Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis
Ralf Gold, Ludwig Kappos, Douglas L Arnold, Amit Bar-Or, Gavin Giovannoni, Krzysztof Selmaj, Carlo Tornatore, Marianne T Sweetser, Minhua Yang, Sarah I Sheikh, Katherine T Dawson, DEFINE Study Investigators, Ralf Gold, Ludwig Kappos, Douglas Arnold, Amit Bar-Or, Gavin Giovannoni, Krzystof Selmaj, Katherine T Dawson, Phillip Gallacher, Carole Milla, Minhua Yang, Jack Antel, George Bakris, Raymond Chung, Peter R Kowey, Chris Polman, John Richert, Burt Seibert, James Ware, David Brandes, David Brassat, Bruce Cohen, Ricarda Diem, Myla Goldman, Robert Herndon, Aaron Miller, Hayrettin Tumani, Michael Barnett, Helmut Butzkueven, Roy Beran, Reynolds Casse, Caron Chapman, Jeannette Lechner-Scott, Richard Macdonell, Mark Paine, Raymond Schwartz, Thomas Berger, Franz Fazekas, Gerhard Ransmayr, Karl Vass, Shibeshih Belachew, Danny Decoo, Peter Paul De Deyn, Bénédicte Dubois, Luc Vande Gaer, Robert Medaer, Pierrette Seeldrayers, Christian Sindic, Ludo Vanopdenbosch, Sanja Grgic, Virender Bhan, Jean-Pierre Bouchart, Suzanne Christie, Amit Bar-Or, François Jacques, Pierre Grammond, Felix Veloso, Galina Vorobeychick, Vesna Brinar, Vida Demarin, Josip Rudež, Silva Soldo-Butković, Ranka Baraba Vurdelja, Zdeněk Ambler, David Doležil, Eva Havrdova, Petr Kanovsky, Eva Meluzinova, Jiří Nova'k, Ivan Rektor, Ondrej Skoda, Marta Vachová, William Camu, Pierre Clavelou, Antoanela Irène Coman, Christian Confavreux, Gilles Edan, Olivier Gout, Christine Lebrun-Frenay, Anne-Caroline Papeix, Patrick Vermersch, Katrin Bachus-Banaschak, Martin Berghoff, Florian Bethke, Hans-Jürgen Boldt, Andrew Chan, Hans-Christoph Diener, Ilonka Eisensehr, Peter Emrich, Bernd Griewing, Judith Haas, Christoph Heesen, Fedor Heidenreich, Frank Hoffmann, Andreas Hufnagel, Ingo Kleiter, Wilfried Lüer, Silke Marckmann-Böenke, Martin Marziniak, Patrick Oschmann, Thorsten Rosenkranz, Hauke Schneider, Veneta Siefjediers, Joachim Springub, Martin Stangel, Florian Stögbauer, Florian Then Bergh, Klaus Tiel-Wilck, Konstanze Tinschert, Nikolaos Grigoriadis, Clementine Karageorgiou, Athanssios Kyritsis, Alexandros Papadimitriou, Thomas Thomaides, Nicholas Vlaikidis, David Yaxcal Chon, Luis Fernando Salguero Gonzalez, Hugo Alfredo Ordoñez Sarg, C S Agrawal, Madhuri Behari, Velmurugendran Cu, Shamsher Dwivedee, Sudhir Kothari, Rahul Kulkarni, Suman Kushwaha, A K Meena, M M Mehndiratta, Subhash Chandra Mukherjee, Lekha Pandit, Arun Shah, Rakesh Shukla, K Vijayan, Anat Achiron, Shlomo Flechter, Ron Milo, Adi Vaknin-Dembinsky, Carlo Pozzilli, José Luis Oropeza de Alba, Freddy Guillermo Castro Farfan, Ricardo Alberto Rangel Guerra, Ildefonso Rodriguez Leyva, Raúl Arcega Revilla, Jose Flores Rivera, Mihail Gavriliuc, Stanislav Groppa, Olesea Odainic, Raymond Hupperts, E A C M Sanders, Deborah Mason, Paul Timmings, Ernest Willoughby, Anna Czlonkowska, Malgorzata Dorobek, Wieslaw Drozdowski, Hanka Hertmanowska, Waldemar Fryze, Magdalena Kleczkowska, Jan Kochanowicz, Hubert Kwieciński, Przemyslaw Nowacki, Ryszard Podemski, Andrzej Potemkowski, Krzysztof Selmaj, Zbigniew Stelmasiak, Andrzej Wajgt, Tomasz Zielinski, Vera Daskalovska, Alexandru Ovidiu Bajenaru, Fior Dafin Muresanu, Sanda Maria Nica, Mihaela Adriana Simu, Svetlana Miletić Drakulić, Congor Nadj, Dragana Obradovic, Slobodan Vojinovic, Edita Kahancová, Viliam Krajnak, Egon Kurca, L'ubomir Lisý, Peter Turčáni, Frans Badenhorst, Judy Green, Jeannine Heckmann, Michael Isaacs, Ludwig Kappos, Michael Linnebank, Stefanie Müller, Nataliya Buchakchyys'ka, Alla Goloborodko, Tetyana Kobys, Volodymyr Lebedynets, Nataliya Lytvynenko, Tetyana Nehrych, Igor Pasyura, Tatyana Ryabichenko, Nataliya Voloshina, Martin Duddy, Clive Hawkins, Richard Nicholas, Jacqueline Palace, Basil Sharrack, Eli Silber, Ben Turner, Ann Camac, Warren Chumley, Heidi Crayton, Shanker Dixit, Jeffrey English, Keith Edwards, P Steven Freedman, Suzanne Gazda, Lawrence Goldstick, Norman Gordon, Christopher Gottschalk, Erica Grazioli, Bart Grelinger, Barbara Green, Ghazala Hayat, Barry Hendin, Todd Janus, Lily Jung Henson, Lawrence Goldstick, William Grainger, Mark Gudesblatt, Ajay Gupta, Afif Hentati, Craig Herrman, Arthur Itkin, Lloyd Kasper, Ellen Lathi, Ellen Mowry, Gareth Parry, Allan Perel, T Hemanth Rao, Peter Riskind, Syed Rizvi, Michael Rossen, Howard Rossman, Thomas Scott, S James Shafer, James Storey Jr, Ben Thrower, Carlo Tornatore, William Tosches, Lori Trefts Jr, Anthony Turel Jr, Bianca Weinstock-Guttman, Ralf Gold, Ludwig Kappos, Douglas L Arnold, Amit Bar-Or, Gavin Giovannoni, Krzysztof Selmaj, Carlo Tornatore, Marianne T Sweetser, Minhua Yang, Sarah I Sheikh, Katherine T Dawson, DEFINE Study Investigators, Ralf Gold, Ludwig Kappos, Douglas Arnold, Amit Bar-Or, Gavin Giovannoni, Krzystof Selmaj, Katherine T Dawson, Phillip Gallacher, Carole Milla, Minhua Yang, Jack Antel, George Bakris, Raymond Chung, Peter R Kowey, Chris Polman, John Richert, Burt Seibert, James Ware, David Brandes, David Brassat, Bruce Cohen, Ricarda Diem, Myla Goldman, Robert Herndon, Aaron Miller, Hayrettin Tumani, Michael Barnett, Helmut Butzkueven, Roy Beran, Reynolds Casse, Caron Chapman, Jeannette Lechner-Scott, Richard Macdonell, Mark Paine, Raymond Schwartz, Thomas Berger, Franz Fazekas, Gerhard Ransmayr, Karl Vass, Shibeshih Belachew, Danny Decoo, Peter Paul De Deyn, Bénédicte Dubois, Luc Vande Gaer, Robert Medaer, Pierrette Seeldrayers, Christian Sindic, Ludo Vanopdenbosch, Sanja Grgic, Virender Bhan, Jean-Pierre Bouchart, Suzanne Christie, Amit Bar-Or, François Jacques, Pierre Grammond, Felix Veloso, Galina Vorobeychick, Vesna Brinar, Vida Demarin, Josip Rudež, Silva Soldo-Butković, Ranka Baraba Vurdelja, Zdeněk Ambler, David Doležil, Eva Havrdova, Petr Kanovsky, Eva Meluzinova, Jiří Nova'k, Ivan Rektor, Ondrej Skoda, Marta Vachová, William Camu, Pierre Clavelou, Antoanela Irène Coman, Christian Confavreux, Gilles Edan, Olivier Gout, Christine Lebrun-Frenay, Anne-Caroline Papeix, Patrick Vermersch, Katrin Bachus-Banaschak, Martin Berghoff, Florian Bethke, Hans-Jürgen Boldt, Andrew Chan, Hans-Christoph Diener, Ilonka Eisensehr, Peter Emrich, Bernd Griewing, Judith Haas, Christoph Heesen, Fedor Heidenreich, Frank Hoffmann, Andreas Hufnagel, Ingo Kleiter, Wilfried Lüer, Silke Marckmann-Böenke, Martin Marziniak, Patrick Oschmann, Thorsten Rosenkranz, Hauke Schneider, Veneta Siefjediers, Joachim Springub, Martin Stangel, Florian Stögbauer, Florian Then Bergh, Klaus Tiel-Wilck, Konstanze Tinschert, Nikolaos Grigoriadis, Clementine Karageorgiou, Athanssios Kyritsis, Alexandros Papadimitriou, Thomas Thomaides, Nicholas Vlaikidis, David Yaxcal Chon, Luis Fernando Salguero Gonzalez, Hugo Alfredo Ordoñez Sarg, C S Agrawal, Madhuri Behari, Velmurugendran Cu, Shamsher Dwivedee, Sudhir Kothari, Rahul Kulkarni, Suman Kushwaha, A K Meena, M M Mehndiratta, Subhash Chandra Mukherjee, Lekha Pandit, Arun Shah, Rakesh Shukla, K Vijayan, Anat Achiron, Shlomo Flechter, Ron Milo, Adi Vaknin-Dembinsky, Carlo Pozzilli, José Luis Oropeza de Alba, Freddy Guillermo Castro Farfan, Ricardo Alberto Rangel Guerra, Ildefonso Rodriguez Leyva, Raúl Arcega Revilla, Jose Flores Rivera, Mihail Gavriliuc, Stanislav Groppa, Olesea Odainic, Raymond Hupperts, E A C M Sanders, Deborah Mason, Paul Timmings, Ernest Willoughby, Anna Czlonkowska, Malgorzata Dorobek, Wieslaw Drozdowski, Hanka Hertmanowska, Waldemar Fryze, Magdalena Kleczkowska, Jan Kochanowicz, Hubert Kwieciński, Przemyslaw Nowacki, Ryszard Podemski, Andrzej Potemkowski, Krzysztof Selmaj, Zbigniew Stelmasiak, Andrzej Wajgt, Tomasz Zielinski, Vera Daskalovska, Alexandru Ovidiu Bajenaru, Fior Dafin Muresanu, Sanda Maria Nica, Mihaela Adriana Simu, Svetlana Miletić Drakulić, Congor Nadj, Dragana Obradovic, Slobodan Vojinovic, Edita Kahancová, Viliam Krajnak, Egon Kurca, L'ubomir Lisý, Peter Turčáni, Frans Badenhorst, Judy Green, Jeannine Heckmann, Michael Isaacs, Ludwig Kappos, Michael Linnebank, Stefanie Müller, Nataliya Buchakchyys'ka, Alla Goloborodko, Tetyana Kobys, Volodymyr Lebedynets, Nataliya Lytvynenko, Tetyana Nehrych, Igor Pasyura, Tatyana Ryabichenko, Nataliya Voloshina, Martin Duddy, Clive Hawkins, Richard Nicholas, Jacqueline Palace, Basil Sharrack, Eli Silber, Ben Turner, Ann Camac, Warren Chumley, Heidi Crayton, Shanker Dixit, Jeffrey English, Keith Edwards, P Steven Freedman, Suzanne Gazda, Lawrence Goldstick, Norman Gordon, Christopher Gottschalk, Erica Grazioli, Bart Grelinger, Barbara Green, Ghazala Hayat, Barry Hendin, Todd Janus, Lily Jung Henson, Lawrence Goldstick, William Grainger, Mark Gudesblatt, Ajay Gupta, Afif Hentati, Craig Herrman, Arthur Itkin, Lloyd Kasper, Ellen Lathi, Ellen Mowry, Gareth Parry, Allan Perel, T Hemanth Rao, Peter Riskind, Syed Rizvi, Michael Rossen, Howard Rossman, Thomas Scott, S James Shafer, James Storey Jr, Ben Thrower, Carlo Tornatore, William Tosches, Lori Trefts Jr, Anthony Turel Jr, Bianca Weinstock-Guttman
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.).
Source: PubMed