Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis
Fox, Robert J; Miller, David H; Phillips, J Theodore; Hutchinson, Michael; Havrdova, Eva; Kita, Mariko; Yang, Minhua; Raghupathi, Kartik; Novas, Mark; Sweetser, Marianne T; Viglietta, Vissia; Dawson, Katherine T; Antel, Jack; Ware, James; Polman, Chris; Kowey, Peter R; Chung, Raymond; Bakris, George; Richert, John; Seibert, Burt; Brandes, David; Brassat, David; Cohen, Bruce; Diem, Ricarda; Goldman, Myla; Herndon, Robert; Miller, Aaron; Tumani, Hayrettin; Alfaro-Vidal, Teresa; Crespo, Carolina; Foster, Jo; Hunter, Kelvin; Garcia-Gomez, Almudena; MacManus, David; Miller, David; Santana, Virginia; Tozer, Dan; Kingshott-Wheeler, Claudia; Yousry, Tarek; Kneebone, Christopher; Fedulau, Aliaksandr; Mikhailova, Elena; Likhachev, Sergey; Naumova, Halina; Vande Gaer, Luc; Decoo, Danny; Sindic, Christian; Grgic, Sanja; Sinanovic, Osman; Suljic, Enra Mehmedika; Georgiev, Dimitar; Haralanov, Lyubomir; Ivanova, Sonyia; Minchev, Dimitar; Tournev, Ivailo; Stamenova, Paraskeva; Deleva, Nadezhda; Zahariev, Zahari; Manchev, Ivan; Vacheva, Elena; Bar-Or, Amit; Kremenchutzky, Marcelo; Veloso, Felix; Witt, Norbert; Blevins, Gregg; Parajeles Vindas, Alexander; Vargas Howell, Roberto; Soldo-Butković, Silva; Rudež, Josip; Habek, Mario; Vurdelja, Ranka Baraba; Havrdova, Eva; Doležil, David; Vaclavik, Daniel; Novak, JiÅ™Ã; Gross-Paju, Katrin; Antsov, Katrin; Haldre, Sulev; Palu, Alla; Toomsoo, Toomas; Camu, William; Pelletier, Jean; Labauge, Pierre; Debouverie, Marc; Defer, Gilles; De Seze, Jérôme; Moreau, Thibault; Al Khedr, Abdullatif; Rumbach, Lucien; Daskalovska, Vera; Landefeld, Harald; Masri, Sabine; Schimrigk, Sebastian; Tackenberg, Björn; Eisensehr, Ilonka; Hoffmann, Frank; Kieseier, Bernd; Lüer, Wilfried; Benes, Heike; Paschen, Christine; Derfuß, Tobias; Sailer, Michael; Storch-Hagenlocher, Brigitte; Berthele, Achim; Oschmann, Patrick; Angnstwurm, Klemens; Hohlfeld, Reinhard; Reifschneider, Gerd; Tiel-Wilck, Klaus; Nelles, Gereon; Boldt, Hans-Jürgen; Emrich, Peter; Kallmann, Boris-Alexander; Feneberg, Wolfgang; Christopher, Angelika; Hüntemann, Reinhard; Spiegel-Meixensberger, Mechthild; Thomaides, Thomas; Vlaikidis, Nicholas; Karageorgiou, Clementine; Papathanasopoulos, Panagiotis; Mehndiratta, Man Mohan; Vijayan, Krishnan; Arjundas, Deepak; Srinivasa, Rangasetty; Ghosh, Amitabha; Kulkarni, Rahul Vitthal; Shah, Shalin Dipinkumar; Mukherji, Joy Dev; Nellikunja, Shankara; Behari, Madhuri; Singh, Gagandeep; Ghosh, Pahari; Ichaporia, Nasli Rustom; Sethi, Prahlad Kumar; Mehta, Neeta Abhay; Misra, Usha Kant; Singh, Maneesh Kumar; Khurana, Dheeraj; Salem, Abdu; Sweeney, Bernard; Gilad, Ronit; Shahien, Radi; Paegle, Anita; Punzo, Guillermo; Santos, Jose; Quiñones, Sandra; Macias, Miguel Angel; Estañol, Bruno; Escamilla, Juan; Lopez, Neyla; Renteria, Mariela; Delgado, Cesar; Odainic, Olesea; Groppa, Stanislav; Gavriliuc, Mihail; Timmings, Paul; Drozdowski, Wieslaw; Fryze, Waldemar; Kochanowicz, Jan; Kaminska, Anna; Selmaj, Krzysztof; Wajgt, Andrzej; Kleczkowska, Magdalena; Nowacki, Przemyslaw; Czlonkowska, Anna; Stelmasiak, Zbigniew; Podemski, Ryszard; Dorobek, Malgorzata; Hertmanowska, Hanka; Pierzchala, Krystyna; Zielinski, Tomasz; Szczudlik, Andrzej; Tutaj, Andrzej; Losy, Jacek; Potemkowski, Andrzej; Nyka, Walenty; Kapelusiak-Pielok, Magdalena; Ionescu-Dimancea, Valentin; Balasa, Rodica; Mihancea, Petru; Popescu, Cristian; Protosevici, Liviu Codrut; Vojinovic, Slobodan; Drakulić, Svetlana Miletić; Raicevic, Ranko; Nadj, Congor; TurÄáni, Peter; Kahancová, Edita; Kurca, Egon; Lisý, Lubomir; Montalbán, Xavier; Izquierdo, Guillermo; Arroyo, Rafael; Prieto, Jose Maria; Fernández, Oscar; Oreja-Guevara, Celia; Sanchez Lopez, Fernando; Guijarro, Cristina; Voloshina, Nataliya; Pasyura, Igor; Palamar, Borys; Nehrych, Tetyana; Kobys, Tetyana; Lytvynenko, Nataliya; Goloborodko, Alla; Buchakchyyska, Nataliya; Lebedynets, Volodymyr; Ryabichenko, Tatyana; Kushnir, Grygory; Moskovko, Sergii; Chmyr, Galyna; Forester, Mary; Ayala, Ricardo; Voci, James; Krolczyk, Stanley; Glaun, Braeme; Smith, Robert; Crowell, Giles; Kinkel, Revere Philip; Patel, Malti; Miller, Tamara; Pardo, Gabriel; Asher, Stephen; LaGanke, Christopher; Ayres, Donald; Baker, Matthew; Williams, Mitzi; Sheremata, William; Vasquez, Alberto; Janicki, Mark; Garmany, George Jr; Hull, Richard; Steiner, David; Herbert, Joseph; Edwards, Keith; Fox, Robert; Khatri, Bhupendra; Levin, Michael; Mattson, David; Applebee, Angela; Phillips, Joseph Jr; Picone, Mary Ann; Felton, Warren 3rd; Fox, Edward; Apperson, Michelle; Gold, Scott; Kita, Mariko; Moses, Harold Jr; Shin, Robert; Rinker, John 2nd; Hutton, George; Krupp, Lauren; Fodor, Patricia; Foley, John; Gazda, Suzanne; Honeycutt, William; Mitchell, Galen; Sadiq, Saud; Steingo, Brian; Jacobs, Dina; Freedman, Steven; Weinstock-Guttman, Bianca; Lynch, Sharon; Vaishnav, Anand; Wray, Sibyl; Hunter, Samuel; Luzzio, Christopher; Huddlestone, John; Cohan, Stanley; Chinea, Angel; Giang, Daniel; Shubin, Richard; Negroski, Donald; Perel, Allan; Stein, Michael; Herskowitz, Allan; Warach, Jonathan; Mikol, Daniel; Bomprezzi, Roberto; Eubank, Geoffery; Licht, Jonathan; Sullivan, Herman; Rao, T Hemanth; Newman, Stephen; Silverman, Stuart; Gudesblatt, Mark; Sunter, William Jr; Minagar, Alireza; Rammohan, Kottil; Gottesman, Malcolm; Schaeffer, John; Carlini, Walter; Stein, Lee; Buckler, Richard; Azizi, S Ausim; Bauer, Brendan; Ford, Corey
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.).
PMID: 22992072
ISSN: 1533-4406
CID: 5347972