Mechanistic Studies of Teriflunomide in RRMS

Study Overview
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Brief Summary
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This study is to address the mechanism of action of teriflunomide in a phase IV open label trial with Teriflunomide in multiple sclerosis. Researchers will recruit 20 relapsing remitting multiple sclerosis patients (Group 1) start on treatment with teriflunomide (Aubagio). Patients will be enrolled from the Multiple Sclerosis Center at the University of Michigan Health System in Ann Arbor. Meanwhile, 10 healthy controls will be recruited, to establish a healthy baseline for B and T cells, which are affected by both MS and its treatment (Group 2). This Study will collect baseline pre-treatment blood samples periodically for up to 2 years. Blood biomarker changes will be correlated with clinical response to teriflunomide treatment intervention.

Detailed Description
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Multiple sclerosis is the most common autoimmune inflammatory and debilitating chronic demyelinating disease of the central nervous system mainly affecting young adults. There is a tremendous need to understand the mechanism of action of the treatment and how they might work in multiple sclerosis patients. Most recently, teriflunomide (AubagioTM) has been demonstrated to act as an immune modulatory therapy for patients with multiple sclerosis. Although one biochemical mechanism of action is understood to be related to inhibition of dihydroorotate dehydrogenase (DHODH) which affects synthesis of pyrimidine nucleotides, there have also been reports that the functions of regulatory T cells are promoted by these drugs independent of DHODH. Much accumulating evidence suggests that specialized subsets of B lymphocytes are important inducers of regulatory T cells, as well as having killer functions that may preferentially target TH1 and TH17 cells. This study aims to address the mechanism of action of teriflunomide in a phase IV open label trial with Teriflunomide in multiple sclerosis

Official Title
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Mechanistic Studies of Teriflunomide in Relapsing Remitting Multiple Sclerosis: Regulatory B Lymphocytes as Central Mediators of the Therapeutic Effects of Teriflunomide in MS

Conditions
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Relapsing Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: Teriflunomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with clinically-defined relapsing-remitting MS (RRMS) who  are newly starting on teriflunomide (AubagioTM) at the time of enrollment  have no evidence of relapse or corticosteroid treatment use within 2 months prior to enrollment OR Healthy controls who do not have a significant medical condition such as cancer, chronic infection, or autoimmune disease, have not taken steroids in the past 2 months, and who are not on an immune suppressant medication. Ability to give informed consent Willing to have blood drawn as scheduled in the protocol Willing and able to complete all procedures and evaluations related to the study Exclusion Criteria: Medical or psychiatric conditions that may affect the patient's ability to give informed consent Has received an experimental drug within 30 days of enrollment Concomitant other disease modifying medications (such as Rebif, Betaseron, Avonex, Copaxone, Gilenya, Tecfidera, Alemtuzumab, methotrexate, azathioprine, mitoxantrone, cyclophosphamide, cyclosporine, natalizumab, rituxan, ocrelizumab, etc.) without the minimal washout period stated below:  rebif, betaseron, avonex, copaxone within 1 month  zinbryta, plegridy, gilenya, tecfidera within 2 months  natalizumab within 3 months  immunosuppressive/chemotherapeutic medications (e.g. azathioprine, methotrexate) within 6 months  cyclophosphamide within 1 year  rituximab, ofatumumab, ocrelizumab, cladribine within 1 year  alemtuzumab at any time  any mitoxantrone during previous 2 years prior to randomization or evidence of cardiotoxicity following mitoxantrone or a cumulative life-time dose of more than 60 mg/m2  lymphoid irradiation, bone marrow transplantation or other immunosuppressive treatments with effects potentially lasting over 6 months, at any time Has any contraindication to high-dose immunotherapy, including pregnancy, trying to become pregnant, or breast feeding during the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 1<br>Patients with RRMS who have been newly prescribed Teriflunomide. | Drug: Teriflunomide<br>* AUBAGIO® (teriflunomide) is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS), which inhibits pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase.<br>* Other names: Aubagio;|
| 2<br>Healthy Controls | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in frequency of regulatory and effector B cell subset | Compare aubagio treatment to baseline and to healthy controls | From baseline to 6 months and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in frequency of CD4+ Th17, Th1, Th2, and Treg cells | Compare aubagio treatment to baseline and to healthy controls | From baseline to 6 months and 12 months | 
| Change in chemokine levels | Compare aubagio treatment to baseline and to healthy controls | From baseline to 6 months and 12 months | 
| Change in cytokine levels | Compare aubagio treatment to baseline and to healthy controls | From baseline to 6 months and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Teriflunomide, B cell, T cell, cytokines