Primary progressive multiple sclerosis (PPMS) MedDRA version: 21.1 Level: PT Classification code 10063401 Term: Primary progressive multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
Conditions
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Diagnosis of PPMS in accordance with the McDonald criteria (Thompson et al. 2017) - Age 18-65 years at time of signing Informed Consent Form - EDSS score at screening and baseline >= 3.0 to 8.0, inclusive - Disease duration from the onset of multiple sclerosis (MS) symptoms relative to randomization date: o Less than 20 years in patients with an EDSS score at screening 7.0-8.0 o Less than 15 years in patients with an EDSS at screening 5.5-6.5 o Less than 10 years in patients with an EDSS at screening 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 - Patients previously treated with immunosuppressant, 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 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) Eligibility Criteria for OLE Phase: - Completed the double-blind treatment phase of the trial and who, in the opinion of the investigator, may benefit from treatment with ocrelizumab Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 812 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - History of relapsing-remitting or secondary progressive MS at screening - Confirmed serious opportunistic infection - Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy - Known active malignancy or are being actively monitored for recurrence of malignancy - Immunocompromised state defined as one or more of the following: CD4 count < 250/µL, absolute neutrophil count <1.5 x 103/µL, Serum IgG < 4.6 g/L - Receipt of a live-attenuated vaccine within 6 weeks prior to randomization - Inability to complete an MRI or contraindication to gadolinium (Gd) administration - Patients requiring symptomatic treatment of multiple sclerosis (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 premedication for infusion-related reactions - Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study, including, but not limited to: history of hemorrhagic or ischemic cerebrovascular disorders or hemorrhage or ischemia of the spinal cord, history or known presence of CNS or spinal cord tumor, history of metabolic myelopathy or known presence of untreated causes of myelopathy, history or known presence of infectious metabolic myelopathy, history of genetically inherited progressive CNS degenerative disorder, neuromyelitis optica, history or known presence of non-MS systemic autoimmune disorders potentially causing progressive neurologic disease, history or known presence of sarcoidosis, history of severe, clinically significant brain or spinal cord trauma - Pregnant or breastfeeding, or intending to become pregnant during the study and 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 immunosuppressant during the course of the study - History of alcohol or other drug abuse - History of primary or secondary (non-drug-related) immunodeficiency - Treatment with any investigational agent within 24 weeks prior to screening or 5 half-lives of the investigational drug, or treatment with any experimental procedure for MS - Previous treatment with B-cell targeting therapies, bone marrow transplantation or 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 ß-hCG measured at screening or positive urine ß -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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •To evaluate the efficacy of ocrelizumab treatment compared with placebo-in patients on progression of upper limb disability, measured based on the time to 20% worsening from baseline in the 9-Hole Peg Test (9-HPT) confirmed for at least 12 weeks in all randomized patients and in patients with magnetic resonance imaging (MRI) activity ;Secondary Objective: •To evaluate the efficacy of ocrelizumab compared with placebo for all randomized patients by the time to 24 week confirmed 20% increase from baseline in 9-HPT, time to 12-week and 24-week confirmed disability progression (CDP) as measured by changes in expanded disability status scale (EDSS) •To evaluate the efficacy of ocrelizumab compared with placebo for all patients by the % change in total volume of T2 lesions and total brain volume as measured by magnetic resonance imaging •To evaluate the safety of ocrelizumab compared with placebo and over time for all patients by the proportion of patients with adverse events, laboratory abnormalities •To assess the immunogenicity, by the presence of anti-drug antibody to ocrelizumab during the study relative to baseline and the relationship to pharmacokinetics (PK), pharmacodynamics, efficacy and safety •To characterize the PK profile of the ocrelizumab and its PD, measured by blood B-cell levels;Primary end point(s): 1.Upper limb disability progression, measured based on time to 20% worsening from baseline in 9-HPT confirmed for at least 12 weeks and in all patients and patients with MRI activity;Timepoint(s) of evaluation of this end point: 1. Double-Blind Treatment (DBT): Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, treatment discontinuation (TD), Follow Up 1: Visits every 12 weeks, 144 being the last visit | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Upper limb disability progression, measured based on time to 20% increase from baseline in 9-HPT confirmed at least 24 weeks 2. Time to 12-week CDP in EDSS, as a pre-defined increase in EDSS score confirmed for at least 12 weeks 3. Time to 24-week CDP in EDSS, as a pre-defined increase in EDSS score confirmed for at least 24 weeks 4. Differences in the percent change in total volume of T2 lesions on MRI from baseline up to Week 120 will be analyzed using analysis of covariance and mixed effect model repeat measurement (MMRM) analyses 5. Differences in the mean percentage change in total brain volume on MRI scans from Week 24 to Week 120 will be analyzed using an MMRM analysis 6. Incidence and nature of adverse events, serious adverse events, adverse events leading to study treatment withdrawal 7. Change from baseline in laboratory test results for hematology and chemistry association of decrease in certain laboratory parameters, and serious infections 8. Presence of ADA of ocrelizumab 9. Total plasma clearances (CL) of ocrelizumab 10. Volumes of distribution(Vd) of ocrelizumab 11. Area under the concentration-time curve (AUC) of ocrelizumab;Timepoint(s) of evaluation of this end point: 1. DBT: Week 0, 12, 24, 36, 48, 60, 72, 84, n, n+12, 144 being the last visit, TD 2-3. DBT: Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 being the last visit, TD; Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, 12, n and TD; OLE: Week 0, 24, 48, n and TD 4. From baseline up to Week 120 5. From Week 24 to Week 120 6. Up to 9.5 years 7. From baseline to 9.5 years 8. DBT: Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144, TD; Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, n and TD; OLE: Week 0, 48, n, TD; Follow-Up 2: Visits every 24 weeks 9-11. DBT: Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144, TD; Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, 2, 12 and n, TD; OLE: Week 0, 48, n, TD; Follow-Up | — |
Countries
Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Colombia, Croatia, Egypt, France, Georgia, Germany, Hungary, Ireland, Italy, Mexico, Netherlands, New Zealand, Poland, Portugal, Romania, Russian Federation, Serbia, Spain, Ukraine, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F. Hoffmann-La Roche Ltd
Outcome results
None listed