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 | 21.1 |
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 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), change from baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) at week 120, annual rate of percent change from baseline in total brain volume, time to 12 week confirmed 4 point worsening in Symbol Digit Modalities 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 BN42082 (RMS) Trials, Phase IIIb Multicenter, Randomized, Double-Blind, Controlled Studies to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults with Relapsing Multiple Sclerosis
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 |
• Ages 18-55 years at time of screening
• Ability to comply with the study protocol
• Diagnosis of RMS (i.e., RRMS or aSPMS where patients still experience relapses) in accordance with the revised McDonald Criteria 2017
• At least two documented clinical relapses within the last 2 years prior to screening, or one clinical relapse in the year prior to screening (with no relapse 30 days prior to screening and at baseline)
• Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments
• Expanded disability status scale (EDSS) score, at screening and baseline, from 0 to 5.5 inclusive
• Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds
• Average 9HPT score over four trials at screening and over four trials at baseline respectively, up to 250 (inclusive) seconds
• Documented MRI of brain with abnormalities consistent with MS at screening
• Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization
• For females of childbearing potential, agreement to remain abstinent or use adequate contraceptive method.
• 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. |
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E.4 | Principal exclusion criteria |
• History of primary 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, including uncontrolled psychosis for corticosteroids or closed angle glaucoma for antihistamines
• Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study
• Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
• Significant, uncontrolled disease that may preclude patient from participating in the study
• History of or currently active primary or secondary (non-drug related) immunodeficiency
• Pregnant or breastfeeding or intending to become pregnant
• 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 or five-half-lives of the investigational drug (whichever is longer) , or treatment with any experimental procedure for MS
• Previous use of anti-CD20s (including ocrelizumab), unless the last infusion was moreif in thanthe last 2 years before screening, or if B-cell count is not normal, andor if the stop of the treatment was not motivated by safety reasons or lack of efficacy
• Any previous treatment with mitoxantrone, cladribine, atacicept, and alemtuzumab
• Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline
• Previous treatment with natalizumab within 4.5 months of baseline
• Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline
• Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label (washout to be completed prior to baseline). 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 of previous history 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, measured by time to onset of cCDP sustained for at least 12 weeks. Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression even measured by EDSS, T25FWT or 9-HPT |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.From Baseline up to 4.3 years (Double blind treatment [DBT]) |
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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. Change from baseline in the Multiple Sclerosis Impact Scale 29 (MSIS29) physical scale at Week 120
7. Annual rate of percent change from baseline in total brain volume
8. Time to 12 week confirmed 4 point worsening in Symbol Digit Modalities test (SDMT)
9. Serum concentration of ocrelizumab at specified timepoints
10. Change in B cell levels in blood
11. Proportion of participant achieving 5 or less B-cells per microliter of blood
12. Proportion of participants achieving 5 or less B-cells per microliter of blood in participants with the high versus low affinity Fcgamma Receptor 3A (FcgR3A) genotype per arm
13. Change from Baseline in the anti-drug antibodies (ADAs) levels
14. Levels of Neurofilament Light Chain (NfL) in blood
15. Levels of interleukin-6 (IL-6) in blood
16. Levels of blood B cells
17. Levels of Lymphocytes in blood
18. Proportion of participants with different DNA genotypes |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. Baseline up to approximately 4.3 years
6. Baseline to Week 120
7-8. Baseline up to approximately 4.3 years
9. : Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
10-11: Baseline up to approximately 4.3 years
12. : Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
13. Week 0, 24, 48, 72, 96, 120
14-17 Baseline up to approximately 4.3 years
18. Week 0, 2, 12, 24, 48, 72, 96, 120 |
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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.8.2 | 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 | 76 |
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 |
Australia |
Brazil |
Canada |
Israel |
Mexico |
New Zealand |
Peru |
Russian Federation |
Turkey |
Ukraine |
United States |
Belgium |
Czechia |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Poland |
Portugal |
United Kingdom |
Netherlands |
Spain |
Switzerland |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | |
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 | 4 |