Short-term B-cell Depletion in Relapsing Multiple Sclerosis

NCT03853746 | Completed Phase 4 Results FDA Drug

• 1 other identifier: IRB00201318
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Several disease-modifying therapies (DMTs) have been shown to be effective in reducing the disease activity in patients with relapsing forms of multiple sclerosis (MS) but these treatments, often need to be used continuously for an unknown duration, rendering the long-term use extremely expensive. In addition, chronic administration of DMTs is often associated with undesirable side effects. Among these medications, B-cell depleting monoclonal antibodies might have the properties of an ideal group of medications: i) B-cell depleting antibodies have proven to be extremely potent in reducing or stopping the disease activity in relapsing MS, ii) B-cell depleting antibodies are very safe if used for a short period and use for a short duration may stop the inflammatory disease activity over long term, although current clinical practice and protocols are based on continuing B-cell depletion for an unknown period of time. Indeed, early phase clinical trials of rituximab and ocrelizumab suggested that a short course treatment with B-cell depleting antibodies can have long term effects and disease activity will not return even long after B-cell repopulation in the blood. This long-term effect might be related to the specific pattern of B-cell tolerance defect in patients with MS and the potential of its normalization with B-cell depleting antibodies. 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 B-cell depleting antibodies in MS may be linked to the B-cell depleting antibodies' normal central B-cell tolerance and the production of a normal B-cell and T-cell compartment after anti-B-cell therapy. The investigators' goal is to provide proof-of-concept that a short duration of treatment with B-cell depleting antibodies can correct B-cell tolerance defects in MS and allow for medication-free prolonged freedom from disease activity, at least in a proportion of subjects with relapsing MS. In an open label study, 10 patients with active 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. Time to the return of disease activity (defined as clinical relapses or new or enhancing lesions on the MRI) will be the primary outcome of the study. The investigators will harvest B-cells before starting the treatment and after B-cell repopulation and assess the central and peripheral tolerance defects. The investigators hypothesize that in most participants, the disease activity will not come back, and this prolonged response to anti cluster of differentiation 20 (CD-20) therapy is associated with normalization of B-cell tolerance defect in these patients. Considering the safety of this approach, it can be adopted widely among people with MS. Hence, the proposed B-cell analyses before and after B-cell depletion in people with MS will provide novel insights regarding the mechanisms underlying the beneficial effect of B-cell depleting antibodies and the potential long-term suppression of disease activity. This strategy can therefore improve the approach to treatment of many people with relapsing MS.

Conditions

Multiple Sclerosis

Outcome Measures

Primary Outcomes (1)

• Number of Patients With a Return of Disease Activity After the Third Month Post-first-infusion

  Number of patients with a 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.

  27 months

Secondary Outcomes (2)

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

  Every 6 months, up to 30 months

• Change in a Quality of Life Measure as Assessed by Neuro-QoL Computer Adaptive Test (CAT) Fatigue Test

  Every 6 months, up to 30 months

Study Arms (1)

Ocrelizumab

EXPERIMENTAL

All participants will receive Ocrelizumab

Drug: Ocrelizumab

Interventions

Ocrelizumab DRUG

Patient 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 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:

• Age 18 years and older.
• Diagnosis of relapsing-remitting multiple sclerosis (RRMS) based on revised McDonald criteria
• At least two Gd-enhancing lesions on the brain or spinal cord MRI done in the prior three months
• Naïve to disease modifying therapies or using an injectable therapy (interferons or glatiramer acetate); or, if history of receiving natalizumab, fingolimod, dimethyl fumarate and teriflunomide, no exposure for past three months
• Expanded Disability Status Scale (EDSS) score at the time of screening =\<3

You may not qualify if:

• Contraindication to treatment with B-cell depleting antibodies, including being seropositive for HBsAg or HIV antibody or T-spot (or Quantiferon-Gold) positive
• Ever received B-cell depleting antibodies (rituximab, ocrelizumab, ofatumumab), alemtuzumab, daclizumab, mitoxantrone or hematopoietic stem-cell transplant
• Female who are pregnant, nursing or unwilling to use contraception up to six months after the second course of the infusion (or 12 months after the first infusion)
• Treatment with steroids in the past 30 days
• Clinically unstable medical or psychiatric disorders at the time of screening that require acute treatment as determined by the PI

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Multiple Sclerosis Society: 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

Interventions

ocrelizumab

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Bardia Nourbakhsh
• Organization: Johns Hopkins Universtiy

bnourba1@jhmi.edu

410-614-1522

Study Officials

• Bardia Nourbakhsh, MD, MAS

  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 22, 2019
• First Posted: February 26, 2019
• Study Start: April 1, 2019
• Primary Completion: March 1, 2024
• Study Completion: July 1, 2024
• Last Updated: February 5, 2025
• Results First Posted: February 5, 2025

Record last verified: 2025-02

Locations

US (1)