E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Progressive multiple sclerosis (PMS) |
|
E.1.1.1 | Medical condition in easily understood language |
Multiple sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the central nervous system |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028245 |
E.1.2 | Term | Multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053395 |
E.1.2 | Term | Progressive multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the effectiveness of ocrelizumab treatment in patients with PMS disease course |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate the effectiveness of ocrelizumab treatment in PMS patients using a range of patient-relevant measures and imaging outcomes • To evaluate the safety and tolerability of ocrelizumab in PMS patients
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
MN39159/ Sub-study 1 U.S.- and Canada-Specific Substudy Protocol
Title: An Open-Label Spinal Cord MRI Substudy in Patients with Progressive Multiple Sclerosis Treated in Study MN39159
Date: 28-July-2023 Version: 1 Objectives: Primary objectives • To assess the effect of ocrelizumab on magnetic resonance imaging (MRI) spinal cord lesion activity in PMS patients
Secondary objectives NA
MN39159/ Sub-study 2 Italy-Specific Substudy Protocol
Title: Measuring Disability in Progressive Multiple Sclerosis by an Engineered Glove: An Italian Multicenter Prospective Study
Date: 28-July-2023 Version: 1 Objectives: Primary objectives • To assess changes in parameters measured by the GAS system over 1-2-3-4 years in a subgroup of patients with PMS enrolled in the main MN39159 study
Secondary objectives • To correlate baseline parameters of the GAS system with baseline levels of disability, cognitive level, upper limb ability, MRI parameters, and smartphone-based RPM test battery • To correlate changes in GAS parameters over the follow-up period with the changes in disability, cognitive level, upper limb ability, MRI parameters, and smartphone-based RPM test battery To compare the GAS parameters changes in more 'active' vs less 'active' PMS, i.e., in subgroups of patients stratified by varying levels of pre-baseline severity of recent disability progression history as measured from a disability progression rating system
|
|
E.3 | Principal inclusion criteria |
- Age 18-65 years - Have a definite diagnosis of PMS (as per the revised McDonald 2010 criteria for PPMS or Lublin et al. 2014 criteria for PMS) - Expanded Disability Status Scale (EDSS) <=6.5 at screening - Able to comply with the study protocol, in the Investigator’s judgment - Have documented evidence of disability progression independent of relapse activity 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 (note: stricter contraception requirements should be followed in countries where mandated) |
|
E.4 | Principal exclusion criteria |
- Relapsing-remitting multiple sclerosis (RRMS) at screening. - Inability to complete an MRI - Gadolinium (Gd) intolerance - Known presence of other neurological disorders, including but not limited to, the following: o History of ischemic or haemorrhagic disorders of the brain or the spinal cord o History or known presence of Central nervous system (CNS) or spinal cord tumour, or potential metabolic causes of myelopathy or infectious causes of myelopathy or systemic autoimmune disorders potentially causing progressive neurologic disease o History of genetically inherited progressive CNS degenerative disorder o Neuromyelitis optica. o History or known presence of systemic autoimmune disorders potentially causing progressive neurologic disease o History of severe, clinically significant brain or spinal cord trauma Exclusions Related to General Health: - Pregnancy or Lactation - Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressant’s during the course of the study - History of 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 the patient from participating in the study - Active infections must be treated and resolved prior to the first infusion of ocrelizumab - Patients in a severely immunocompromised state (until the condition resolves) - Patients with known active malignancies or being actively monitored for recurrence of malignancy - Patients who have or have had confirmed progressive multifocal leukoencephalopathy (PML) Exclusions Related to Medications Absolute exclusions: - Previous treatment with ocrelizumab - Hypersensitivity to ocrelizumab or to any of its excipients - Previous treatment with B-cell targeted therapies 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 B-cell levels are above the lower limit of normal (LLN) prior to screening - Any previous treatment with alemtuzumab, total body irradiation, or bone marrow transplantation. - Previous treatment with natalizumab where PML has not been excluded according to a specific algorithm - Contraindications to or intolerance of oral or intravenous (IV) corticosteroids Relative exclusions: 4 to 8 weeks prior to screening - 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 or fingolimod in the last 8 weeks - Treatment with fampridine/dalfampridine or other symptomatic MS treatment unless on stable dose for >=30 days prior to screening. Wherever possible, patients should remain on stable doses throughout the treatment period 12 weeks prior to screening - Previous treatment with natalizumab, azathioprine, cyclophosphamide, mycophenolate mofetil or methotrexate in the last 12 weeks 24 weeks prior to screening - Treatment with any investigational agent within 24 weeks of screening or five half-lives of the investigational drug or treatment (whichever is longer) with any experimental procedures for MS within 24 weeks of screening 96 weeks prior to screening - Previous treatment with mitoxantrone, cyclosporine or cladribine in the last 96 weeks. - Patients previously treated with teriflunomide within the last two years, unless measured plasma concentrations are less than 0.02 mg/l. If levels are above 0.02 mg/l or not known an accelerated elimination procedure should be implemented before screening visit Exclusions Related to Laboratory Findings - Any abnormal screening laboratory value that is clinically relevant should be retested only once in order to rule out any progressive or uncontrolled underlying condition. The last value before randomization must meet study criteria - Positive screening tests for hepatitis B. All patients must be tested for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (total HBcAb) For Subjects participating in the Optical coherence tomography assessments - Patients with clinically relevant ocular pathologies, potentially interfering with clinical and instrumental evaluations For Subjects participating in the measurement of Motor Evoked Potentials - History of seizures - Prior craniotomy or skull fracture - Movable metallic implant in the head - Implanted stimulators - Known history of high intracranial pressure |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Proportion of patients with no evidence of progression (NEP) sustained for at least 24 weeks 2. Proportion of patients with NEP and no active disease (NEPAD) sustained for at least 24 weeks
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-2. From baseline to Week 96, Week 96 to Week 192 and baseline to Week 192 |
|
E.5.2 | Secondary end point(s) |
1. Change from baseline in cognitive function as measured by the Symbol Digit Modalities Test (SDMT) and the Brief Visuospatial Memory Test – Revised (BVMT-R) 2. Change from baseline in the patient-reported outcomes including Multiple Sclerosis Impact Scale -29, Multiple Sclerosis Walking scale -12 items, ABILHAND-56 Questionnaire, Fatigue Scale for Motor and Cognitive (FSMC) function, SymptoMScreen, 88-item Multiple Sclerosis Spasticity Scale, Numerical Pain Rating Scale, Patient Global Impression of Severity (PGIS) for upper limb, lower limb and cognitive functions 3. Mean change from baseline in the EDSS score over the course of the study 4. Time to onset of first confirmed disability progression (as measured by EDSS) sustained for at least 24 and 48 weeks 5. Time to onset of first >=20% increase in timed 25-foot walk test sustained for at least 24 weeks 6. Time to onset of first >=20% increase in 9-hole peg test sustained for at least 24 weeks 7. Proportion of patients with NEP 8. Proportion of patients with NEPAD 9. Proportion of patients with confirmed disability improvement sustained for at least 24 weeks 10. Change in the following MRI volumetric measures: whole brain volume, cerebral white matter volume change, cortical gray matter volume, deep grey matter volume, thalamic volumes, whole and regional cerebellar volume 11. Change in the following lesion and tissue integrity parameters: • Number of new/enlarging T2 lesions and Total T2 lesion volume • Number of T1 Gd+ lesions and total volume • Number of T1 lesions and total volume • Gd-enhancing fluid-attenuated inversion-recovery (FLAIR) meningeal lesions 12. Rate and nature of adverse events 13. Changes in clinical laboratory results 14. Rates of study treatment discontinuation due to adverse events 15. Change in the number of falls and near-falls |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. From baseline to Weeks 48, 96, 144, 192 4-6. From baseline to Week 192 7-8. From Week 24 to Week 96, Week 24 to Week 192 and Week 48 to Week 192 9. From baseline to Week 96, Week 96 to Week 192 and baseline to Week 192 10-11. From baseline to Weeks 48, 96, 144, 192 12-15. From baseline to Week 192
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Algeria |
Colombia |
Costa Rica |
Egypt |
Guatemala |
Panama |
United Arab Emirates |
Bosnia and Herzegovina |
Brazil |
Canada |
Lebanon |
Mexico |
Morocco |
Russian Federation |
Czechia |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Netherlands |
Poland |
Spain |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the last patient last visit in the B-cell monitoring of the follow-up period |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |