Multiple Sclerosis
Conditions
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.
Interventions
DRUGOcrelizumab
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.
Sponsors
National Multiple Sclerosis Society
Johns Hopkins University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With a Return of Disease Activity After the Third Month Post-first-infusion | 27 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Disability as Assessed by Expanded Disability Status Scale (EDSS) | Every 6 months, up to 30 months | EDSS scores range from 0 to 10, with 0.5 steps. The higher the score, the worse the MS-related disability. Although the outcome was measured every six months, we used a linear mixed-effects model to analyze the data. The coefficient from this model represents the change in the outcome per unit of time (month), allowing for a consistent interpretation of the rate of change. |
| 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 | The CAT produces a T-score (standardized score 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. Here is the change in score from baseline to month 30. Although the outcome was measured every six months, we used a linear mixed-effects model to analyze the data. The coefficient from this model represents the change in the outcome per unit of time (month), allowing for a consistent interpretation of the rate of change. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ocrelizumab All participants will receive Ocrelizumab
Ocrelizumab: 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. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Ocrelizumab |
|---|---|
| Age, Continuous | 29.3 years STANDARD_DEVIATION 9.9 |
| Disease Duration | 2.9 years STANDARD_DEVIATION 4.2 |
| Expanded Diability Status Scale | 2 points |
| Participants Who Received Prior Disease Modifying Therapy Glatiramer | 2 Count |
| Participants Who Received Prior Disease Modifying Therapy No medication | 7 Count |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 6 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
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.
Time frame: 27 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ocrelizumab | Number of Patients With a Return of Disease Activity After the Third Month Post-first-infusion | Participants who experienced a return of disease activity | 3 Participants |
| Ocrelizumab | Number of Patients With a Return of Disease Activity After the Third Month Post-first-infusion | Participants who did not experience a return of disease activity | 6 Participants |
Secondary
Change in a Quality of Life Measure as Assessed by Neuro-QoL Computer Adaptive Test (CAT) Fatigue Test
The CAT produces a T-score (standardized score 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. Here is the change in score from baseline to month 30. Although the outcome was measured every six months, we used a linear mixed-effects model to analyze the data. The coefficient from this model represents the change in the outcome per unit of time (month), allowing for a consistent interpretation of the rate of change.
Time frame: Every 6 months, up to 30 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ocrelizumab | Change in a Quality of Life Measure as Assessed by Neuro-QoL Computer Adaptive Test (CAT) Fatigue Test | -0.012 point chnage per month |
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. Although the outcome was measured every six months, we used a linear mixed-effects model to analyze the data. The coefficient from this model represents the change in the outcome per unit of time (month), allowing for a consistent interpretation of the rate of change.
Time frame: Every 6 months, up to 30 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ocrelizumab | Change in Disability as Assessed by Expanded Disability Status Scale (EDSS) | -0.009 Points change per month |