Clinical trial NCT04261790: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Multiple Sclerosis, Relapsing-Remitting
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2020-02-10
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Change in Peripheral B-cell Tolerance Checkpoints in People With MS Before and After Ocrelizumab Therapy.
timeFrame: Baseline and 18-24 months
measure: Change in B-cell Subpopulations
timeFrame: Baseline and 18-24 months
measure: Change in Frequency of T-cell Phenotypes
timeFrame: Baseline and 18-24 months
measure: Change in the Production of Pro Inflammatory Cytokines Produced by Activated T-cells
timeFrame: Baseline and 18-24 months
measure: Change in the Production of Anti-inflammatory Cytokines Produced by Activated T-cells
timeFrame: Baseline and 18-24 months
Secondary outcomes:
measure: Patients With Return of Disease Activity
timeFrame: Up to 30 months
measure: Change in Disability as Assessed by Expanded Disability Status Scale (EDSS)
timeFrame: Screening visit and month 30 visit
measure: Change in Quality of Life as Assessed by Neuro-QoL Fatigue T-score
timeFrame: Screening visit and month 30 visit
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Bardia Nourbakhsh
role: PRINCIPAL_INVESTIGATOR
References: