Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis
Robert J Fox, David H Miller, J Theodore Phillips, Michael Hutchinson, Eva Havrdova, Mariko Kita, Minhua Yang, Kartik Raghupathi, Mark Novas, Marianne T Sweetser, Vissia Viglietta, Katherine T Dawson, CONFIRM Study Investigators, Robert J Fox, J Theodore Phillips, Michael Hutchinson, Eva Havrdova, Mariko Kita, Kate Wilson, Minhua Yang, Katherine T Dawson, Jack Antel, James Ware, Chris Polman, Peter R Kowey, Raymond Chung, George Bakris, John Richert, Burt Seibert, David Brandes, David Brassat, Bruce Cohen, Ricarda Diem, Myla Goldman, Robert Herndon, Aaron Miller, Hayrettin Tumani, Teresa Alfaro-Vidal, Carolina Crespo, Jo Foster, Kelvin Hunter, Almudena Garcia-Gomez, David MacManus, David Miller, Virginia Santana, Dan Tozer, Claudia Kingshott-Wheeler, Tarek Yousry, Christopher Kneebone, Aliaksandr Fedulau, Elena Mikhailova, Sergey Likhachev, Halina Naumova, Luc Vande Gaer, Danny Decoo, Christian Sindic, Sanja Grgic, Osman Sinanovic, Enra Mehmedika Suljic, Dimitar Georgiev, Lyubomir Haralanov, Sonyia Ivanova, Dimitar Minchev, Ivailo Tournev, Paraskeva Stamenova, Nadezhda Deleva, Zahari Zahariev, Ivan Manchev, Elena Vacheva, Amit Bar-Or, Marcelo Kremenchutzky, Felix Veloso, Norbert Witt, Gregg Blevins, Alexander Parajeles Vindas, Roberto Vargas Howell, Silva Soldo-Butković, Josip Rudež, Mario Habek, Ranka Baraba Vurdelja, Eva Havrdova, David Doležil, Daniel Vaclavik, Jiří Nova'k, Katrin Gross-Paju, Katrin Antsov, Sulev Haldre, Alla Palu, Toomas Toomsoo, William Camu, Jean Pelletier, Pierre Labauge, Marc Debouverie, Gilles Defer, Jérôme De Seze, Thibault Moreau, Abdullatif Al Khedr, Lucien Rumbach, Vera Daskalovska, Harald Landefeld, Sabine Masri, Sebastian Schimrigk, Björn Tackenberg, Ilonka Eisensehr, Frank Hoffmann, Bernd Kieseier, Wilfried Lüer, Heike Benes, Christine Paschen, Tobias Derfuß, Michael Sailer, Brigitte Storch-Hagenlocher, Achim Berthele, Patrick Oschmann, Klemens Angnstwurm, Reinhard Hohlfeld, Gerd Reifschneider, Klaus Tiel-Wilck, Gereon Nelles, Hans-Jürgen Boldt, Peter Emrich, Boris-Alexander Kallmann, Wolfgang Feneberg, Angelika Christopher, Reinhard Hüntemann, Mechthild Spiegel-Meixensberger, Thomas Thomaides, Nicholas Vlaikidis, Clementine Karageorgiou, Panagiotis Papathanasopoulos, Man Mohan Mehndiratta, Krishnan Vijayan, Deepak Arjundas, Rangasetty Srinivasa, Amitabha Ghosh, Rahul Vitthal Kulkarni, Shalin Dipinkumar Shah, Joy Dev Mukherji, Shankara Nellikunja, Madhuri Behari, Gagandeep Singh, Pahari Ghosh, Nasli Rustom Ichaporia, Prahlad Kumar Sethi, Neeta Abhay Mehta, Usha Kant Misra, Maneesh Kumar Singh, Dheeraj Khurana, Abdu Salem, Michael Hutchinson, Bernard Sweeney, Ronit Gilad, Radi Shahien, Anita Paegle, Guillermo Punzo, Jose Santos, Sandra Quiñones, Miguel Angel Macias, Bruno Estañol, Juan Escamilla, Neyla Lopez, Mariela Renteria, Cesar Delgado, Olesea Odainic, Stanislav Groppa, Mihail Gavriliuc, Paul Timmings, Wieslaw Drozdowski, Waldemar Fryze, Jan Kochanowicz, Anna Kaminska, Krzysztof Selmaj, Andrzej Wajgt, Magdalena Kleczkowska, Przemyslaw Nowacki, Anna Czlonkowska, Zbigniew Stelmasiak, Ryszard Podemski, Malgorzata Dorobek, Hanka Hertmanowska, Krystyna Pierzchala, Tomasz Zielinski, Andrzej Szczudlik, Andrzej Tutaj, Jacek Losy, Andrzej Potemkowski, Walenty Nyka, Magdalena Kapelusiak-Pielok, Valentin Ionescu-Dimancea, Rodica Balasa, Petru Mihancea, Cristian Popescu, Liviu Codrut Protosevici, Slobodan Vojinovic, Svetlana Miletić Drakulić, Ranko Raicevic, Congor Nadj, Peter Turčáni, Edita Kahancová, Egon Kurca, L'ubomir Lisý, Xavier Montalbán, Guillermo Izquierdo, Rafael Arroyo, Jose Maria Prieto, Oscar Fernández, Celia Oreja-Guevara, Fernando Sanchez Lopez, Cristina Guijarro, Nataliya Voloshina, Igor Pasyura, Borys Palamar, Tetyana Nehrych, Tetyana Kobys, Nataliya Lytvynenko, Alla Goloborodko, Nataliya Buchakchyys'ka, Volodymyr Lebedynets, Tatyana Ryabichenko, Grygory Kushnir, Sergii Moskovko, Galyna Chmyr, Mary Forester, Ricardo Ayala, James Voci, Stanley Krolczyk, Braeme Glaun, Robert Smith, Giles Crowell, Revere Philip Kinkel, Malti Patel, Tamara Miller, Gabriel Pardo, Stephen Asher, Christopher LaGanke, Donald Ayres, Matthew Baker, Mitzi Williams, William Sheremata, Alberto Vasquez, Mark Janicki, George Garmany Jr, Richard Hull, David Steiner, Joseph Herbert, Keith Edwards, Robert Fox, Bhupendra Khatri, Michael Levin, David Mattson, Angela Applebee, Joseph Phillips Jr, Mary Ann Picone, Warren Felton 3rd, Edward Fox, Michelle Apperson, Scott Gold, Mariko Kita, Harold Moses Jr, Robert Shin, John Rinker 2nd, George Hutton, Lauren Krupp, Patricia Fodor, John Foley, Suzanne Gazda, William Honeycutt, Galen Mitchell, Saud Sadiq, Brian Steingo, Dina Jacobs, Steven Freedman, Bianca Weinstock-Guttman, Sharon Lynch, Anand Vaishnav, Sibyl Wray, Samuel Hunter, Christopher Luzzio, John Huddlestone, Stanley Cohan, Angel Chinea, Daniel Giang, Richard Shubin, Donald Negroski, Allan Perel, Michael Stein, Allan Herskowitz, Jonathan Warach, Daniel Mikol, Roberto Bomprezzi, Geoffery Eubank, Jonathan Licht, Herman Sullivan, T Hemanth Rao, Stephen Newman, Stuart Silverman, Mark Gudesblatt, William Sunter Jr, Alireza Minagar, Kottil Rammohan, Malcolm Gottesman, John Schaeffer, Walter Carlini, Lee Stein, Richard Buckler, S Ausim Azizi, Brendan Bauer, Corey Ford, Robert J Fox, David H Miller, J Theodore Phillips, Michael Hutchinson, Eva Havrdova, Mariko Kita, Minhua Yang, Kartik Raghupathi, Mark Novas, Marianne T Sweetser, Vissia Viglietta, Katherine T Dawson, CONFIRM Study Investigators, Robert J Fox, J Theodore Phillips, Michael Hutchinson, Eva Havrdova, Mariko Kita, Kate Wilson, Minhua Yang, Katherine T Dawson, Jack Antel, James Ware, Chris Polman, Peter R Kowey, Raymond Chung, George Bakris, John Richert, Burt Seibert, David Brandes, David Brassat, Bruce Cohen, Ricarda Diem, Myla Goldman, Robert Herndon, Aaron Miller, Hayrettin Tumani, Teresa Alfaro-Vidal, Carolina Crespo, Jo Foster, Kelvin Hunter, Almudena Garcia-Gomez, David MacManus, David Miller, Virginia Santana, Dan Tozer, Claudia Kingshott-Wheeler, Tarek Yousry, Christopher Kneebone, Aliaksandr Fedulau, Elena Mikhailova, Sergey Likhachev, Halina Naumova, Luc Vande Gaer, Danny Decoo, Christian Sindic, Sanja Grgic, Osman Sinanovic, Enra Mehmedika Suljic, Dimitar Georgiev, Lyubomir Haralanov, Sonyia Ivanova, Dimitar Minchev, Ivailo Tournev, Paraskeva Stamenova, Nadezhda Deleva, Zahari Zahariev, Ivan Manchev, Elena Vacheva, Amit Bar-Or, Marcelo Kremenchutzky, Felix Veloso, Norbert Witt, Gregg Blevins, Alexander Parajeles Vindas, Roberto Vargas Howell, Silva Soldo-Butković, Josip Rudež, Mario Habek, Ranka Baraba Vurdelja, Eva Havrdova, David Doležil, Daniel Vaclavik, Jiří Nova'k, Katrin Gross-Paju, Katrin Antsov, Sulev Haldre, Alla Palu, Toomas Toomsoo, William Camu, Jean Pelletier, Pierre Labauge, Marc Debouverie, Gilles Defer, Jérôme De Seze, Thibault Moreau, Abdullatif Al Khedr, Lucien Rumbach, Vera Daskalovska, Harald Landefeld, Sabine Masri, Sebastian Schimrigk, Björn Tackenberg, Ilonka Eisensehr, Frank Hoffmann, Bernd Kieseier, Wilfried Lüer, Heike Benes, Christine Paschen, Tobias Derfuß, Michael Sailer, Brigitte Storch-Hagenlocher, Achim Berthele, Patrick Oschmann, Klemens Angnstwurm, Reinhard Hohlfeld, Gerd Reifschneider, Klaus Tiel-Wilck, Gereon Nelles, Hans-Jürgen Boldt, Peter Emrich, Boris-Alexander Kallmann, Wolfgang Feneberg, Angelika Christopher, Reinhard Hüntemann, Mechthild Spiegel-Meixensberger, Thomas Thomaides, Nicholas Vlaikidis, Clementine Karageorgiou, Panagiotis Papathanasopoulos, Man Mohan Mehndiratta, Krishnan Vijayan, Deepak Arjundas, Rangasetty Srinivasa, Amitabha Ghosh, Rahul Vitthal Kulkarni, Shalin Dipinkumar Shah, Joy Dev Mukherji, Shankara Nellikunja, Madhuri Behari, Gagandeep Singh, Pahari Ghosh, Nasli Rustom Ichaporia, Prahlad Kumar Sethi, Neeta Abhay Mehta, Usha Kant Misra, Maneesh Kumar Singh, Dheeraj Khurana, Abdu Salem, Michael Hutchinson, Bernard Sweeney, Ronit Gilad, Radi Shahien, Anita Paegle, Guillermo Punzo, Jose Santos, Sandra Quiñones, Miguel Angel Macias, Bruno Estañol, Juan Escamilla, Neyla Lopez, Mariela Renteria, Cesar Delgado, Olesea Odainic, Stanislav Groppa, Mihail Gavriliuc, Paul Timmings, Wieslaw Drozdowski, Waldemar Fryze, Jan Kochanowicz, Anna Kaminska, Krzysztof Selmaj, Andrzej Wajgt, Magdalena Kleczkowska, Przemyslaw Nowacki, Anna Czlonkowska, Zbigniew Stelmasiak, Ryszard Podemski, Malgorzata Dorobek, Hanka Hertmanowska, Krystyna Pierzchala, Tomasz Zielinski, Andrzej Szczudlik, Andrzej Tutaj, Jacek Losy, Andrzej Potemkowski, Walenty Nyka, Magdalena Kapelusiak-Pielok, Valentin Ionescu-Dimancea, Rodica Balasa, Petru Mihancea, Cristian Popescu, Liviu Codrut Protosevici, Slobodan Vojinovic, Svetlana Miletić Drakulić, Ranko Raicevic, Congor Nadj, Peter Turčáni, Edita Kahancová, Egon Kurca, L'ubomir Lisý, Xavier Montalbán, Guillermo Izquierdo, Rafael Arroyo, Jose Maria Prieto, Oscar Fernández, Celia Oreja-Guevara, Fernando Sanchez Lopez, Cristina Guijarro, Nataliya Voloshina, Igor Pasyura, Borys Palamar, Tetyana Nehrych, Tetyana Kobys, Nataliya Lytvynenko, Alla Goloborodko, Nataliya Buchakchyys'ka, Volodymyr Lebedynets, Tatyana Ryabichenko, Grygory Kushnir, Sergii Moskovko, Galyna Chmyr, Mary Forester, Ricardo Ayala, James Voci, Stanley Krolczyk, Braeme Glaun, Robert Smith, Giles Crowell, Revere Philip Kinkel, Malti Patel, Tamara Miller, Gabriel Pardo, Stephen Asher, Christopher LaGanke, Donald Ayres, Matthew Baker, Mitzi Williams, William Sheremata, Alberto Vasquez, Mark Janicki, George Garmany Jr, Richard Hull, David Steiner, Joseph Herbert, Keith Edwards, Robert Fox, Bhupendra Khatri, Michael Levin, David Mattson, Angela Applebee, Joseph Phillips Jr, Mary Ann Picone, Warren Felton 3rd, Edward Fox, Michelle Apperson, Scott Gold, Mariko Kita, Harold Moses Jr, Robert Shin, John Rinker 2nd, George Hutton, Lauren Krupp, Patricia Fodor, John Foley, Suzanne Gazda, William Honeycutt, Galen Mitchell, Saud Sadiq, Brian Steingo, Dina Jacobs, Steven Freedman, Bianca Weinstock-Guttman, Sharon Lynch, Anand Vaishnav, Sibyl Wray, Samuel Hunter, Christopher Luzzio, John Huddlestone, Stanley Cohan, Angel Chinea, Daniel Giang, Richard Shubin, Donald Negroski, Allan Perel, Michael Stein, Allan Herskowitz, Jonathan Warach, Daniel Mikol, Roberto Bomprezzi, Geoffery Eubank, Jonathan Licht, Herman Sullivan, T Hemanth Rao, Stephen Newman, Stuart Silverman, Mark Gudesblatt, William Sunter Jr, Alireza Minagar, Kottil Rammohan, Malcolm Gottesman, John Schaeffer, Walter Carlini, Lee Stein, Richard Buckler, S Ausim Azizi, Brendan Bauer, Corey Ford
Abstract
Background: BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).
Methods: In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.
Results: At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.
Conclusions: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).
Source: PubMed