E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing Multiple Sclerosis (MS) |
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E.1.1.1 | Medical condition in easily understood language |
MS is a condition that can affect the brain and spinal cord, causing a wide range of potential symptoms, including problems with vision, arm or leg movement, sensation or balance. |
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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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039720 |
E.1.2 | Term | Sclerosis multiple |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 | 10063401 |
E.1.2 | Term | Primary progressive multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 demonstrate the superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab as assessed by risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks |
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E.2.2 | Secondary objectives of the trial |
• To demonstrate superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab on the basis of time to onset of 24 week cCDP (cCDP24), CDP12, CDP24, time to >= 20% increase in 12 and 24 week confirmed timed 25 foot walk test (T25FWT) and 9 hole peg test (9 HPT), change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29), percent change in total brain volume, Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT) • To evaluate the safety profile of a higher dose of ocrelizumab compared with the approved dose of ocrelizumab as well as the overall safety profile and safety profile by treatment arm over time • To assess the exposure to ocrelizumab in serum in all patients in both study arms • To characterize the ocrelizumab PD profile • To evaluate the immune response to ocrelizumab • To identify biomarkers that are predictive of response to a higher dose of ocrelizumab |
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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 |
A CSF BIOMARKER SUBSTUDY WITHIN BN42083 TRIAL, PHASE IIIB MULTICENTER, RANDOMIZED, DOUBLE-BLIND, CONTROLLED STUDIES TO EVALUATE THE EFFICACY, SAFETY AND PHARMACOKINETICS OF A HIGHER DOSE OF OCRELIZUMAB IN ADULTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS
Version 1 dated 19th May 2020
Primary objective • To compare a higher dose of ocrelizumab versus the approved dose of ocrelizumab Secondary objective • To assess the correlation between changes in CSF biomarkers with those in blood and to compare higher dose of ocrelizumab versus the approved dose of ocrelizumab • To characterize the ocrelizumab concentration in CSF and to investigate the relationship between changes in biomarkers in CSF/blood and ocrelizumab concentration in CSF |
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E.3 | Principal inclusion criteria |
•Signed ICF •Ages 18-55 years at time of screening •Ability to comply with the study protocol •Diagnosis of PPMS, in accordance with the revised McDonald criteria 2017 (Thompson et al. 2018) •EDSS score at screening and baseline, from 3 to 6.5 inclusive •Score of >= 2.0 on the Functional Systems (FS) scale for the pyramidal system that was due to lower extremity findings •Patients requiring symptomatic treatment for MS (e.g. fampridine, cannabis) and/or physiotherapy must be treated at a stable dose during the screening period prior to the initiation of study drug on Day 1 and must have a plan to remain at a stable dose for the duration of study treatment •Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments •Disease duration from the onset of MS symptoms: Less than 15 years in patients with an EDSS score at screening >5.0 Less than 10 years in patients with an EDSS score at screening >5.0 •Documented evidence of the presence of cerebrospinal fluid-specific oligoclonal bands (established by a historical lumbar puncture or presence at screening in a newly obtained CSF specimen (source documentation of historical laboratory results and method must be verified) •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 (as applicable by the ocrelizumab [Ocrevus] local label) after the final dose of ocrelizumab. •For female patients without reproductive potential: Females may be enrolled if post menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile (i.e., hysterectomy, complete bilateral oophorectomy).
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E.4 | Principal exclusion criteria |
•History of relapsing remitting or secondary progressive MS at screening •Any known or suspected active infection at screening or baseline, or any major episode of infection requiring hospitalization or treatment with IV anti microbials within 8 weeks prior to and during screening or treatment with oral anti microbials within 2 weeks prior to and during screening •History of confirmed or suspected progressive multifocal leukoencephalopathy (PML) •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, including, but not limited to, the following: History of ischemic cerebrovascular disorders or ischemia of the spinal cord History or known presence of CNS or spinal cord tumor History or known presence of potential metabolic causes of myelopathy History or known presence of infectious causes of myelopathy History of genetically inherited progressive CNS degenerative disorder Neuromyelitis optica spectrum disorders History or known presence of systemic autoimmune disorders potentially causing progressive neurologic disease History or known presence of sarcoidosis History of severe, clinically significant brain or spinal cord trauma •Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study •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 •History of or currently active primary or secondary immunodeficiency •Pregnant or breastfeeding or intending to become pregnant during the study or 6 or 12 months (as applicable from the local label for ocrelizumab) after final dose of the study drug Females of childbearing potential must have a negative serum and urine pregnancy test • Lack of peripheral venous access • History of alcohol or other drug abuse within 12 months prior to screening • Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or five half lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency) • Previous use of anti-CD20s is allowed if the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by 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. The PD effects of the previous medication must also be considered when determining the required time for washout. • 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 screening tests for active, latent, or inadequately treated hepatitis B • Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab • Any additional exclusionary criterion as per ocrelizumab (Ocrevus) local label, if more stringent than the above |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Reduction in cCDP sustained for at least 12 weeks |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to Week 120 (Double blind treatment [DBT]) and Week 96 (Open label extension [OLE]) |
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E.5.2 | Secondary end point(s) |
1. Time to onset of 24 week cCDP (cCDP24) 2. Time to onset of 12-week CDP (CDP12) 3. Time to onset of 24-week CDP (CDP24) 4. Time to >= 20% increase in 12 week confirmed T25FWT 5. Time to >= 20% increase in 24 week confirmed T25FWT 6. Time to >= 20% increase in 12 week confirmed 9 HPT 7. Time to >= 20% increase in 24 week confirmed 9 HPT 8. Change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29) physical scale at Week 120 9. Percent change in total brain volume from Week 24 to Week 120 10. Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT) 11. Presence, frequency, timing, outcome and severity of AEs, serious adverse events (SAE) and AEs leading to study treatment withdrawal 12. Proportion of patients with AEs and SAEs 13. Incidence and severity of adverse events, with severity determined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 14. Change from baseline in clinical laboratory test results (including hematology, chemistry, Ig levels) 15. Change from baseline in vital signs (including systolic and diastolic blood pressure, pulse rate) following study treatment administration 16. Serum concentration of ocrelizumab at specified timepoints 17. B cell levels in blood as the pharmacodynamic marker of ocrelizumab (including comparing the degree of B-cell depletion between the doses) 18. Proportion of patients achieving 5 or less B-cells per microliter of blood 19. Proportion of patients achieving 5 or less B-cells per microliter of blood in patients with the high versus low affinity Fcgamma Receptor 3A (FcgR3A) genotype per arm 20. Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study 21. Levels of soluble biomarkers 22. Levels of blood B-cells based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood 23. Levels of B or T cell subsets in blood 24. DNA genotype of patients |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-7. Up to Week 120 (DBT) and Week 96 (OLE) 8. Baseline to Week 120 9. Week 24 to Week 120 10. Up to Week 120 (DBT) and Week 96 (OLE) 11-13. Up to Week 120 (DBT) and Week 96 (OLE) 14-15. Baseline to Week 120 (DBT) and Week 96 (OLE) 16-19. Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96 20. Week 0, 24, 48, 72, 96 21-24. DBT: Week 0, 2, 12, 24, 48, 72, 96; OLE: Week 0, 48, 96 |
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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 | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.1.7.1 | Other trial design description |
Ocrelizumab approved dose compared to higher dose |
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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 | Yes |
E.8.2.3.1 | Comparator description |
Ocrelizumab approved dose compared to higher dose |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 111 |
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 |
Argentina |
Belgium |
Brazil |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Mexico |
New Zealand |
Peru |
Poland |
Portugal |
Russian Federation |
Spain |
Switzerland |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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The end of the study will occur when all patients, who are not being treated with an alternative B-cell depleting therapy, have repleted their B-cells (i.e., B-cell level of the patient has returned to the baseline value or the lower limit of normal, whichever is lower). |
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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 | 31 |
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 | 31 |