Teriflunomide's Therapeutic Mechanisms of Action in Patients With Relapsing Remitting Multiple Sclerosis.

RELAPSING REMITTING MULTIPLE SCLEROSIS Clinical Trial

Official title:

Characterization of Teriflunomide's Therapeutic Mechanisms of Action in Patients With Relapsing Remitting Multiple Sclerosis.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02833714
• Other study ID #: 14-2877
• Status: Terminated
• Phase: N/A
• First received: June 21, 2016
• Last updated: September 14, 2017
• Start date: January 2016
• Est. completion date: December 21, 2016

Study information

• Verified date: September 2017
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of this research is to characterize the effect of teriflunomide on the activation of B-cells, as well as its capacity to modify B-cell cytokine secretion. The in-vitro identified effects of teriflunomide on the expression of B-cell activation markers, costimulatory and antigen presenting molecules, as well as on cytokine secretion, will then be confirmed in a cohort of Relapsing Remitting Multiple Sclerosis (RRMS) patients treated with this medication.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 26
• Est. completion date: December 21, 2016
• Est. primary completion date: December 21, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• confirmed diagnosis of RRMS according to McDonald's diagnostic criteria,

• age 18-55,

• an extended disability status score (EDSS) of 1.5-5.5.

Exclusion Criteria:

• Previous treatment with DMT.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• RELAPSING REMITTING MULTIPLE SCLEROSIS
• Sclerosis

Locations

Country	Name	City	State
United States	University of North Carolina	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	Genzyme, a Sanofi Company

Country where clinical trial is conducted

United States, 

References & Publications (20)

Bar-Or A, Fawaz L, Fan B, Darlington PJ, Rieger A, Ghorayeb C, Calabresi PA, Waubant E, Hauser SL, Zhang J, Smith CH. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Ann Neurol. 2010 Apr;67(4):452-61. doi: 10.1002/ana.21939. — View Citation

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. Review. — View Citation

Dimitrova P, Skapenko A, Herrmann ML, Schleyerbach R, Kalden JR, Schulze-Koops H. Restriction of de novo pyrimidine biosynthesis inhibits Th1 cell activation and promotes Th2 cell differentiation. J Immunol. 2002 Sep 15;169(6):3392-9. — View Citation

Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002 Oct;3(10):944-50. Epub 2002 Sep 3. — View Citation

Fox RI. Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. Review. — View Citation

Freedman MS, Wolinsky JS, Wamil B, Confavreux C, Comi G, Kappos L, Olsson TP, Miller A, Benzerdjeb H, Li H, Simonson C, O'Connor PW; Teriflunomide Multiple Sclerosis Trial Group and the MRI Analysis Center. Teriflunomide added to interferon-ß in relapsing — View Citation

Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH; HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008 Feb 14;358(7 — View Citation

Hirotani M, Niino M, Fukazawa T, Kikuchi S, Yabe I, Hamada S, Tajima Y, Sasaki H. Decreased IL-10 production mediated by Toll-like receptor 9 in B cells in multiple sclerosis. J Neuroimmunol. 2010 Apr 15;221(1-2):95-100. doi: 10.1016/j.jneuroim.2010.02.01 — View Citation

Kim SH, Huh SY, Lee SJ, Joung A, Kim HJ. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 2013 Sep 1;70(9):1110-7. — View Citation

Li L, Liu J, Delohery T, Zhang D, Arendt C, Jones C. The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro. J Neuroimmunol. 2013 Dec 15;265(1-2):82-90. doi: 10.1016/j.jneuroim.2013.10.003. Epub 2013 — View Citation

Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol. 1999 Feb 15;162(4):2095-102. — View Citation

O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, Benzerdjeb H, Truffinet P, Wang L, Miller A, Freedman MS; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011 Oct 6;365(14):1293 — View Citation

Prineas JW, Wright RG. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest. 1978 Apr;38(4):409-21. — View Citation

Ramgolam VS, Sha Y, Marcus KL, Choudhary N, Troiani L, Chopra M, Markovic-Plese S. B cells as a therapeutic target for IFN-ß in relapsing-remitting multiple sclerosis. J Immunol. 2011 Apr 1;186(7):4518-26. doi: 10.4049/jimmunol.1000271. Epub 2011 Mar 2. — View Citation

Sellam J, Rouanet S, Hendel-Chavez H, Abbed K, Sibilia J, Tebib J, Le Loët X, Combe B, Dougados M, Mariette X, Taoufik Y. Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis. Arthritis Rheum. 2011 — View Citation

Serreze DV, Fleming SA, Chapman HD, Richard SD, Leiter EH, Tisch RM. B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Immunol. 1998 Oct 15;161(8):3912-8. — View Citation

Yan J, Harvey BP, Gee RJ, Shlomchik MJ, Mamula MJ. B cells drive early T cell autoimmunity in vivo prior to dendritic cell-mediated autoantigen presentation. J Immunol. 2006 Oct 1;177(7):4481-7. — View Citation

Zhang X, Tao Y, Chopra M, Ahn M, Marcus KL, Choudhary N, Zhu H, Markovic-Plese S. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multi — View Citation

Zhang X, Tao Y, Troiani L, Markovic-Plese S. Simvastatin inhibits IFN regulatory factor 4 expression and Th17 cell differentiation in CD4+ T cells derived from patients with multiple sclerosis. J Immunol. 2011 Sep 15;187(6):3431-7. doi: 10.4049/jimmunol.1 — View Citation

Zhong X, Gao W, Degauque N, Bai C, Lu Y, Kenny J, Oukka M, Strom TB, Rothstein TL. Reciprocal generation of Th1/Th17 and T(reg) cells by B1 and B2 B cells. Eur J Immunol. 2007 Sep;37(9):2400-4. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Inhibition of activated/memory B-cells derived from RRMS patients.		1 year
Secondary	Change in Cytokine Secretion Profile of T-cells stimulated by teriflunomide treatment		1 year
Secondary	Measure the effect of oral teriflunomide on the cytokine secretion as measured in the ex-vivo obtained longitudinal samples from the treated patients.		1 year
Secondary	Measure the effect of oral teriflunomide on the B cell activation as measured in the ex-vivo obtained longitudinal samples from the treated patients.		1 year