A randomized trial of teriflunomide added to glatiramer acetate in relapsing multiple sclerosis

M S Freedman, J S Wolinsky, P Truffinet, G Comi, L Kappos, A E Miller, T P Olsson, M Benamor, S Chambers, P W O'Connor, M S Freedman, J S Wolinsky, P Truffinet, G Comi, L Kappos, A E Miller, T P Olsson, M Benamor, S Chambers, P W O'Connor

Abstract

Background: Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing-remitting MS.

Objective: To evaluate the safety and tolerability of teriflunomide as add-on therapy to a stable dose of glatiramer acetate (GA) in patients with relapsing forms of MS (RMS).

Methods: Phase II, randomized, double-blind, add-on, placebo-controlled study. The primary objective was to assess safety and tolerability; secondary objectives were to evaluate effects of treatment on disease activity assessed by MRI and relapse.

Results: Patients with RMS on GA (N = 123) were randomized 1:1:1 to receive teriflunomide 14 mg (n = 40), 7 mg (n = 42), or placebo (n = 41) for 24 weeks; 96 patients entered the 24-week extension, remaining on original treatment allocation. Teriflunomide was well tolerated over 48 weeks. The frequency of adverse events (AEs) was low across all groups; 5 (12.2%), 3 (7.1%), and 2 (5.0%) patients in the 14 mg, 7 mg, and placebo groups, respectively, discontinued treatment due to AEs. Teriflunomide reduced the number of T1-Gd lesions vs placebo (14 mg: 46.6% relative reduction, p = 0.1931; 7 mg: 64.0%: relative reduction, p = 0.0306).

Conclusions: Teriflunomide added to stable-dose GA had acceptable safety and tolerability, and reduced some MRI markers of disease activity compared with GA alone. NCT00475865 (core study); NCT00811395 (extension).

Keywords: MRI; Randomized clinical trial; multiple sclerosis; relapsing − remitting multiple sclerosis; safety.

Figures

Figure 1.
Figure 1.
Study disposition GA = glatiramer acetate.
Figure 2.
Figure 2.
MRI outcomes of teriflunomide as an adjunct to glatiramer acetate (mITT population). (a) Number of Gd-enhancing T1 (T1-Gd) lesions per scan at 24 and 48 weeks (the total number of T1-Gd lesions that occurred during the study divided by the total number of scans during the study, adjusted for baseline number of T1-Gd lesions, treatment, and region using a Poisson model with robust variance estimation). Error bars represent 95% confidence intervals. (b) Volume of T1-Gd lesions per scan at 24 and 48 weeks. The total volume of lesions that occurred during the study divided by the total number of scans during the study. GA = glatiramer acetate; Gd = gadolinium; mITT = modified intent-to-treat; RR = relative reduction.

References

    1. sanofi-aventis. Aubagio® (teriflunomide 14 mg tablets). Summary of product characteristics, 2013.
    1. Genzyme Corporation, a Sanofi company. Aubagio® (teriflunomide). Prescribing Information, 2012.
    1. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365: 1293–1303.
    1. Confavreux C, O’Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13(3): 247–256.
    1. Wolinsky JS, Narayana PA, Nelson F, et al. Magnetic resonance imaging outcomes from a phase III trial of teriflunomide. Mult Scler 2013; 19: 1310–1319.
    1. Freedman MS, Wolinsky JS, Wamil B, et al. Teriflunomide added to interferon-beta in relapsing multiple sclerosis: A randomized phase II trial. Neurology 2012; 78: 1877–1885.
    1. Freedman M, Wolinsky J, Comi G, et al. Safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis treated with interferon-beta. In: The 8th world congress on controversies in neurology, Berlin, Germany, 8–11 May 2014.
    1. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for MS: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001; 50(1): 121–127.
    1. Goodin DS, Frohman EM, Garmany GPJr., et al. Disease modifying therapies in multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58: 169–178.
    1. Goodman AD, Rossman H, Bar-Or A, et al. GLANCE: Results of a phase 2, randomized, double-blind, placebo-controlled study. Neurology 2009; 72: 806–812.
    1. Radue EW, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis. J Neurol Sci 2010; 292: 28–35.
    1. Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol 2013; 73: 327–340.
    1. Conway D, Cohen JA. Combination therapy in multiple sclerosis. Lancet Neurol 2010; 9: 299–308.
    1. Milo R, Panitch H. Combination therapy in multiple sclerosis. J Neuroimmunol 2011; 231: 23–31.
    1. Gajofatto A, Bacchetti P, Grimes B, et al. Switching first-line disease-modifying therapy after failure: Impact on the course of relapsing−remitting multiple sclerosis. Mult Scler J 2009; 15: 50–58.
    1. Freedman MS. Treatment options for patients with multiple sclerosis who have a suboptimal response to interferon-beta therapy. Eur J Neurol 2013; 21(3): 377–387.
    1. Tremlett HL, Oger J. Interrupted therapy: Stopping and switching of the beta-interferons prescribed for MS. Neurology 2003; 61: 551–554.

Source: PubMed

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