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 |
Multiple sclerosis is a disabling disease of brain and spinal cord that disrupts flow of information within brain, characterized by flare-ups with periods of remission in between (relapsing remitting) |
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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 | 20.0 |
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 | 20.1 |
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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To assess the efficacy of ocrelizumab 600 mg intravenous (IV) given every 24 weeks on the basis of the following endpoint
- Proportion of patients who have no evidence of disease activity
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E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of ocrelizumab 600 mg IV given every 24 weeks on the basis of the following endpoints
- Proportions of patients free from a protocol-defined event of disease activity
- Time to first protocol-defined event of disease activity
- Change in Expanded Disability Status Scale (EDSS)
- Proportion of patients who have Confirmed Disability Improvement (CDI), Confirmed Disability Progression (CDP) or stable disability
- Annualized rate of protocol-defined relapses
- Time to onset of first protocol-defined relapse, 24 weeks CDP, first new and/or enlarging T2 lesion
- Total number of T1 Gd-enhanced lesions detected by brain MRI
- Total number of new/enlarging T2 lesions detected by brain MRI
- Volume and number of new and/or enlarging T2 hyperintense lesions
- Change in T1 hypointense lesions
- Change in cognitive performance
•To evaluate the safety and tolerability of ocrelizumab 600 mg IV given every 24 weeks |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age 18-55 years
- Have a definite diagnosis of RRMS, confirmed as per the revised McDonald 2010 criteria
- Have a length of disease duration, from first symptom, of < 10 years. If the date of first symptom is unknown, then the diagnosis of RRMS should be of ≤ 5 years
- Have received no more than two prior disease modifying treatments (DMTs), and the discontinuation of the most recent DMT was due to lack of efficacy
- Suboptimal disease control while on a DMT
- EDSS of 0.0 to 4.0, 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 (SPMS) or history of primary progressive or progressive relapsing MS
- Inability to complete an MRI
- Known presence of other neurological disorders
Exclusions Related to General Health
- 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
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
- History of opportunistic infections
- History or known presence of recurrent or chronic infection
- History of malignancy
- Congestive heart failure
- Known active bacterial, viral, fungal, mycobacterial infection or other infection, excluding fungal infection of nail beds
Exclusions Related to Medications
- Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the baseline visit
- Treatment with any investigational agent within 24 weeks of screening (Visit 1) or five half-lives of the investigational drug (whichever is longer) or treatment with any experimental procedures for MS
- Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stable dose for >= 30 days prior to screening. Wherever possible, patients should remain on stable doses throughout the 96-week treatment period.
- Contraindications to or intolerance of oral or IV corticosteroids, according to the country label, including a) Psychosis not yet controlled by a treatment; b) Hypersensitivity to any of the constituents
- Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab)
- Systemic corticosteroid therapy within 4 weeks prior to screening
- Any previous treatment with alemtuzumab (Campath/Mabcampath/Lemtrada), cladribine, mitoxantrone, daclizumab, laquinimod, total body irradiation, or bone marrow transplantation
- Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine or methotrexate
- Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stable dose for >= 30 days prior to screening. Wherever possible, patients should remain on stable doses throughout the 96-week treatment period.
- Previous treatment with natalizumab unless natalizumab was discontinued because of persistent anti-natalizumab antibodies
- Treatment with IV immunoglobulin (Ig) within 12 weeks prior to baseline
- Any previous treatment with an investigational MS DMT not yet approved at time of screening
Exclusions Related to Laboratory Findings
- Positive serum β human chorionic gonadotropin (hCG) measured at screening
- Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, or positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA polymerase chain reaction [PCR]) or hepatitis C (HepCAb)
- Lymphocyte count below lower limit of normal (LLN)
- CD4 count<250/mcL
- Aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT) /serum glutamic pyruvic transaminase (SGPT)=> 3.0 × the upper limit of normal (ULN)
- Platelet count <100,000/µL (<100 × 109/L)
- Absolute neutrophil count <1.0 × 103/mcL |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Proportion of patients who have no evidence of disease activity (NEDA), as per protocol defined events over 96-weeks (with MRI baseline at Week 8) |
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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. Proportions of patients free from a protocol-defined event of disease activity during a 24-week period and a 48-week period
2. Time to first protocol-defined event of disease activity
3. Change in EDSS from Baseline to Week 96
4. Proportion of patients who, over a 96-week period, have CDI, CDP or stable disability
5. Annualized rate of protocol-defined relapses at Week 96
6. Time to onset of first protocol-defined relapse
7. Time to onset of 24 weeks CDP
8. Time to onset of first new and/or enlarging T2 lesion
9. Total number of T1 Gd-enhanced lesions detected by brain MRI at Weeks 24, 48 and 96
10. Change in total T2 lesion volume detected by brain MRI from Baseline to Weeks 96
11. Change in T1 hypointense volume from Baseline to Weeks 48 and 96
12. Change in brain volume from baseline measured at Weeks 24, 48 and 96
13. Volume and number of new and/or enlarging T2 hyperintense lesions from baseline to Weeks 24, 48 and 96
14. hange from Baseline in cognitive performance at Week 48 and Week 96 as measured by the BICAMS
15. Incidence of adverse events
16. 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. at Weeks 24 and 48
2. Up to 96 weeks
3. Baseline and Week 96
4. Up to 96 weeks
5. at Week 96
6-8. Up to 96 weeks
9. at Weeks 24, 48 and 96
10. Baseline and 96
11. Baseline, Weeks 48, and 96
12-13. Baseline, Weeks 24, 48, and 96
14. Baseline, Weeks 48, and 96
15-16. Up to Week 192 |
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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 | No |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 220 |
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 |
Belgium |
Czech Republic |
Denmark |
Estonia |
Finland |
France |
Germany |
Greece |
Ireland |
Italy |
Netherlands |
Norway |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
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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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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 | |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |