Mechanistic Studies of Teriflunomide in RRMS

NCT ID: NCT03464448

Last Updated: 2022-12-27

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

COMPLETED

Total Enrollment

30 participants

Study Classification

OBSERVATIONAL

Study Start Date

2018-04-17

Study Completion Date

2021-10-13

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

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

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Relapsing Remitting Multiple Sclerosis

Keywords

Explore important study keywords that can help with search, categorization, and topic discovery.

Teriflunomide B cell T cell cytokines

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

1

Patients with RRMS who have been newly prescribed Teriflunomide.

Teriflunomide

Intervention Type DRUG

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.

2

Healthy Controls

No interventions assigned to this group

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

Teriflunomide

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.

Intervention Type DRUG

Other Intervention Names

Discover alternative or legacy names that may be used to describe the listed interventions across different sources.

Aubagio

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

Inclusion Criteria

1. 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.
2. Ability to give informed consent
3. Willing to have blood drawn as scheduled in the protocol
4. Willing and able to complete all procedures and evaluations related to the study

Exclusion Criteria

1. Medical or psychiatric conditions that may affect the patient's ability to give informed consent
2. Has received an experimental drug within 30 days of enrollment
3. 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
4. Has any contraindication to high-dose immunotherapy, including pregnancy, trying to become pregnant, or breast feeding during the study.
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

Meet the organizations funding or collaborating on the study and learn about their roles.

University of Michigan

OTHER

Sponsor Role lead

Responsible Party

Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.

Yang Mao-Draayer

Professor of Neurology

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

Learn about the lead researchers overseeing the trial and their institutional affiliations.

Yang Mao-Draayer, MD/PHD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

Explore where the study is taking place and check the recruitment status at each participating site.

University of Michigan

Ann Arbor, Michigan, United States

Site Status

Countries

Review the countries where the study has at least one active or historical site.

United States

References

Explore related publications, articles, or registry entries linked to this study.

Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006 Oct 5;52(1):61-76. doi: 10.1016/j.neuron.2006.09.011.

Reference Type BACKGROUND
PMID: 17015227 (View on PubMed)

Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci. 2008;31:247-69. doi: 10.1146/annurev.neuro.30.051606.094313.

Reference Type BACKGROUND
PMID: 18558855 (View on PubMed)

Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014 Apr;74(6):659-74. doi: 10.1007/s40265-014-0212-x.

Reference Type BACKGROUND
PMID: 24740824 (View on PubMed)

Lundy SK, Wu Q, Wang Q, Dowling CA, Taitano SH, Mao G, Mao-Draayer Y. Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets. Neurol Neuroimmunol Neuroinflamm. 2016 Mar 3;3(2):e211. doi: 10.1212/NXI.0000000000000211. eCollection 2016 Apr.

Reference Type BACKGROUND
PMID: 27006972 (View on PubMed)

Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS: teriflunomide. Clin Immunol. 2012 Jan;142(1):49-56. doi: 10.1016/j.clim.2011.02.011. Epub 2011 Mar 1.

Reference Type BACKGROUND
PMID: 21367665 (View on PubMed)

Baban B, Liu JY, Mozaffari MS. Aryl hydrocarbon receptor agonist, leflunomide, protects the ischemic-reperfused kidney: role of Tregs and stem cells. Am J Physiol Regul Integr Comp Physiol. 2012 Dec;303(11):R1136-46. doi: 10.1152/ajpregu.00315.2012. Epub 2012 Oct 24.

Reference Type BACKGROUND
PMID: 23100028 (View on PubMed)

Korn T, Magnus T, Toyka K, Jung S. Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide--mechanisms independent of pyrimidine depletion. J Leukoc Biol. 2004 Nov;76(5):950-60. doi: 10.1189/jlb.0504308. Epub 2004 Aug 24.

Reference Type BACKGROUND
PMID: 15328336 (View on PubMed)

Weigmann B, Jarman ER, Sudowe S, Bros M, Knop J, Reske-Kunz AB. Induction of regulatory T cells by leflunomide in a murine model of contact allergen sensitivity. J Invest Dermatol. 2006 Jul;126(7):1524-33. doi: 10.1038/sj.jid.5700228. Epub 2006 Mar 16.

Reference Type BACKGROUND
PMID: 16543898 (View on PubMed)

Carter NA, Rosser EC, Mauri C. Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis. Arthritis Res Ther. 2012 Feb 8;14(1):R32. doi: 10.1186/ar3736.

Reference Type BACKGROUND
PMID: 22315945 (View on PubMed)

Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, Mauri C. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013 Feb 20;5(173):173ra23. doi: 10.1126/scitranslmed.3005407.

Reference Type BACKGROUND
PMID: 23427243 (View on PubMed)

Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, Szabolcs PM, Bernstein SH, Magro CM, Williams AD, Hall RP, St Clair EW, Tedder TF. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011 Jan 13;117(2):530-41. doi: 10.1182/blood-2010-07-294249. Epub 2010 Oct 20.

Reference Type BACKGROUND
PMID: 20962324 (View on PubMed)

Mann MK, Maresz K, Shriver LP, Tan Y, Dittel BN. B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J Immunol. 2007 Mar 15;178(6):3447-56. doi: 10.4049/jimmunol.178.6.3447.

Reference Type BACKGROUND
PMID: 17339439 (View on PubMed)

Matsushita T, Horikawa M, Iwata Y, Tedder TF. Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis. J Immunol. 2010 Aug 15;185(4):2240-52. doi: 10.4049/jimmunol.1001307. Epub 2010 Jul 12.

Reference Type BACKGROUND
PMID: 20624940 (View on PubMed)

Ray A, Basu S, Williams CB, Salzman NH, Dittel BN. A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J Immunol. 2012 Apr 1;188(7):3188-98. doi: 10.4049/jimmunol.1103354. Epub 2012 Feb 24.

Reference Type BACKGROUND
PMID: 22368274 (View on PubMed)

Klinker MW, Lundy SK. Multiple mechanisms of immune suppression by B lymphocytes. Mol Med. 2012 Feb 10;18(1):123-37. doi: 10.2119/molmed.2011.00333.

Reference Type BACKGROUND
PMID: 22033729 (View on PubMed)

Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2006 Nov;180(1-2):63-70. doi: 10.1016/j.jneuroim.2006.06.029. Epub 2006 Aug 14.

Reference Type BACKGROUND
PMID: 16904756 (View on PubMed)

Other Identifiers

Review additional registry numbers or institutional identifiers associated with this trial.

HUM00136966

Identifier Type: -

Identifier Source: org_study_id