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N Engl J Med. 2012 Sep 20;367(12):1098-107.

Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.

Collaborators (246)

Gold R, Kappos L, Arnold D, Bar-Or A, Giovannoni G, Selmaj K, Dawson KT, Gallacher P, Milla C, Yang M, Antel J, Bakris G, Chung R, Kowey PR, Polman C, Richert J, Seibert B, Ware J, Brandes D, Brassat D, Cohen B, Diem R, Goldman M, Herndon R, Miller A, Tumani H, Barnett M, Butzkueven H, Beran R, Casse R, Chapman C, Lechner-Scott J, Macdonell R, Paine M, Schwartz R, Berger T, Fazekas F, Ransmayr G, Vass K, Belachew S, Decoo D, De Deyn PP, Dubois B, Vande Gaer L, Medaer R, Seeldrayers P, Sindic C, Vanopdenbosch L, Grgic S, Bhan V, Bouchart JP, Christie S, Bar-Or A, Jacques F, Grammond P, Veloso F, Vorobeychick G, Brinar V, Demarin V, Rudež J, Soldo-Butković S, Vurdelja RB, Ambler Z, Doležil D, Havrdova E, Kanovsky P, Meluzinova E, Nova'k J, Rektor I, Skoda O, Vachová M, Camu W, Clavelou P, Coman AI, Confavreux C, Edan G, Gout O, Lebrun-Frenay C, Papeix AC, Vermersch P, Bachus-Banaschak K, Berghoff M, Bethke F, Boldt HJ, Chan A, Diener HC, Eisensehr I, Emrich P, Griewing B, Haas J, Heesen C, Heidenreich F, Hoffmann F, Hufnagel A, Kleiter I, Lüer W, Marckmann-Böenke S, Marziniak M, Oschmann P, Rosenkranz T, Schneider H, Siefjediers V, Springub J, Stangel M, Stögbauer F, Bergh FT, Tiel-Wilck K, Tinschert K, Grigoriadis N, Karageorgiou C, Kyritsis A, Papadimitriou A, Thomaides T, Vlaikidis N, Yaxcal Chon D, Salguero Gonzalez LF, Ordoñez Sarg HA, Agrawal CS, Behari M, Cu V, Dwivedee S, Kothari S, Kulkarni R, Kushwaha S, Meena AK, Mehndiratta MM, Mukherjee SC, Pandit L, Shah A, Shukla R, Vijayan K, Achiron A, Flechter S, Milo R, Vaknin-Dembinsky A, Pozzilli C, Oropeza de Alba JL, Castro Farfan FG, Rangel Guerra RA, Rodriguez Leyva I, Arcega Revilla R, Flores Rivera J, Gavriliuc M, Groppa S, Odainic O, Hupperts R, Sanders EA, Mason D, Timmings P, Willoughby E, Czlonkowska A, Dorobek M, Drozdowski W, Hertmanowska H, Fryze W, Kleczkowska M, Kochanowicz J, Kwieciński H, Nowacki P, Podemski R, Potemkowski A, Selmaj K, Stelmasiak Z, Wajgt A, Zielinski T, Daskalovska V, Bajenaru AO, Muresanu FD, Nica SM, Simu MA, Drakulić SM, Nadj C, Obradovic D, Vojinovic S, Kahancová E, Krajnak V, Kurca E, Lisý L, Turčáni P, Badenhorst F, Green J, Heckmann J, Isaacs M, Kappos L, Linnebank M, Müller S, Buchakchyys'ka N, Goloborodko A, Kobys T, Lebedynets V, Lytvynenko N, Nehrych T, Pasyura I, Ryabichenko T, Voloshina N, Duddy M, Hawkins C, Nicholas R, Palace J, Sharrack B, Silber E, Turner B, Camac A, Chumley W, Crayton H, Dixit S, English J, Edwards K, Freedman P, Gazda S, Goldstick L, Gordon N, Gottschalk C, Grazioli E, Grelinger B, Green B, Hayat G, Hendin B, Janus T, Henson LJ, Goldstick L, Grainger W, Gudesblatt M, Gupta A, Hentati A, Herrman C, Itkin A, Kasper L, Lathi E, Mowry E, Parry G, Perel A, Rao T, Riskind P, Rizvi S, Rossen M, Rossman H, Scott T, Shafer S, Storey J Jr, Thrower B, Tornatore C, Tosches W, Trefts L Jr, Turel A Jr, Weinstock-Guttman B.

Author information

  • 1Department of Neurology, St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany. ralf.gold@ruhr-uni-bochum.de

Erratum in

  • N Engl J Med. 2012 Dec 13;367(24):2362.

Abstract

BACKGROUND:

BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis.

METHODS:

We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI.

RESULTS:

The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T(2)-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.

CONCLUSIONS:

In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).

Comment in

PMID:
22992073
[PubMed - indexed for MEDLINE]
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