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Completed

NCT Number: NCT04261790

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

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.

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Key information

Conditions

Multiple Sclerosis, Relapsing-Remitting Autoimmune Diseases Autoimmune Diseases of the Nervous System Demyelinating Autoimmune Diseases, CNS Demyelinating Diseases Immune System Diseases Multiple Sclerosis Nervous System Diseases

Age range

18 year–99 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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.

Other names: Ocrevus

Primary outcomes

  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 outcomes

  1. Patients With Return of Disease Activity

    Time frame: Up to 30 months

    Patients with the 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: Screening visit and month 30 visit

    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 Fatigue T-score

    Time frame: Screening visit and month 30 visit

    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

Sponsors and collaborators

Lead sponsor

Johns Hopkins University

Other

Collaborators

  • Genentech, Inc.

Registry information

Official study title

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

Important dates

Study start
2020
Primary completion
2024
Study completion
2024
First posted
Feb 10, 2020
Registry last updated
Feb 17, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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