Assessing Reduced Oligodendrocyte-specific Cytotoxicity of Peripheral Blood Leukocytes in Patients With Multiple Sclerosis Following Treatment With Ofatumumab
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Assessment of oligodendrocyte death and mitochondrial dysfunction comparing supernatant samples from patients after 6 months treatment (M06) to pre-treatment, drug naïve supernatants (M00) and to supernatants collected from healthy control subjects
研究概览
简要总结
In this study the investigators wish to test the hypothesis that the repertoire of solutes secreted by leukocytes isolated from patients with relapsing-remitting forms of Multiple Sclerosis (MS) following 6 months of treatment with Ofatumumab (Kesimpta®) will be less toxic to mouse-derived oligodendrocyte lineage cells, grown in a dish, than solutes secreted by the same leukocyte populations prior to treatment with Ofatumumab.
详细描述
Background and Rationale:
The role of B-cells in multiple sclerosis (MS) pathogenesis is still not fully understood, however studies have shown that: 1) intrathecal synthesis of immunoglobulin can be detected in the cerebral spinal fluid of >90% of MS patients; 2) there are multiple clonally expanded B-cell populations in chronic MS brain lesions; 3) ectopic lymphoid follicles containing proliferating B-cells have been identified within the meninges of secondary progressive MS patients; and 4) anti-B cell depleting therapies have been shown to have clinical benefit in MS. In addition to these findings B-cells have been shown to:
- Secrete autoantibodies.
- Serve as antigen-presenting cells.
- Facilitate T-cell activation.
- Contribute to the micro-environment by local secretion of immune mediators such as cytokines and chemokines.
It is important that investigators not only understand the clinical effects of B-cell depletion, but also, critically, that investigators understand the ongoing mechanisms of action following treatment with Ofatumumab. Specifically, how the remaining pathogenic leukocyte populations, such as T-cells, monocytes, neutrophils and natural killer (NK) cells are modulated indirectly by Ofatumumab such that they may be less pathogenic to the myelinating oligodendrocyte population.
Ofatumumab is an anti-CD20 human monoclonal antibody that has demonstrated efficacy in lowering relapse rates, magnetic resonance Imaging (MRI) activity and neurofilament light (NF-L) levels, as well as significant reductions in confirmed disability worsening in patients with relapsing forms MS.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •RR-MS patients only:
- •This investigator-initiated study/trial (IIT) will be carried out secondary to the discussion of treatment with Ofatumumab and thus our study will not influence or impact the determination of the suitability for candidates to commence therapy with Ofatumumab. This decision will be made by the patient's physician as part of the patient's standard care, and will occur independently of this study. Patients to be enrolled in this longitudinal study will only be asked if they would like to take part in this IIT if their clinician independently chooses Ofatumumab as a treatment option:
- •Patients must qualify to receive treatment with Ofatumumab (Kesimpta), according to the Multiple Sclerosis Comprehensive Care Center at USC Keck School of Medicine or LAC+USC Medical Center and meet the inclusion criteria defined in, and aligned with, the US Kesimpta (Ofatumumab) Prescribing Information.
- •Patients must have clinically definite Multiple Sclerosis as defined by the revised McDonald criteria of the relapsing-remitting form with an Expanded Disability Status Scale (EDSS) score of 0 to 5.
- •Patients must be treatment naive to Ofatumumab (Kesimpta)
- •Patients must have the ability to understand and sign this study-specific IRB-approved informed consent form.
- •Patients must be willing to donate ~80ml of blood each for M00 and M06 that will be used for testing the specific aims described in this proposal.
- •Patients must have a lymphocyte count within the normal range at baseline (3.8-10.8 x1,000/ml)
- •Healthy Control Subjects only:
- •Patients must not have clinically definite Multiple Sclerosis as defined by the revised McDonald criteria, any other autoimmune disease, demyelinating co-morbidity, neurological disease or immune system altering disease (e.g. HIV).
- •Patients must have the ability to understand and sign this study-specific IRB-approved informed consent form.
- •Patients must be willing to donate ~80ml of blood at one time only that will be used for testing the specific aims described in this proposal.
- •Patients must have a lymphocyte count within the normal range at baseline (3.8-10.8 x1,000/ml).
排除标准
- •RR-MS patients only:
- •Treatment with any of the following within 90 days of commencing treatment with Ofatumumab: teriflunomide (Aubagio®), IV immunoglobulin or plasmapheresis.
- •Previous treatment with natalizumab (Tysabri®) within 30 days of commencing treatment with Ofatumumab.
- •Documented relapse within 30 days prior to baseline.
- •Systemic corticosteroid therapy within 4 weeks prior to baseline.
- •Prior treatment with Mitoxantrone, Cyclophosphamide, Cyclosporine, Azathioprine or Methotrexate or any other immunosuppressant, or total body irradiation or bone marrow transplantation.
- •Prior treatment with a B-cell targeted therapies (e.g., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab).
- •Prior treatment with alemtuzumab (Lemtrada®).
- •Current supplemental treatment with high dose biotin.
- •Women who are pregnant, lactating, breast feeding or of childbearing age who do not consent to approved contraceptive use during the study.
- •Prior or current treatment with a drug that is experimental
- •Meet any of the exclusion criteria defined in, and aligned with, the US Kesimpta/Ofatumumab Prescribing Information.
- •Healthy Control Subjects:
- •Treatment with any FDA-approved drug or experimental drug for any condition.
- •Systemic corticosteroid therapy within 4 weeks prior to blood collection.
- •Women who are pregnant, lactating, or could be pregnant.
研究组 & 干预措施
Healthy Control Subjects
Enrolled subjects must not have clinically definite Multiple Sclerosis as defined by the revised McDonald criteria, any other autoimmune disease, demyelinating co-morbidity, neurological disease or immune system altering disease.
Relapsing-remitting Multiple Sclerosis
Enrolled subjects in this group will have clinically definite Multiple Sclerosis as defined by the revised McDonald criteria of the relapsing-remitting form with an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 and will be treated with Ofatumumab.
干预措施: Ofatumumab (Drug)
结局指标
主要结局
Assessment of oligodendrocyte death and mitochondrial dysfunction comparing supernatant samples from patients after 6 months treatment (M06) to pre-treatment, drug naïve supernatants (M00) and to supernatants collected from healthy control subjects
时间窗: 27 months
To determine if solutes secreted by T cells, monocytes, neutrophils or NK cells isolated from patients with relapsing-remitting forms of MS following 6 months (M06) of treatment with Ofatumumab are less toxic to mouse-derived oligodendrocytes and their progeny (OPC) than solutes secreted by the same sub-populations of leukocytes collected prior to treatment (M00 drug naive), and how this compares to samples from healthy control subjects.
次要结局
- Identify factor(s) associated with oligodendrocyte and OPC stress/death(27 months)
研究者
Brett T. Lund
Associate Professor of Research
University of Southern California