Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

Official title:

Evaluating the Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04261790
• Other study ID #: IRB00230800
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: August 1, 2020
• Est. completion date: July 1, 2025

Study information

• Verified date: December 2023
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 10
• Est. completion date: July 1, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

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.

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Johns Hopkins University	Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Baseline and 18-24 months
Primary	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.	Baseline and 18-24 months
Primary	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.	Baseline and 18-24 months
Primary	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.	Baseline and 18-24 months
Primary	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	Baseline and 18-24 months
Secondary	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.	Up to 30 months
Secondary	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.	Every 6 months, up to 30 months
Secondary	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	Every 6 months, up to 30 months