Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis
Primary Purpose
Multiple Sclerosis, Relapsing-Remitting
Status
Active
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Ocrelizumab
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Sclerosis, Relapsing-Remitting
Eligibility 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
Sites / Locations
- Johns Hopkins University
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Ocrelizumab
Arm Description
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.
Outcomes
Primary Outcome Measures
Change in peripheral B-cell tolerance checkpoints in people with MS before and after ocrelizumab therapy.
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
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
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
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
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
Time to return of disease activity
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)
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
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
Full Information
NCT ID
NCT04261790
First Posted
February 6, 2020
Last Updated
September 7, 2023
Sponsor
Johns Hopkins University
Collaborators
Genentech, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT04261790
Brief Title
Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis
Official Title
Evaluating the Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 1, 2020 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
July 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins University
Collaborators
Genentech, Inc.
4. Oversight
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
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis, Relapsing-Remitting
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Ocrelizumab
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ocrelizumab
Other Intervention Name(s)
Ocrevus
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in peripheral B-cell tolerance checkpoints in people with MS before and after ocrelizumab therapy.
Description
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.
Time Frame
Baseline and 18-24 months
Title
Change in B-cell subpopulations
Description
Change in the frequency (percentage) of different B-cell subpopulation (assessed by flow cytometry) before and after treatment with ocrelizumab.
Time Frame
Baseline and 18-24 months
Title
Change in frequency of T-cell phenotypes
Description
Change in the frequency (percentage) of different T-cells subpopulation (assessed by flow cytometry) before and after treatment with ocrelizumab.
Time Frame
Baseline and 18-24 months
Title
Change in the production of pro inflammatory cytokines produced by activated T-cells
Description
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.
Time Frame
Baseline and 18-24 months
Title
Change in the production of anti-inflammatory cytokines produced by activated T-cells
Description
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 Frame
Baseline and 18-24 months
Secondary Outcome Measure Information:
Title
Time to return of disease activity
Description
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.
Time Frame
Up to 30 months
Title
Change in disability as assessed by Expanded Disability Status Scale (EDSS)
Description
EDSS scores range from 0 to 10, with 0.5 steps. The higher the score, the worse the MS-related disability.
Time Frame
Every 6 months, up to 30 months
Title
Change in quality of life as assessed by Neuro-QoL
Description
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
Time Frame
Every 6 months, up to 30 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bardia Nourbakhsh
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis
We'll reach out to this number within 24 hrs