Journal of Neurology

, Volume 260, Issue 9, pp 2286–2296 | Cite as

Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the CONFIRM study

  • Michael Hutchinson
  • Robert J. Fox
  • David H. Miller
  • J. Theodore Phillips
  • Mariko Kita
  • Eva Havrdova
  • John O’Gorman
  • Ray Zhang
  • Mark Novas
  • Vissia Viglietta
  • Katherine T. Dawson
Original Communication


In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing–remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34 % [rate ratio 0.664 (95 % confidence interval 0.422–1.043)] to 53 % [0.466 (0.313–0.694)] and from 13 % [0.870 (0.551–1.373)] to 67 % [0.334 (0.226–0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing–remitting multiple sclerosis with varied demographic and disease characteristics.


BG-12 Dimethyl fumarate Glatiramer acetate Multiple sclerosis Randomized controlled trial Subgroup analysis 



This study was supported by Biogen Idec Inc. (Weston, MA, USA). EH was supported by the Czech Ministry of Education, VZ MSM 0021620849 and PRVOUK-P26/LF1/4. The authors would like to thank the CONFIRM study investigators. Medical writing support and editorial assistance were provided by Samantha Holmes (CircleScience, Tytherington, UK), funded by Biogen Idec Inc.

Conflict of interest

Michael Hutchinson serves on a medical advisory board [BG00012] for Biogen Idec, is an assistant editor of Multiple Sclerosis Journal, and reports having received speaker’s honoraria from Bayer Schering, Biogen Idec, and Novartis, and research support from Dystonia Ireland and the Health Research Board of Ireland. Robert J. Fox reports having received consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva, and grant and research support from Novartis. David H. Miller reports having received honoraria from Bayer Schering Pharma, Biogen Idec, and GlaxoSmithKline and research grants from Apitope, Biogen Idec, GlaxoSmithKline, Novartis, Richmond Pharma, and Schering AG. J. Theodore Phillips reports having received honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva, and research support from Biogen Idec and Roche. Mariko Kita reports having received research support from Biogen Idec. Eva Havrdova reports having received honoraria from Bayer, Biogen Idec, Genzyme, Novartis, Serono, and Teva. John O’Gorman, Ray Zhang, Mark Novas, Vissia Viglietta, and Katherine T. Dawson are employees of Biogen Idec.

Supplementary material

415_2013_6968_MOESM1_ESM.pdf (274 kb)
Supplementary material 1 (PDF 273 kb)


  1. 1.
    US Food and Drug Administration (2013) TECFIDERA™ prescribing information. Accessed 2 April 2013
  2. 2.
    Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O’Neill GN (2008) Efficacy and safety of oral fumarate in patients with relapsing–remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 372:1463–1472PubMedCrossRefGoogle Scholar
  3. 3.
    Gold R, Kappos L, Arnold DL, Bar-Or A, Giavannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT, On behalf of the DEFINE Study Investigators (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107PubMedCrossRefGoogle Scholar
  4. 4.
    Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT, On behalf of the CONFIRM Study Investigators (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097PubMedCrossRefGoogle Scholar
  5. 5.
    Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717PubMedCrossRefGoogle Scholar
  6. 6.
    Tremlett H, Zhao Y, Rieckmann P, Hutchinson M (2010) New perspectives in the natural history of multiple sclerosis. Neurology 74:2004–2015PubMedCrossRefGoogle Scholar
  7. 7.
    Chofflon M (2005) Mechanisms of action for treatments in multiple sclerosis: does a heterogeneous disease demand a multi-targeted therapeutic approach? BioDrugs 19:299–308PubMedCrossRefGoogle Scholar
  8. 8.
    Degenhardt A, Ramagopalan SV, Scalfari A, Ebers GC (2009) Clinical prognostic factors in multiple sclerosis: a natural history review. Nat Rev Neurol 5:672–682PubMedCrossRefGoogle Scholar
  9. 9.
    Disanto G, Berlanga AJ, Handel AE, Para AE, Burrell AM, Fries A, Handunnetthi L, De Luca GC, Morahan JM (2010) Heterogeneity in multiple sclerosis: scratching the surface of a complex disease. Autoimmune Dis 2011:932351PubMedGoogle Scholar
  10. 10.
    Mowry EM (2011) Natural history of multiple sclerosis: early prognostic factors. Neurol Clin 29:279–292PubMedCrossRefGoogle Scholar
  11. 11.
    Renoux C (2011) Natural history of multiple sclerosis: long-term prognostic factors. Neurol Clin 29:293–308PubMedCrossRefGoogle Scholar
  12. 12.
    Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Thompson AJ, Miller DH (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:158–164PubMedCrossRefGoogle Scholar
  13. 13.
    Confavreux C, Vukusic S, Adeleine P (2003) Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 126:770–782PubMedCrossRefGoogle Scholar
  14. 14.
    Losseff NA, Miller DH, Kidd D, Thompson AJ (2001) The predictive value of gadolinium enhancement for long-term disability in relapsing–remitting multiple sclerosis-preliminary results. Mult Scler 7:23–25PubMedGoogle Scholar
  15. 15.
    Scott TF, Schramke CJ, Novero J, Chieffe C (2000) Short-term prognosis in early relapsing–remitting multiple sclerosis. Neurology 55:689–693PubMedCrossRefGoogle Scholar
  16. 16.
    Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302PubMedCrossRefGoogle Scholar
  17. 17.
    Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 33:1444–1452PubMedCrossRefGoogle Scholar
  18. 18.
    ICH harmonised tripartite guideline–guideline for good clinical practice: E6 (R1) (1996) International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, June 10, 1996. Accessed 30 March 2011
  19. 19.
    World Medical Association (2010) Declaration of Helsinki: ethical principles for medical research involving human subjects. Accessed 22 Nov 2010
  20. 20.
    European Medicines Agency (EMA) (2006) Committee for medicinal products for human use (CHMP). Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. Accessed 11 Feb 2011
  21. 21.
    Bar-Or A, Gold R, Kappos L, Arnold DL, Giovannoni G, Selmaj K, O’Gorman J, Stephan M, Dawson KT (2012) Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the DEFINE study. Submitted to J NeurolGoogle Scholar
  22. 22.
    Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Eraksoy M, Meluzinova E, Dufek M, Yang M, Dawson K, O’Neill GN (2011) Effect of BG-12 on contrast-enhancing lesions in patients with relapsing–remitting multiple sclerosis: subgroup analyses from the phase 2b study. Mult Scler 18:314–321PubMedCrossRefGoogle Scholar
  23. 23.
    Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA (2011) Alemtuzumab versus interferon beta-1a in early relapsing–remitting multiple sclerosis: post hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 10:338–348PubMedCrossRefGoogle Scholar
  24. 24.
    Devonshire V, Havrdova E, Radue EW, O’Connor P, Zhang-Auberson L, Agoropoulou C, Haring DA, Francis G, Kappos L (2012) Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol 11:420–428PubMedCrossRefGoogle Scholar
  25. 25.
    Giovannoni G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, Vermersch P, Hamlett A, Viglietta V, Greenberg S (2011) Sustained disease-activity-free status in patients with relapsing–remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post hoc and subgroup analysis. Lancet Neurol 10:329–337PubMedCrossRefGoogle Scholar
  26. 26.
    Hutchinson M, Kappos L, Calabresi PA, Confavreux C, Giovannoni G, Galetta SL, Havrdova E, Lublin FD, Miller DH, O’Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA (2009) The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol 256:405–415PubMedCrossRefGoogle Scholar
  27. 27.
    Miller AE, O’Connor P, Wolinsky JS, Confavreux C, Kappos L, Olsson TP, Truffinet P, Wang L, D’Castro L, Comi G, Freedman MS (2012) Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. Mult Scler 18:1625–1632PubMedCrossRefGoogle Scholar
  28. 28.
    Tremlett H, Zhao Y, Joseph J, Devonshire V (2008) Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry 79:1368–1374PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Michael Hutchinson
    • 1
  • Robert J. Fox
    • 2
  • David H. Miller
    • 3
  • J. Theodore Phillips
    • 4
  • Mariko Kita
    • 5
  • Eva Havrdova
    • 6
  • John O’Gorman
    • 7
  • Ray Zhang
    • 7
  • Mark Novas
    • 7
  • Vissia Viglietta
    • 7
  • Katherine T. Dawson
    • 7
  1. 1.St. Vincent’s University HospitalDublin 4Ireland
  2. 2.The Mellen Center for Multiple Sclerosis Treatment and ResearchCleveland ClinicClevelandUSA
  3. 3.NMR Research Unit, Department of NeuroinflammationUCL Institute of NeurologyLondonUK
  4. 4.Multiple Sclerosis ProgramBaylor Institute for Immunology ResearchDallasUSA
  5. 5.Virginia Mason Medical CenterSeattleUSA
  6. 6.Department of Neurology, First Faculty of MedicineCharles University in PraguePragueCzech Republic
  7. 7.Biogen Idec Inc.WestonUSA

Personalised recommendations