Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis
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|ClinicalTrials.gov Identifier: NCT04261790|
Recruitment Status : Recruiting
First Posted : February 10, 2020
Last Update Posted : September 25, 2020
B-cells have an important role in the pathogenesis of multiple sclerosis (MS). Ocrelizumab, a medication that targets B-cells have been found to be highly effective in stopping the disease activity in relapsing-remitting MS.
The efficacy of ocrelizumab might be related to the specific pattern of B-cell tolerance defect in patients with MS and the potential of its normalization with treatment with ocrelizumab. By analyzing the reactivity of recombinant antibodies expressed from single B-cells, the investigators' collaborators have demonstrated that the pattern of B-cell tolerance defect is different in people with MS who only display an impaired removal of developing autoreactive B-cells in the periphery while central B-cell tolerance in the bone marrow is functional in most patients. In contrast, patients with rheumatoid arthritis (RA), type-1 diabetes (T1D) or Sjögren's syndrome (SS) show defective central and peripheral B-cell tolerance checkpoints. As a consequence, while anti-B-cell therapy does not correct defective early B-cell tolerance checkpoints in T1D and only temporarily slows down autoimmune processes before newly generated autoreactive B-cells likely induce patient relapse, the investigators postulate that the efficacy of ocrelizumab in MS may be linked to normal central B-cell tolerance and the production of a normal B-cell and T-cell compartment after ocrelizumab therapy.
In an open-label study, 10 patients with relapsing MS will be treated with two courses of ocrelizumab and will be followed clinically and radiologically for at least two and a half years. Assessment of T and B-cell phenotypes and function at baseline and 18-24 months post-B-cell depletion will be the primary outcome of the study.
|Condition or disease||Intervention/treatment||Phase|
|Multiple Sclerosis, Relapsing-Remitting||Drug: Ocrelizumab||Phase 4|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Evaluating the Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis|
|Actual Study Start Date :||August 1, 2020|
|Estimated Primary Completion Date :||September 1, 2023|
|Estimated Study Completion Date :||March 1, 2024|
Patients will be treated with two courses of ocrelizumab (Ocrevus) for one year and then will stop the medication and will be monitored for the return of the disease activity. Those who experience the return of the disease activity can go back on the medication.
Patients will be treated with two courses of ocrelizumab (Ocrevus) 600mg/course, for one year and then will stop the medication and will be monitored for the return of the disease activity. Those who experience the return of the disease activity can go back on the medication.
Other Name: Ocrevus
- Change in peripheral B-cell tolerance checkpoints in people with MS before and after ocrelizumab therapy. [ Time Frame: Baseline and 18-24 months ]By assessing the antibodies produced by isolated B-cells, changes in the frequencies (percentage) of polyreactive, and anti-nuclear clones of new emigrant/transitional and mature naive B-cells will be determined.
- Change in B-cell subpopulations [ Time Frame: Baseline and 18-24 months ]Change in the frequency (percentage) of different B-cell subpopulation (assessed by flow cytometry) before and after treatment with ocrelizumab.
- Change in frequency of T-cell phenotypes [ Time Frame: Baseline and 18-24 months ]Change in the frequency (percentage) of different T-cells subpopulation (assessed by flow cytometry) before and after treatment with ocrelizumab.
- Change in the production of pro inflammatory cytokines produced by activated T-cells [ Time Frame: Baseline and 18-24 months ]Pro inflammatory cytokines, produced by Tregs and other T cell subsets after activating peripheral blood mononucleated cell with phorbol-12-myristate-13-acetate (PMA) and ionomycin will be measured by enzyme-linked immunosorbent assay.
- Change in the production of anti-inflammatory cytokines produced by activated T-cells [ Time Frame: Baseline and 18-24 months ]Anti-inflammatory cytokines, produced by Tregs and other T cell subsets after activating peripheral blood mononucleated cell with phorbol-12-myristate-13-acetate (PMA) and ionomycin will be measured by enzyme-linked immunosorbent assay
- Time to return of disease activity [ Time Frame: Up to 30 months ]Time (months) to return of disease activity after the third month post-first-infusion, objectively demonstrated by development of new T2 hyperintense lesions or Gd-enhancing lesions on the MRI or a clinical relapse that is confirmed with an objective change in the neurological examination.
- Change in disability as assessed by Expanded Disability Status Scale (EDSS) [ Time Frame: Every 6 months, up to 30 months ]EDSS scores range from 0 to 10, with 0.5 steps. The higher the score, the worse the MS-related disability.
- Change in quality of life as assessed by Neuro-QoL [ Time Frame: Every 6 months, up to 30 months ]T-score (standardized scores with a mean of 50 and a standard deviation (SD) of 10). A higher Neuro-QoL T-score represents more of the concept being measured. There is no specific upper or lower limit for this scoring
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04261790
|Contact: Andrea Salazarfirstname.lastname@example.org|
|Contact: Bardia Nourbakhsh||410-614-1522|
|United States, Maryland|
|Johns Hopkins University||Recruiting|
|Baltimore, Maryland, United States, 21287|
|Contact: Bardia Nourbakhsh email@example.com|
|Principal Investigator:||Bardia Nourbakhsh||Johns Hopkins University|