E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing remitting multiple sclerosis (RRMS) |
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E.1.1.1 | Medical condition in easily understood language |
RRMS is an autoimmune disease that causes inflammation of the insulating membranes (myelin) that surround nerves within the central nervous system. |
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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 | 20.0 |
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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting 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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10048393 |
E.1.2 | Term | Multiple sclerosis relapse |
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 | 20.0 |
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.1.3 | 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 in early stage of RRMS |
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E.2.2 | Secondary objectives of the trial |
- To overview the different effectiveness measures evaluated for ocrelizumab in early stage of RRMS - To evaluate the safety and tolerability of ocrelizumab in early stage of RRMS
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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 |
One sub-study applicable in France TITLE : " A SUBSTUDY TO EVALUATE THE INDIRECT IMPACT OF OCRELIZUMAB ON THE T AND B CELL IMMUNE SYSTEM IN RELAPSING-REMITTING MULTIPLE SCLEROSIS PATIENTS ASSOCIATED WITH MA30143 CORE STUDY" version included in Appendix 7 of protocol version 3.2 Objectives : Impact of ocrelizumab-dependant B cell depletion on T cell subsets and functions in naïve RRMS patients, indirect impact of ocrelizumab on B cell repopulation and relationship between immunological biomarkers levels and clinical and/or subclinical change assessed by neurological markers in naïve RRMS patients treated with ocrelizumab. |
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E.3 | Principal inclusion criteria |
- Able to comply with the study protocol, in the investigator’s judgment - Age 18 − 55 years, inclusive - Have a definite diagnosis of RRMS, as per the revised McDonald 2010 criteria - Have a length of disease duration, from first documented clinical attack consistent with multiple sclerosis (MS) disease of <= 3 years - Within the last 12 months: one or more clinically reported relapse(s) or one or more signs of MRI activity - Expanded Disability Status Scale (EDSS) of 0.0 to 3.5 inclusive, at screening - For women of childbearing potential: agreement to use an acceptable birth control method during the treatment period and for at least 6 months after the last dose of study drug
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E.4 | Principal exclusion criteria |
- Secondary progressive multiple sclerosis or history of primary progressive or progressive relapsing MS - Inability to complete an Magnetic resonance imaging (MRI) - Known presence of other neurological disorders, including but not limited to, the following: • History of ischemic cerebrovascular disorders or ischemia of the spinal cord • History or known presence of central nervous system (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 • History or known presence of systemic autoimmune disorders potentially causing progressive neurologic disease • 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 immunosuppressants during the course of the study - History or currently active primary or secondary immunodeficiency - Lack of peripheral venous access - History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies - Significant or uncontrolled somatic disease or any other significant disease that may preclude patient from participating in the study - Congestive heart failure - Known active bacterial, viral, fungal, mycobacterial infection or other infection, or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to screening or oral antibiotics 2 weeks prior to screening - History of major opportunistic infections - History or known presence of recurrent or chronic infection - History of malignancy, including solid tumors and hematological malignancies - History of alcohol or drug abuse within 24 weeks prior to baseline - History or laboratory evidence of coagulation disorders Exclusions Related to Medications - Received any prior approved Disease modifying treatment (DMT) with a label for MS, for example, interferons, glatiramer acetate, natalizumab, alemtuzumab, daclizumab, fingolimod, teiflunomide and dimethylfumarate - Receipt of a vaccine within 6 weeks prior to the baseline visit - Treatment with any investigational agent within 24 weeks of screening or five half-lives of the investigational drug or treatment with any experimental procedures for MS - Contraindications to or intolerance of oral or intravenous (IV) corticosteroids, including methylprednisolone administered IV, according to the country label, including phychosis not yet controlled by a treatment and hypersensitivity to any of the constituents - Previous treatment with B-cell targeted therapies - Systemic corticosteroid therapy within 4 weeks prior to screening. - Any previous treatment with immunosuppressants/ immunomodulators/ antineoplastic therapies - Treatment with IV Immunoglobulin within 12 weeks prior to baseline - Treatment with investigational DMT - History of recurrent aspiration pneumonia requiring antibiotic therapy - Treatment with fampridine/dalfamipridine unless on stable dose for ≥ 30 days prior to screening. Wherever possible, patients should remain on stable doses throughout the 96-week treatment period Exclusions Related to Laboratory Findings - Positive serum β human chorionic gonadotropin measured at screening - Positive screening tests for hepatitis B - Lymphocyte count below lower limit of normal - CD4 count<250/μL - Aspartate aminotransferase/ serum glutamic oxaloacetic transaminase or alanine aminotransferase/serum glutamic pyruvic transaminase >= 3.0 × Upper limit of normal - Serum creatinine >1.4 mg/dL for women or > 1.6 mg/dL for men - Hemoglobin < 8.5 g/dL, Platelet count <100,000/μL, Absolute neutrophil count <1.0 × 10 3/μL
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Time to onset of confirmed disability progression (CDP) sustained for at least 24 weeks and 48 weeks 2. Proportion of patients who have confirmed disability improvement (CDI), CDP for at least 24 weeks and 48 weeks at Years 1, 2 and 4 3. Proportion of patients who have improved, stable or worsened disability compared with baseline measured by EDSS annually 4. Mean change from baseline in EDSS score over the course of the study 5. Time to first protocol-defined event of disease activity 6. Time to first relapse 7. Annualized relapse rate 8. Proportion of patient relapse free by Weeks 48, 96, 144 and 192 9. Proportion of patients with no evidence of protocol-defined disease activity (NEDA) over Week 96, Week 144 and Week 192 10. Proportion of patients with no evidence of progression sustained for at least 24 weeks on all the following three components (CDP; 20% increase in timed 25 Foot Walk Test [T25FWT]; 20% increase in timed 9 hole peg test [9HPT]) between baseline and Week 96/192 11. Proportion of patients with no active disease between Baseline and Week 96/192 12. Change from baseline of multiple sclerosis functional composite (MSFC) and its composites (T25FW, 9HP, and Paced Auditory Serial Addition Test [PASAT]) over time 13. Change from baseline in cognitive performance as measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) performed annually 14. Total number of T1 Gd-enhancing lesions; and new and/or enlarging T2 lesion as detected by brain MRI over time 15. Change in T1 volume over time 16. Total number of fluid-attenuated inversion-recovery (FLAIR) lesion counts as detected by brain MRI over time 17. Change in brain volume (including white and grey matter fractions) as detected by brain MRI over time 18. Time to treatment discontinuation/switch 19. Employment status score (Work Productivity and Activity Impairment Questionnaire [WPAI]) 20. SymptoMScreen score 21. Quality of life score (Multiple Sclerosis Impact Scale [MSIS]-29) 22. Rate and nature of adverse events 23. Changes in vital signs, physical and neurological examinations, clinical laboratory results, locally reviewed MRI for safety and concomitant medications
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 48 weeks after the last dose of ocrelizumab 2. Up to 4 years 3-7. Up to 48 weeks after the last dose of ocrelizumab 8. Weeks 48, 96, 144 and 192 9. Weeks 96, 144 and 192 10-11. Baseline and Week 96/192 12-23. Up to 48 weeks after the last dose of ocrelizumab |
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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 | 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 | 31 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 161 |
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 |
Austria |
Belgium |
Brazil |
Bulgaria |
Croatia |
Denmark |
Finland |
France |
Germany |
Hungary |
Italy |
Mexico |
Netherlands |
Norway |
Poland |
Portugal |
Romania |
Slovakia |
Slovenia |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
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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
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The end of the study is defined as the last patient last visit in the B-cell monitoring of the Follow-up Period. |
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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 | |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |