A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis
- Conditions
- Multiple Sclerosis, Primary Progressive
- Interventions
- Drug: Placebo
- Registration Number
- NCT04035005
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This study will evaluate the efficacy and safety of ocrelizumab ( Ocrevus®) compared with placebo in participants with primary progressive multiple sclerosis (PPMS), including participants later in their disease course. This study focuses on upper limit disability progression. This study will consist of the following phases: screening, double-blind treatment, follow-up 1 (FU1), an optional open-label extension (OLE), follow-up 2 (FU2), and B-cell monitoring (BCM).
- Detailed Description
The screening phase will last up to 24 weeks. In the double-blind treatment phase, participants will undergo at least 120 weeks of study treatment. Study drug (ocrelizumab or placebo) will be administered every 24 weeks. In the FU1 phase, all participants who discontinue prematurely from the double-blind treatment phase will enter the FU1 phase, including participants who receive post-double progression ocrelizumab (PDP OCR) treatment, other immunomodulatory or immunosuppressive treatment(s) for MS, commercial ocrelizumab, or no treatment. The FU1 phase will run in parallel with the double-blind treatment phase until the primary analysis is performed. If the primary analysis is positive, an optional OLE phase is planned for eligible participants who either have remained in the double-blind treatment phase or are on PDP OCR treatment at the time of the primary analysis and, in the opinion of the investigator, could benefit from ocrelizumab treatment. The follow-up 2 (FU2) phase will begin after the primary analysis is performed. The following participants will move into the FU2 phase: participants who are ongoing in the FU1 and not on PDP OCR treatment at the time of primary analysis; participants who are ongoing in the double-blind treatment phase or receiving PDP OCR at the time of the primary analysis and do not enter the OLE phase; participants who complete or withdraw from the OLE phase. At the end of the FU2, all participants will move into B-cell monitoring (BCM) phase until the end of the study. This study will end when all participants who are not being treated with an alternative B-cell depleting therapy have repleted his or her B-cells.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 1000
- EDSS score at screening and baseline >= 3.0 to 8.0, inclusive
- Disease duration from the onset of MS symptoms relative to randomization date:
Less than 20 years in patients with an EDSS score at screening 7.0 - 8.0 Less than 15 years in patients with an EDSS at screening 5.5 - 6.5 Less than 10 years in patients with an EDSS at screening <= 5.0
- Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen: Elevated IgG index or one or more IgG oligoclonal bands detected by isoelectric focusing
- Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands)
- Neurological stability for ≥ 30 days prior to baseline
- Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline
- Neurological stability for >/= 30 days prior to baseline
- Patients previously treated with immunosuppressants, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
- For female patients without reproductive potential: Women may be enrolled if surgically sterile (i.e hysterectomy, complete bilateral oophorectomy) or post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile
- History of relapsing-remitting or secondary progressive MS at screening
- Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease
- Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML)
- Known active malignancy or are being actively monitored for recurrence of malignancy
- Immunocompromised state
- Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
- Inability to complete an MRI or contraindication to Gd administration.
- Patients requiring symptomatic treatment of MS and/or physiotherapy who are not on a stable regimen. Patients must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization.
- Contraindications to mandatory premedications for infusion-related reactions, including:
uncontrolled psychosis for corticosteroids and closed-angle glaucoma for antihistamines
- Known presence of other neurologic disorders
- Pregnant or breastfeeding, or intending to become pregnant during the study and for 6 or 12 months after last infusion of the study drug
- Lack of peripheral venous access
- Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study
- Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
- History of alcohol or other drug abuse
- History of primary or secondary immunodeficiency
- Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS
- Previous treatment with B-cell targeting therapies
- Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
- Any previous history of transplantation or anti-rejection therapy
- Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
- Systemic corticosteroid therapy within 4 weeks prior to screening
- Positive serum hCG measured at screening or positive urine β-hCG at baseline
- Positive screening tests for hepatitis B
- Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above
- Lack of MRI activity at screening/baseline if more than 650 patients without MRI activity have already been enrolled, as defined by T1 Gd+ lesion(s) and/or new and/or enlarged T2 lesion(s) in the screening, to ensure that at least 350 patients with MRI activity will be randomized
Eligibility Criteria for Open-Label Extension Phase:
- Completed the double-blind treatment phase of the trial or have received PDP OCR in the FU1 phase, and who, in the opinion of the investigator, may benefit from treatment with Ocrelizumab. Patients who withdrew from study treatment and received another disease-modifying therapy (DMT) or commercial ocrelizumab will not be allowed to enter in the OLE phase.
- Meet the re-treatment criteria for ocrelizumab
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
- For female patients without reproductive potential: Women may be enrolled if surgically sterile (i.e. hysterectomy, complete bilateral oophorectomy) or post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants will receive placebo matched to ocrelizumab by IV infusion every 24 weeks. Ocrelizumab Ocrelizumab Participants will receive ocrelizumab by IV infusion every 24 weeks.
- Primary Outcome Measures
Name Time Method Time to Upper Limb Disability Progression Confirmed For at Least 12 Weeks Baseline up to approximately 5.5 years 20% increase from baseline in Nine-Hole Peg Test (9-HPT) confirmed for at least 12 weeks.
- Secondary Outcome Measures
Name Time Method Percentage of Participants with Adverse Events Baseline up to 8.5 years Percent Change in Total Brain Volume on MRI Scans Week 24 to Week 120 Evaluation of Ocrelizumab Pharmacodynamics, as measured by B-Cell Levels in Blood Baseline, Weeks 2, 24, 48, 72 and every 12 weeks till the end of the double-blind period and Weeks 0, 22, 46, 70 and 96 of the OLE period Time to Disability Progression Confirmed For at Least 24 Weeks Baseline up to approximately 5.5 years Increase in EDSS Score is defined as an increase of \>= 1.0 point from baseline EDSS score in participants with a baseline EDSS score \<= 5.5 or an increase of \>= 0.5 point in participants with a baseline EDSS score of \> 5.5.
Percentage of Participants With Serious Adverse Events Baseline up to 8.5 years Time to Upper Limb Disability Progression Confirmed For at Least 24 Weeks Baseline up to approximately 5.5 years 20% increases from baseline in 9-HPT confirmed for at least 24 weeks.
Time to Disability Progression Confirmed For at Least 12 Weeks Baseline up to approximately 5.5 years Increase in EDSS Score is defined as an increase of \>= 1.0 point from baseline EDSS score in participants with a baseline EDSS score \<= 5.5 or an increase of \>= 0.5 point in participants with a baseline EDSS score of \> 5.5.
Percent Change in Total Volume of T2 Lesions on MRI Baseline up to week 120 Area Under the Serum Concentration-Time Curve (AUC) of Ocrelizumab Baseline, Weeks 2, 12, 24, 48, 60, 72, and every 12 weeks till the end of the double-blind period and Weeks 0 and 48 of the OLE period
Trial Locations
- Locations (159)
Multiprofile Hospital For Active Treatment Avis Medica
🇧🇬Pleven, Bulgaria
Multiprofile Hospital for Active Treatment of Neurology and Psychiatry Sv. Naum EAD
🇧🇬Sofia, Bulgaria
CHU de Bordeaux - Hôpital Pellegrin
🇫🇷Bordeaux, France
Hospital Angeles Chihuahua
🇲🇽Chihuahua, Mexico
Unidad de Investigacion en Salud de Chihuahua
🇲🇽Mexico City, Mexico
Clinical Research Institute
🇲🇽Tlalnepantla de Baz, Mexico
CHU Mohammed VI
🇲🇦Marrakech, Morocco
Centre Hospitalier Ibn Sina CHIS - Hopital des Specialites
🇲🇦Rabat, Morocco
Hopital Militaire d'Instruction Mohamed V
🇲🇦Rabat, Morocco
New Zealand Clinical Research - Christchurch
🇳🇿Christchurch, New Zealand
Waikato Hospital
🇳🇿Hamilton, New Zealand
Przychodnia EuroMediCare
🇵🇱Wroclaw, Dolnoslaskie, Poland
Specjalistyczna Praktyka Lekarska Dr n.med. Stanislaw Ochudlo
🇵🇱Katowice, Poland
SP ZOZ Szpital Uniwersytecki w Krakowie
🇵🇱Kraków, Poland
Centrum Neurologii Krzysztof Selmaj
🇵🇱Lodz, Poland
Galen Clinic
🇵🇱Lublin, Poland
Wojewodzki Szpital Specjalistyczny
🇵🇱Olsztyn, Poland
Med-Polonia Sp. z o.o.
🇵🇱Poznan, Poland
EUROMEDIS Sp z o o
🇵🇱Szczecin, Poland
Centrum Medyczne NeuroProtect Zablocinska 10
🇵🇱Warsaw, Poland
Austin Hospital
🇦🇺Heidelberg, Victoria, Australia
Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
UZ Antwerpen
🇧🇪Edegem, Antwerpen, Belgium
Cliniques Universitaires St-Luc
🇧🇪Bruxelles, Belgium
MS & Neurologisch Revalidatie Centrum
🇧🇪Overpelt, Belgium
Military Medical Academy HBAT
🇧🇬Pleven, Bulgaria
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Complejo Asistencial Universitario de Salamanca ? H. Clinico
🇪🇸Salamanca, Spain
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain
Hopital Razi
🇹🇳LA Mannouba, Tunisia
Communal Non-commercial Enterprise of Kharkiv Regional Council Regional Clinical Hospital
🇺🇦Kharkiv, Ukraine
Medical Center of LLC Medical Center Dopomoga Plus
🇺🇦Kyiv, Ukraine
Volyn Regional Clinical Hospital
🇺🇦Lutsk, Ukraine
LLC Medical Center INET 09
🇺🇦Zaporizhzhia, Ukraine
Municipal Non-profit Enterprise Zaporizhzhya Regional Hospital Zaporizhzhya Regional Council
🇺🇦Zaporizhzhia, Ukraine
University Hospital of Wales
🇬🇧Cardiff, United Kingdom
Queen Elizabeth University Hospital - PPDS
🇬🇧Glasgow, United Kingdom
Raigmore Hospital - PPDS
🇬🇧Inverness, United Kingdom
The National Hospital for Neurology & Neurosurgery
🇬🇧London, GT LON, United Kingdom
The Royal London Hospital
🇬🇧London, United Kingdom
University of Nottingham
🇬🇧Nottingham, United Kingdom
Peninsula College of Medicine and Dentistry
🇬🇧Plymouth, United Kingdom
Salford Royal Hospital
🇬🇧Salford, United Kingdom
Royal Hallamshire Hospital
🇬🇧Sheffield, United Kingdom
Morriston Hospital
🇬🇧Swansea, United Kingdom
Medical Center Artes Medicum LLC
🇺🇦Kyiv, Kyiv Oblast, Ukraine
Medical Center Salutem
🇺🇦Vinnytsia, Podolia Governorate, Ukraine
LLC Medical Center Health Clinic
🇺🇦Vinnytsia, Volhynian Governorate, Ukraine
LLC Medical Center Unimed
🇺🇦Zaporizhzhia, Zaporiz'ka Oblast, Ukraine
Fattouma Bourguiba University Hospital
🇹🇳Monastir, Tunisia
Hospital Habib Bourguiba
🇹🇳Sfax, Tunisia
Military Hospital of Tunis
🇹🇳Tunis, Tunisia
Separated structural unit ?University hospital? of Dnipro State Medical University
🇺🇦Dnipro, Dnipropetrovs'ka Oblast, Ukraine
Treatment and diagnostic Center Neuro Global of LLC Neuro Global
🇺🇦Krykhivtsi, Ivano-Frankivs'ka Oblast, Ukraine
Communal noncommercial enterprise of Lviv Regional Council Lviv Regional Clinical Hospital
🇺🇦Lviv, L'vivs'ka Oblast, Ukraine
Municipal Non-profit Enterprise Kherson City Clinical Hospital named after Ye.Ye. Karabelesh
🇺🇦Kherson, Kherson Governorate, Ukraine
Treatment and Diagnostic Center of LLC MRT Elit
🇺🇦Kropyvnytskyi, KIEV Governorate, Ukraine
Medical Centre of PE First Private Clinic
🇺🇦Kyiv, KIEV Governorate, Ukraine
Kyiv City Clinical Hospital #4
🇺🇦Kyiv, KIEV Governorate, Ukraine
Communal Non-Commercial Enterprise Clinical Hospital #15 of the Podilskyi District ofthe Kyiv City
🇺🇦Kyiv, KIEV Governorate, Ukraine
LLC Smart Medical Center
🇺🇦Kyiv, KIEV Governorate, Ukraine
Municipal NPE Regional Clinical Center of Neurosurgery and Neurology of Transcarpathian RC
🇺🇦Uzhhorod, KIEV Governorate, Ukraine
LLC Medical Center Family Medicine Clinic
🇺🇦Dnipro, Ukraine
Multiple Sclerosis Center of California
🇺🇸Laguna Hills, California, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
MS and Neuromuscular Center of Excellence
🇺🇸Clearwater, Florida, United States
Neurological Services of Orlando
🇺🇸Orlando, Florida, United States
Vero Neurology
🇺🇸Vero Beach, Florida, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
Michigan Neurology Associates P.C.
🇺🇸Clinton Township, Michigan, United States
The Boster Center for MS
🇺🇸Columbus, Ohio, United States
Columbus Neuroscience
🇺🇸Westerville, Ohio, United States
Albert Einstein Medical Center
🇺🇸Philadelphia, Pennsylvania, United States
Maxine Mesinger MS Clinic/Baylor College of Medicine
🇺🇸Houston, Texas, United States
Brain and Mind Research Institute
🇦🇺Camperdown, New South Wales, Australia
Dalhousie Multiple Sclerosis Research Unit
🇨🇦Halifax, Nova Scotia, Canada
St. Michael's Hospital
🇨🇦Toronto, Ontario, Canada
Recherche Sepmus Inc.
🇨🇦Greenfield Park, Quebec, Canada
Instituto Neurologico de Colombia INDEC
🇨🇴Medellin, Antioquia, Colombia
Clinica Colsanitas S.A. sede Clinica Universitaria Colombia
🇨🇴Bogota, Colombia
Clinical Hospital Centre Osijek
🇭🇷Osijek, Croatia
General Hospital Varazdin
🇭🇷Varaždin, Croatia
Clinical Hospital Sestre Milosrdnice
🇭🇷Zagreb, Croatia
University Hospital Center Zagreb
🇭🇷Zagreb, Croatia
Centre Hospitalier Universitaire de Clermont Ferrand
🇫🇷Clermont ferrand, France
CHRU Nancy
🇫🇷Nancy, France
Hopital Guillaume Et Rene Laennec
🇫🇷Nantes, France
CHU de Nimes - Hopital Universitaire Caremeau
🇫🇷Nimes, France
Hopital Civil
🇫🇷Strasbourg, France
Pineo Medical Ecosystem LTD
🇬🇪Tbilisi, Georgia
The First University Clinic of Tbilisi State Medical University
🇬🇪Tbilisi, Georgia
Khechinashvili University Hospital
🇬🇪Tbilisi, Georgia
AOU dell Universita degli Studi della Campania Luigi Vanvitelli Piazza Luigi Miraglia 2
🇮🇹Napoli, Campania, Italy
Fondazione PTV Policlinico Tor Vergata
🇮🇹Rome, Lazio, Italy
Azienda Ospedaliera Sant'andrea
🇮🇹Rome, Lazio, Italy
IRCCS Ospedale Policlinico San Martino
🇮🇹Genova, Liguria, Italy
Ospedale San Raffaele S.r.l. - PPDS
🇮🇹Milano, Lombardia, Italy
Fondazione Istituto Neurologico Mondino IRCCS
🇮🇹Pavia, Lombardia, Italy
Azienda Ospedaliero-Universitaria San Luigi Gonzaga
🇮🇹Orbassano, Piemonte, Italy
Fondazione Istituto G. Giglio di Cefalu
🇮🇹Cefalù, Sicilia, Italy
Hotel Dieu de France
🇱🇧Achrafieh Beirut, Lebanon
Saint George University Medical Hospital
🇱🇧Achrafieh, Lebanon
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸Valencia, Spain
Hospital Universitario Puerta de Hierro - Majadahonda
🇪🇸Madrid, Spain
Grupo Medico Camino
🇲🇽Mexico city, Mexico CITY (federal District), Mexico
Neurociencias Estudios Clinicos S.C.
🇲🇽Culiacán, Sinaloa, Mexico
Neurocentrum Bydgoszcz sp z o.o
🇵🇱Bydgoszcz, Kujawsko-pomorskie, Poland
Rejdak Konrad Indywidualna Praktyka Lekarska dr hab. Konrad Rejdak
🇵🇱Lublin, Lubelskie, Poland
Centrum Medyczne Medyk
🇵🇱Rzeszów, Podkarpackie, Poland
SPZOZ Wojewodzki Szpital Specjalistyczny nr 3
🇵🇱Rybnik, Slaskie, Poland
RESMEDICA Spolka z o.o.
🇵🇱Kielce, Swietokrzyskie, Poland
Uniwersytecki Szpital Kliniczny w Bialymstoku Marii Sklodowskiej Curie 24a
🇵🇱Bia?ystok, Poland
Copernicus Podmiot Leczniczy Sp z o o
🇵🇱Gdansk, Poland
Mazowieckie Centrum Badan Klinicznych
🇵🇱Grodzisk Mazowiecki, Poland
MA-LEK Clinical Sp. Z o.o.
🇵🇱Katowice, Poland
Novo-Med Zielinski i wsp SpJ
🇵🇱Katowice, Poland
NEURO-MEDIC Sp. z o. o.
🇵🇱Katowice, Poland
ULS de Loures-Odivelas, EPE - Hospital de Loures
🇵🇹Loures, Lisboa, Portugal
Hospital Garcia de Orta
🇵🇹Almada, Portugal
Hospital de Braga
🇵🇹Braga, Portugal
Hospital de Santo Antonio
🇵🇹Porto, Portugal
Campus Neurologico Senior
🇵🇹Torres Vedras, Portugal
Spitalul Judetean de Urgenta Deva
🇷🇴Deva, Hunedoara, Romania
SC Clubul Sanatatii SRL
🇷🇴Campulung, Romania
Cai Ferate Clinical Hospital
🇷🇴Constanta, Romania
Targu Mures Clinical Emergency County Hospital
🇷🇴Târgu Mure?, Romania
Krasnoyarsk State Medical Academy
🇷🇺Krasnoyarsk, Krasnojarsk, Russian Federation
City Clinical Hospital a n Buyanov V M
🇷🇺Moscow, Moskovskaja Oblast, Russian Federation
City Clinical Hospital #24
🇷🇺Moscow, Moskovskaja Oblast, Russian Federation
Moscow Regional Research Clinical Institute Na Mfvladimirskiy
🇷🇺Moscow, Moskovskaja Oblast, Russian Federation
Research Center of Neurology of RAMS
🇷🇺Moskva, Moskovskaja Oblast, Russian Federation
Neftyanik Medical and Sanitary Unit
🇷🇺Tumen, Moskovskaja Oblast, Russian Federation
SBHI of Nizhny Novgorod region City Clinical Hospital #3
🇷🇺Nizhnij Novgorod, Niznij Novgorod, Russian Federation
Nizhegorodskaya Regional Clinical Hospital n.a. Semashko
🇷🇺Nizhny Novgorod, Niznij Novgorod, Russian Federation
MEDIS Limited Liability Company
🇷🇺Nizhny Novgorod, Niznij Novgorod, Russian Federation
National Center of Socially Significant Diseases
🇷🇺Saint-Petersburg, Sankt Petersburg, Russian Federation
City Hospital #40 of Kurortniy Administrative District
🇷🇺St. Petersburg, Sankt Petersburg, Russian Federation
City Clinical Hospital #4
🇷🇺Saransk, Saratov, Russian Federation
Sverdlovsk Regional Clinical Hospital 1
🇷🇺Yekaterinburg, Sverdlovsk, Russian Federation
Vertebronevrologiya LLC
🇷🇺Kazan, Tatarstan, Russian Federation
Ulyanovsk Regional Clinical Hospital
🇷🇺Ulyanovsk, Uljanovsk, Russian Federation
Belyayev Clinical Hospital of the Kuzbass
🇷🇺Kemerovo, Russian Federation
Kirov State Medical Academy
🇷🇺Kirov, Russian Federation
FSBIH Siberian Regional Medical Centre of FMBA of Russia
🇷🇺Novosibirsk, Russian Federation
Perm Regional Clinical Hospital of Znak Pocheta Medal
🇷🇺Perm, Russian Federation
Siberian State Medical University of Roszdrav
🇷🇺Tomsk, Russian Federation
Military Medical Academy
🇷🇸Belgrade, Serbia
University Clinical Center of Serbia -PPDS
🇷🇸Belgrade, Serbia
Clinical Hospital Centre Zemun
🇷🇸Belgrade, Serbia
University Clinical Center Kragujevac
🇷🇸Kragujevac, Serbia
Clinical Center Nis
🇷🇸NIS, Serbia
Clinical Centre of Vojvodina
🇷🇸Nova Sad, Serbia
General Hospital Uzice
🇷🇸Uzice, Serbia
Hospital Universitario Quironsalud Madrid
🇪🇸Pozuelo de Alarcón, Madrid, Spain
Hospital Universitario Virgen de La Arrixaca
🇪🇸El Palmar, Murcia, Spain
Complejo Hospitalario Universitario de Vigo
🇪🇸Vigo, Pontevedra, Spain
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain