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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
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Johns Hopkins University

Brief Summary:

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

Drug Information available for: Ocrelizumab

Arm Intervention/treatment
Ocrelizumab
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.
Drug: Ocrelizumab
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




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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



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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of relapsing remitting multiple sclerosis (RRMS) based on revised McDonald criteria
  • At least one Gd-enhancing lesions on the brain or spinal cord MRI done in the prior three months OR at least one new T2/FLAIR lesion on the brain or spinal cord MRI done in the prior three months (compared to a prior MRI performed within 18 months of the most recent MRI)
  • Naïve to Disease modifying therapy (DMT) or at least off these DMTs (natalizumab, fingolimod, DMF) for three months or on an injectable DMT (interferons or glatiramer acetate)
  • Expanded Disability Status Scale (EDSS) score at the time of screening =<3
  • Negative urine or serum pregnancy test must be available for premenopausal women and for women <12 months after the onset of menopause unless these women have undergone surgical sterilization
  • Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use one method of contraception with a failure rate of <1% per year or a barrier method supplemented with spermicide. Contraception must continue for the duration of study treatment and for at least 24 weeks after the last dose of study treatment

Exclusion Criteria:

  • Contraindication to treatment with an anti- cluster of differentiation antigen 20 (CD20) antibodies, including being seropositive for HBsAg
  • Active hepatitis B virus infection
  • Ever received B-cell depleting antibodies (rituximab, ocrelizumab, ofatumumab), alemtuzumab, daclizumab, mitoxantrone or hematopoietic stem-cell transplant
  • Pregnant or lactating women
  • Hypersensitivity to ocrelizumab
  • Treatment with steroids in the past 30 days

Information from the National Library of Medicine

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


Contacts
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Contact: Andrea Salazar 410-614-1522 rsalaza8@jhmi.edu
Contact: Bardia Nourbakhsh 410-614-1522

Locations
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United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Bardia Nourbakhsh       bnourba1@jhmi.edu   
Sponsors and Collaborators
Johns Hopkins University
Genentech, Inc.
Investigators
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Principal Investigator: Bardia Nourbakhsh Johns Hopkins University
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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT04261790    
Other Study ID Numbers: IRB00230800
First Posted: February 10, 2020    Key Record Dates
Last Update Posted: September 25, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Ocrelizumab
Immunologic Factors
Physiological Effects of Drugs