjalistyczny | Olsztyn, 10-561, Poland
Instytut Zdrowia Dr Boczarska-Jedynak Sp. z o.o. Sp. k. | Oswiecim, 32-600, Poland
Neurologiczny Niepubliczny ZOZ Centrum Leczenia SM Osrodek Badań Klinicznych | Plewiska, 62-064, Poland
EMC Instytut Medyczny SA | Poznań, 60-309, Poland
Wojewódzki Szpital Specjalistyczny Nr 3 | Rybnik, 44-200, Poland
Nzoz Palomed | Rzeszów, 35-060, Poland
NEURO-CARE Sp. z o.o. Sp. Komandytowa | Siemianowice Śląskie, 41-100, Poland
Osrodek Badan Klinicznych Euromedis | Szczecin, 70-111, Poland
mMED Maciej Czarnecki | Warszawa, 01-684, Poland
Instytut Psychiatrii i Neurologii II Klinika Neurologiczna | Warszawa, 02-957, Poland
Wojskowy Instytut Medyczny Centralny Szpital Kliniczny MON | Warszawa, 04-141, Poland
Hospital Garcia de Orta; Servico de Neurologia | Almada, 2801-951, Portugal
Hospital de Braga; Centro Clínico Académico (Piso 1, Ala E) | Braga, 4710-243, Portugal
Hospital Santo Antonio dos Capuchos; Servico de Neurologia | Lisboa, 1169-050, Portugal
Centro Hospitalar de Lisboa Ocidental - Hospital Egas Moniz; Neurologia | Lisboa, 1349-019, Portugal
Hospital Geral de Santo Antonio; Servico de Neurologia | Porto, 4099-001, Portugal
Centro Hospitalar de Setubal, EPE - Hospital São Bernardo; Serviço de Neurologia | Setúbal, 2910-446, Portugal
Hospital Quiron de Madrid; Servicio de Neurologia | Pozuelo de Alarcon, Madrid, 28223, Spain
Hospital Vall de Hebrón; Servicio de Neurologia. Centre d'Esclerosi Multiple de Catalunya CEMCAT | Barcelona, 8035, Spain
Hospital Universitario Puerta de Hierro; Servicio de Neurologia | Madrid, 28222, Spain
Hospital Universitario Virgen de Arrixaca; Servicio de Neurología | Murcia, Spain
University Hospital of Wales | Cardiff, CF14 4XW, United Kingdom
University Hospital Coventry | Coventry, CV2 2DX, United Kingdom
Charing Cross Hospital | London, W6 8RF, United Kingdom
National Hospital for Neurology and Neurosurgery,; MRC Centre for Neuromuscular Diseases | London, WC1 3BG, United Kingdom
Royal Victoria Infirmary | Newcastle upon Tyne, NE1 4LP, United Kingdom
University of Nottingham | Nottingham, NG7 2UH, United Kingdom
Derriford Hospital | Plymouth, PL6 8DH, United Kingdom
Royal Hallamshire Hospita | Sheffield, S10 2JF, United Kingdom
Location Countries

Argentina

Belgium

Brazil

Canada

Czechia

Denmark

Greece

Hungary

Italy

Mexico

Peru

Poland

Portugal

Spain

United Kingdom

United States

Verification Date

September 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Ocrelizumab Higher Dose

Type: Experimental

Description: Participants will be randomized to receive a minimum of 5 higher treatment doses (1200 mg or 1800 mg) of ocrelizumab administered by intravenous (IV) infusion every 24 weeks in the double blind treatment (DBT) phase. 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). 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.

Label: Ocrelizumab Approved Dose

Type: Active Comparator

Description: Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by intravenous (IV) infusion every 24 weeks 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.

Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Double (Participant, Investigator)

Source: ClinicalTrials.gov