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

NCT04261790 | Completed Phase 4 Results FDA Drug

• 1 other identifier: IRB00230800
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Sclerosis, Relapsing-Remitting

Outcome Measures

Primary Outcomes (5)

• 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

• 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

• 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

• 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

• 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 Outcomes (3)

• Patients With Return of Disease Activity

  Up to 30 months

• Change in Disability as Assessed by Expanded Disability Status Scale (EDSS)

  Screening visit and month 30 visit

• Change in Quality of Life as Assessed by Neuro-QoL Fatigue T-score

  Screening visit and month 30 visit

Study Arms (1)

Ocrelizumab

OTHER

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

Interventions

Ocrelizumab DRUG

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.

Also known as: Ocrevus

Ocrelizumab

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• Genentech, Inc.: collaborator

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Related Publications (1)

• Salazar-Camelo A, Vega L, Fadlallah Y, Bou Rjeily N, Balshi A, Morris B, Ghajarzadeh M, Mowry EM, Waubant E, Nourbakhsh B. Finite-course ocrelizumab in relapsing multiple sclerosis: Results of two prospective open-label trials with matched controls. Mult Scler. 2025 Oct;31(11):1338-1347. doi: 10.1177/13524585251375350. Epub 2025 Sep 19.

  PMID: 40970353 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

ocrelizumab

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Limitations and Caveats

The primary outcome measure was based on lab results; however, none of the antibodies from the immune cells were able to cloned for analysis, none of the lab samples from any participants could be analyzed, and consequently, no data for the primary outcome were generated. The study was considered completed as all participant data collection was conducted per the protocol. The failure of lab analysis affected only the primary outcome, the overall completion status is complete.

Results Point of Contact

• Title: Bardia Nourbakhsh
• Organization: Johns Hopkins Universtiy

bnourba1@jhmi.edu

410-614-1522

Study Officials

• Bardia Nourbakhsh

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2020
• First Posted: February 10, 2020
• Study Start: August 1, 2020
• Primary Completion: October 31, 2024
• Study Completion: November 1, 2024
• Last Updated: February 17, 2025
• Results First Posted: February 17, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)