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Multiple sclerosis and cognition: correlation of symbol digit modalities test (SDMT) and MindStreams computerized cognitive testing [Meeting Abstract]
Gudesblatt, M.; Chadha, J.; Zarif, M.; Buhse, M.; Bumstead, B.; Thotam, S.; Fafard, L.; Sullivan, C.; Wilken, J.; Doniger, G.
ISI:000328751401102
ISSN: 1352-4585
CID: 5343212
Fatigue in multiple sclerosis: an exploration of the relationship between obstructive sleep apnea, body mass index, fatigue severity scale, Epworth sleepiness scale and expanded disability status score (EDSS) in a community cohort [Meeting Abstract]
Gudesblatt, M.; Xian, S.; Zarif, M.; Bumstead, B.; Buhse, M.; Thotam, S.; Fafard, L.; Strober, L.; DeLuca, J.; Brass, S.
ISI:000328751401103
ISSN: 1352-4585
CID: 5343222
Multiple sclerosis and driving: correlation between patient self-reported driving and cognitive function [Meeting Abstract]
Gudesblatt, M.; Zarif, M.; Bumstead, B.; Buhse, M.; Thotam, S.; Fafard, L.; Sullivan, C.; Wilken, J.; Doniger, G.
ISI:000328751402246
ISSN: 1352-4585
CID: 5343232
Natalizumab: real life adherence to disease modifying therapy in multiple sclerosis care [Meeting Abstract]
Gudesblatt, M.; Gorbatsevych, O.; Bumstead, B.; Zarif, M.; Thippeswamy, G.; Thotam, S.; Fafard, L.; Buhse, M.
ISI:000328751403101
ISSN: 1352-4585
CID: 5343242
An overview of JC virus and progressive multifocal leukoencephalopathy
Gudesblatt, Mark
ORIGINAL:0016172
ISSN: 1075-4598
CID: 5347902
Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial
Cohen, Jeffrey A; Coles, Alasdair J; Arnold, Douglas L; Confavreux, Christian; Fox, Edward J; Hartung, Hans-Peter; Havrdova, Eva; Selmaj, Krzysztof W; Weiner, Howard L; Fisher, Elizabeth; Brinar, Vesna V; Giovannoni, Gavin; Stojanovic, Miroslav; Ertik, Bella I; Lake, Stephen L; Margolin, David H; Panzara, Michael A; Compston, D Alastair S; Arnold, Doug; Panitch, Hillel; Clifford, David; Antel, Jack; Barkhof, Frederik; Snydman, David; DeGroot, Leslie; Cines, Douglas; D'Agostino, Ralph; Greenberg, Benjamin; Krauss, Jörg; Markowitz, Clyde; Naismith, Robert; Tabby, David; Gupta, Ajay S; Fox, Edward J; Glyman, Steven A; Cascione, Mark; Boster, Aaron; Rammohan, Kottil; Gazda, Suzanne; Wynn, Daniel R; Wray, Sibyl; Ford, Corey C; Goodman, Andrew; Hutton, George; Kaufman, Michael; Khan, Omar Azhar; Vaishnav, Anand; Kirzinger, Stephen; Lynch, Sharon G; Braley, Tiffany; Mikol, Daniel; Miller, Tamara; Ionete, Carolina; Riskind, Peter; Bomprezzi, Roberto; Carter, Jonathan; Steingo, Brian; Twyman, Cary; Bass, Ann; Lallana, Enrico; Kasper, Lloyd; Minagar, Alireza; Hunter, Samuel; Sheppard, Christopher; Herbert, Joseph; Pardo, Gabriel; Rowe, Vernon D; LaGanke, Christopher C; Edwards, Keith; Wendt, Jeanette K; Jones, David; Clauser, Gary; Vincent, Stephen Gerard; Gudesblatt, Mark; Freedman, Mark; Yeung, Michael; Grand'Maison, Francois; Jacques, Francois; Traboulsee, Anthony; Macdonell, Richard; King, John; Paine, Mark; Boundy, Karyn; Broadley, Simon; Vucic, Steve Ostoja; Reddel, Stephen; Dreyer, Michael; McCombe, Pamela; Ferreira, Maria Lucia; Callegaro, Dagoberto; Martins, Marcio Menna Barreto; Villanueva, Jesus Arturo Violante; Caballero, Noemi Santos; Deri, Norma Haydee; Coles, Alasdair; Robertson, Neil; Giovannoni, Gavin; Sharrack, Basil; Clanet, Michel; Haas, Judith; Stangel, Martin; Ziemssen, Tjalf; Baum, Karl; Faiss, Juergen; Ziemann, Ulf; Lycke, Jan; Kovarova, Ivana; Vachova, Marta; Selmaj, Krzysztof; Szczudlik, Andrzej; Stelmasiak, Zbigniew; Kozubski, Wojciech; Gusev, Evgeniy; Stolyarov, Igor; Zavalishin, Igor; Skoromets, Alexander; Boyko, Alexei; Belova, Anna; Malkova, Nadezhda; Barantsevich, Evgeniy; Yakupov, Eduard; Mishin, Gennadiy; Poverennova, Irina; Magzhanov, Rim; Orzheshkovskyi, Vasyl; Malyy, Volodymyr; Voloshyna, Natalia; Nehrych, Tetyana; Kobys, Tetyana; Habek, Mario; Brinar, Vesna; Trkanjec, Zlatko; Vladić, Anton; Antonelli, Licija; Rudež, Josip; Kidemet-Piskać, Spomenka; Drulović, Jelena; Nadj, ÄŒongor; DinÄić, Evica; Vojinović, Slobodan; Stojanović, Miroslav; Pantović, Mihailo
BACKGROUND:The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. METHODS:In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. FINDINGS/RESULTS:187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. INTERPRETATION/CONCLUSIONS:Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. FUNDING/BACKGROUND:Genzyme (Sanofi) and Bayer Schering Pharma.
PMID: 23122652
ISSN: 1474-547x
CID: 5347982
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial
Coles, Alasdair J; Twyman, Cary L; Arnold, Douglas L; Cohen, Jeffrey A; Confavreux, Christian; Fox, Edward J; Hartung, Hans-Peter; Havrdova, Eva; Selmaj, Krzysztof W; Weiner, Howard L; Miller, Tamara; Fisher, Elizabeth; Sandbrink, Rupert; Lake, Stephen L; Margolin, David H; Oyuela, Pedro; Panzara, Michael A; Compston, D Alastair S; Panitch, Hillel; Clifford, David; Antel, Jack; Barkhof, Frederik; Snydman, David; DeGroot, Leslie; Cines, Douglas; D'Agostino, Ralph; Greenberg, Benjamin; Krauss, Jörg; Limmroth, Volker; Markowitz, Clyde; Naismith, Robert; Tabby, David; Gupta, Ajay S; Fox, Edward; Glyman, Steven A; Thoits, Timothy K; Sullivan, Herman C; Cascione, Mark C; Rammohan, Kottil W; Gazda, Suzanne K; Wynn, Daniel R; Wray, Sibyl E; Elias, Stanton; Ford, Corey C; Goodman, Andrew; Hughes, Bruce L; Khan, Omar Azhar; Vaishnav, Anand G; Kirzinger, Stephen; Lynch, Sharon G; Mattson, David H; Braley, Tiffany J; Mikol, Daniel D; Krieger, Stephen; Miller, Aaron; Miller, Tamara Ann; Collins, Fort; Riskind, Peter N; Bomprezzi, Roberto; Wingerchuk, Dean M; Steingo, Brian; Cohen, Jeffrey Alan; Crayton, Heidi J; Royal, Walter 3rd; Twyman, Cary L; Cooper, Joanna A; Weiner, Leslie P; Moses, Harold Jr; Agius, Mark A; Bass, Ann Doan-Do; Lallana, Enrico C; Mitchell, Galen W; Krolczyk, Stanley J; Minagar, Alireza; Jubelt, Burk; Evans, Bradley K; Hunter, Samuel F; Rizvi, Syed A; Sheppard, Christopher A; Honeycutt, W M David; Herbert, Joseph; Lathi, Ellen S; Pardo, Gabriel; Ilenson, Lily Jung; Rothstein, Ted L; Thrower, Ben W; Picone, Mary Ann; Kita, Mariko; Grazioli, Erica M; Silliman, Scott L; Giancarlo, Thomas; Gottesman, Malcolm H; Zeid, Nuhad E Abou; Rowe, Vernon D 3rd; Boutwell, Christine M; Schaeffer, John D; LaGanke, Christopher C; Riley, Claire S; Gottschalk, Christopher; Preiningerova, Jana; Edwards, Keith R; Wendt, Jeanette K; Bigley, Kim Jr; Singer, Barry A; Shubin, Richard A; Markovic-Plese, Silva; Jones, Davis E; Clauser, Gary; Freedman, Mark S; Grand'Maison, Francois; Jacques, Francois H; Traboulsee, Anthony L; Brunet, Donald G; Kremenchutzky, Marcelo; Ayotte, Charles; Lava, Neil S; Waldman, Stephen R; Janus, Todd J; Vincent, Stephen Gerard; Gudesblatt, Mark; Rossen, Michael; Stein, Lee S; Machanic, Bennett-Irving; Vollmer, Timothy; Gitt, Jeffrey S; Dunn, Jeffrey; Negroski, Donald; Fletcher, Mark H; Javed, Adil; Frohman, Elliot M; Macdonell, Richard; Owen, John; Paine, Mark A; Boundy, Karyn; Broadley, Simon; Vucic, Steve; Reddel, Stephen; Dreyer, Michael D; Schwartz, Raymond; McCombe, Pamela Ann; Hodgkinson, Suzanne; Tilbery, Charles; Ferreira, Maria Lucia B; Callegaro, Dagoberto; Martins, Marcio Mena Barreto; Villanueva, Jesus Arturo Violante; Caballero, Noemi Santos; Mendoza, Claudia Venzor; Deri, Norma Haydee; Coles, Alasdair; Scolding, Neil James; Giovannoni, Gavin; Sharrack, Basil; Rog, David J; Comi, Giancarlo; Ghezzi, Angelo; Mancardi, Giovanni L; Durelli, Luca; Bertolotto, Antonio; Capra, Ruggero; Pozzilli, Carlo; Marrosu, Maria Giovanna; Hupperts, Raymond M M; van Munster, Erik; Montalbán, Xavier; González, Rafael Arroyo; Ayuso, Guillermo Izquierdo; Fernández, Óscar Fernández; Haya, Carlos; Confavreux, Christian; Vermersch, Patrick; de Seze, Jerome; Moreau, Thibault; Clavelou, Pierre; Lubetzki, Catherine; Clanet, Michel; Debouverie, Marc; Edan, Gilles; Hartung, Hans-Peter; Haas, Judith; Stangel, Martin; Ziemssen, Tjalf; Hemmer, Bernhard; Baum, Karl; Zettl, U Klaus; Herrlinger, U; Köhler, Wolfgang; Ochs, Gunter; Oschmann, Patrick; Tiel-Wilck, Klaus; Tumani, Hayrettin; Urban, Peter P; Lycke, Jan; Svenningsson, Anders; Kovarova, Ivana; Vachova, Marta; Rektor, Ivan; Talab, Radomir; Selmaj, Krzysztof; Stelmasiak, Zbigniew; Kozubski, Wojciech; Dubois, Benedicte D P; Dive, Dominique; Grandfossé, Rue; Sindic, Christian; Vass, Karl; Sørensen, Per Soelberg; Petersen, Thor; Ravnborg, Mads; Achiron, Anat; Dembinsky, Adi Vaknin; Karni, Arnon; Gusev, Evgeny I; Stolyarov, Igor D; Zavalishin, Igor A; Skoromets, Alexander A; Boyko, Alexei N; Belova, Anna N; Malkova, Nadezhda A; Barantsevich, Evgeniy R; Yakupov, Eduard Z; Perfiliev, Semen V; Poverennova, Irina E; Voloshyna, Natalia P; Nehrych, Tetyana I; Kobys, Tetyana O; Habek, Mario; Brinar, Vesna; Trkanjec, Zlatko; Vladić, Anton; Piskać, Spomenka Kidemet; MeÅ¡trovića, Ivana; Antonelli, Licia; Drulović, Jelena; Nadj, ÄŒongor; DinÄić, Evica; TonÄev, Gordana
BACKGROUND:The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment. METHODS:In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405. FINDINGS/RESULTS:202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia. INTERPRETATION/CONCLUSIONS:For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity. FUNDING/BACKGROUND:Genzyme (Sanofi) and Bayer Schering Pharma.
PMID: 23122650
ISSN: 1474-547x
CID: 5347992
Multiple sclerosis: Employment and employability-patient reported perspectives [Meeting Abstract]
Gudesblatt, M; Goldstein, R; Kalina, J; Zarif, M; Bumstead, B; Fafard, L; Topalli, I; Buhse, M
Background: Patients with MS may experience both disability and unemployment. Understanding what specific symptoms are related to unemployment or employability from a patient perspective might allow interventions at the earliest possible time to maintain employability. Studies have identified many factors that may be related to changes in employment status, but none have focused on specifically which disease-related symptoms patients reported directly limit their ability to work. Objective: To obtain information from MS patients perspectives about specific symptoms that impair perceived ability to maintain employment. Methods: Retrospective review of cross-sectional data from MS patient reported symptoms that were obtained by means of self-reported information in the form of a validated standardized questionnaire. Results: 244 MS patients: 75% women, age 48 + 11 yrs, 40% employed, 60% unemployed. Most unemployed patients were on disability (40%). Employed patients experienced the fewest symptoms affecting work. Most patients already on disability experienced greatest difficulties in: multi-tasking (72%), tasks taking longer to complete (84%), and remembering tasks (64%). These same patients reported each symptom affecting work more frequently than those in any other employment category overall. Tasks taking longer to complete were reported to be the most job-limiting symptom overall (77%), especially in patients who were let go (71%), retired (78%), and volunteering (67%). Difficulty multi-tasking (61%) and difficulty remembering tasks (55%) were the next reported symptoms. The greatest symptoms in the disabled group were fatigue (85%) and physical difficulties (81%). Fatigue symptoms were experienced by the majority in all groups (86% overall), and was also reported as the symptom that most affected patients employability in all groups (73% overall). The average number of symptoms experienced for all groups did not vary between the employment groups. The average number of symptoms affecting wo!
EMBASE:71361659
ISSN: 1352-4585
CID: 853412
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
Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis
Gold, Ralf; Kappos, Ludwig; Arnold, Douglas L; Bar-Or, Amit; Giovannoni, Gavin; Selmaj, Krzysztof; Tornatore, Carlo; Sweetser, Marianne T; Yang, Minhua; Sheikh, Sarah I; Dawson, Katherine T; Selmaj, Krzystof; Gallacher, Phillip; Milla, Carole; Antel, Jack; Bakris, George; Chung, Raymond; Kowey, Peter R; Polman, Chris; Richert, John; Seibert, Burt; Ware, James; Brandes, David; Brassat, David; Cohen, Bruce; Diem, Ricarda; Goldman, Myla; Herndon, Robert; Miller, Aaron; Tumani, Hayrettin; Barnett, Michael; Butzkueven, Helmut; Beran, Roy; Casse, Reynolds; Chapman, Caron; Lechner-Scott, Jeannette; Macdonell, Richard; Paine, Mark; Schwartz, Raymond; Berger, Thomas; Fazekas, Franz; Ransmayr, Gerhard; Vass, Karl; Belachew, Shibeshih; Decoo, Danny; De Deyn, Peter Paul; Dubois, Bénédicte; Vande Gaer, Luc; Medaer, Robert; Seeldrayers, Pierrette; Sindic, Christian; Vanopdenbosch, Ludo; Grgic, Sanja; Bhan, Virender; Bouchart, Jean-Pierre; Christie, Suzanne; Bar-Or, Amit; Jacques, François; Grammond, Pierre; Veloso, Felix; Vorobeychick, Galina; Brinar, Vesna; Demarin, Vida; Rudež, Josip; Soldo-Butković, Silva; Vurdelja, Ranka Baraba; Ambler, ZdenÄ›k; Doležil, David; Havrdova, Eva; Kanovsky, Petr; Meluzinova, Eva; Nova'k, JiÅ™Ã; Rektor, Ivan; Skoda, Ondrej; Vachová, Marta; Camu, William; Clavelou, Pierre; Coman, Antoanela Irène; Confavreux, Christian; Edan, Gilles; Gout, Olivier; Lebrun-Frenay, Christine; Papeix, Anne-Caroline; Vermersch, Patrick; Bachus-Banaschak, Katrin; Berghoff, Martin; Bethke, Florian; Boldt, Hans-Jürgen; Chan, Andrew; Diener, Hans-Christoph; Eisensehr, Ilonka; Emrich, Peter; Griewing, Bernd; Haas, Judith; Heesen, Christoph; Heidenreich, Fedor; Hoffmann, Frank; Hufnagel, Andreas; Kleiter, Ingo; Lüer, Wilfried; Marckmann-Böenke, Silke; Marziniak, Martin; Oschmann, Patrick; Rosenkranz, Thorsten; Schneider, Hauke; Siefjediers, Veneta; Springub, Joachim; Stangel, Martin; Stögbauer, Florian; Bergh, Florian Then; Tiel-Wilck, Klaus; Tinschert, Konstanze; Grigoriadis, Nikolaos; Karageorgiou, Clementine; Kyritsis, Athanssios; Papadimitriou, Alexandros; Thomaides, Thomas; Vlaikidis, Nicholas; Yaxcal Chon, David; Salguero Gonzalez, Luis Fernando; Ordoñez Sarg, Hugo Alfredo; Agrawal, C S; Behari, Madhuri; Cu, Velmurugendran; Dwivedee, Shamsher; Kothari, Sudhir; Kulkarni, Rahul; Kushwaha, Suman; Meena, A K; Mehndiratta, M M; Mukherjee, Subhash Chandra; Pandit, Lekha; Shah, Arun; Shukla, Rakesh; Vijayan, K; Achiron, Anat; Flechter, Shlomo; Milo, Ron; Vaknin-Dembinsky, Adi; Pozzilli, Carlo; Oropeza de Alba, José Luis; Castro Farfan, Freddy Guillermo; Rangel Guerra, Ricardo Alberto; Rodriguez Leyva, Ildefonso; Arcega Revilla, Raúl; Flores Rivera, Jose; Gavriliuc, Mihail; Groppa, Stanislav; Odainic, Olesea; Hupperts, Raymond; Sanders, E A C M; Mason, Deborah; Timmings, Paul; Willoughby, Ernest; Czlonkowska, Anna; Dorobek, Malgorzata; Drozdowski, Wieslaw; Hertmanowska, Hanka; Fryze, Waldemar; Kleczkowska, Magdalena; Kochanowicz, Jan; KwieciÅ„ski, Hubert; Nowacki, Przemyslaw; Podemski, Ryszard; Potemkowski, Andrzej; Selmaj, Krzysztof; Stelmasiak, Zbigniew; Wajgt, Andrzej; Zielinski, Tomasz; Daskalovska, Vera; Bajenaru, Alexandru Ovidiu; Muresanu, Fior Dafin; Nica, Sanda Maria; Simu, Mihaela Adriana; Drakulić, Svetlana Miletić; Nadj, Congor; Obradovic, Dragana; Vojinovic, Slobodan; Kahancová, Edita; Krajnak, Viliam; Kurca, Egon; Lisý, L'ubomir; TurÄáni, Peter; Badenhorst, Frans; Green, Judy; Heckmann, Jeannine; Isaacs, Michael; Kappos, Ludwig; Linnebank, Michael; Müller, Stefanie; Buchakchyys'ka, Nataliya; Goloborodko, Alla; Kobys, Tetyana; Lebedynets, Volodymyr; Lytvynenko, Nataliya; Nehrych, Tetyana; Pasyura, Igor; Ryabichenko, Tatyana; Voloshina, Nataliya; Duddy, Martin; Hawkins, Clive; Nicholas, Richard; Palace, Jacqueline; Sharrack, Basil; Silber, Eli; Turner, Ben; Camac, Ann; Chumley, Warren; Crayton, Heidi; Dixit, Shanker; English, Jeffrey; Edwards, Keith; Freedman, P Steven; Gazda, Suzanne; Goldstick, Lawrence; Gordon, Norman; Gottschalk, Christopher; Grazioli, Erica; Grelinger, Bart; Green, Barbara; Hayat, Ghazala; Hendin, Barry; Janus, Todd; Henson, Lily Jung; Goldstick, Lawrence; Grainger, William; Gudesblatt, Mark; Gupta, Ajay; Hentati, Afif; Herrman, Craig; Itkin, Arthur; Kasper, Lloyd; Lathi, Ellen; Mowry, Ellen; Parry, Gareth; Perel, Allan; Rao, T Hemanth; Riskind, Peter; Rizvi, Syed; Rossen, Michael; Rossman, Howard; Scott, Thomas; Shafer, S James; Storey, James Jr; Thrower, Ben; Tornatore, Carlo; Tosches, William; Trefts, Lori Jr; Turel, Anthony Jr; Weinstock-Guttman, Bianca
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.).
PMID: 22992073
ISSN: 1533-4406
CID: 5348002
