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Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage

2013; BMJ; Volume: 85; Issue: 8 Linguagem: Inglês

10.1136/jnnp-2013-306132

1468-330X

Massimo Filippi, Maria A. Rocca, Elisabetta Pagani, Nicola De Stefano, Douglas Jeffery, Ludwig Kappos, Xavier Montalbán, Alexey Boyко, Gıancarlo Comı, Massimo Filippi, Maria A. Rocca, Martina Absinta, Giulia Longoni, Sebastiano Galantucci, Elisabetta Pagani, Luca Dall’Occhio, Paolo Misci, Melissa Petrolini, Stefania Sala, Roberto Vuotto, Gıancarlo Comı, Alexey Boyко, Massimo Filippi, Douglas Jeffery, Ludwig Kappos, Xavier Montalbán, H. McFarland, Kenneth A. Bauer, N. Galay, Johannes Weber, Claudia Franta, C. Lampi, Penko Shotekov, S Bozhinov, Надежда Делева, L. Haralanov, Svetlana Hristova, Igor Petrov, Ivan Milanov, M. Kremenchutzky, Hyman H. Rabinovitch, Christiane Ayotte, François Grand’Maison, Albert Lamontagne, Richard Leckey, L. H. N. Lee, Pavel Hradílek, Petr Kaňovský, Katrin Gross‐Paju, Pille Taba, P. Vermersch, L. Rumbach, Pierre Clavelou, Cyrille B. Confavreux, Jean Pelletier, Gilles Edan, R Shakarishvili, Alexander Tsiskaridze, E. Becker, Andrew Chan, Jeffrey S. Eggers, Jürgen Haas, C. Heesen, Fedor Heidenreich, J. Koehler, H. W. Koelmel, Ralf A. Linker, Patrick Oschmann, Sebastian Rauer, M. Maschke, Meike Mueller, Gerd Reifschneider, Britt Wildemann, Alice Steinbrecher, Hayrettin Tumani, Uwe Ziebold, Tjalf Ziemssen, J. Kanya, Gábor Jakab, A. Valikovics, Laura M. Bartos, D. Karussis, Hanna Rawashdeh, Arnon Karni, Jeremy R. Chapman, Gıancarlo Comı, D. Caputo, Diego Centonze, Salvatore Cottone, Angelo Ghezzi, Davide Maimone, E. Montanari, Katrin Plewnia, Elio Scarpini, Marco Metra, Daiva Rastenytė, S. Sceponaviciute, Bas de Jong, S. T. F. M. Frequin, L. Visser, Cees Zwanikken, Krzysztof Selmaj, B. Blaszczyk, A Wajgt, Richard J. Nowak, Elżbieta Jasińska, Waldemar Brola, M. Sobkowiak-Osinska, Janusz Kapustecki, Jacek Zaborski, Cristina Panea, Mihaela Simu, Angelo Bulboacă, Rodica Bălașa, N. Cârciumaru, Alexey Boyко, A A Skoromets, I. D. Stolyarov, S. Perfilyev, M. Odinak, Olga A. Amelina, N A Malkova, А В Густов, Л. И. Волкова, А М Шутов, Jelena Drulović, Slobodan Vojinović, Montalban, Rosa Arroyo-García, Albert Saiz Hinarejos, Luís Brieva, Lluís Ramió, José Meca Lallana, M. Amigo Jorrin, José M. Prieto, D. Gracia, Yolanda Aladro, Francisco Coret, Antonio Escartín, Exuperio Díez–Tejedor, Jan Hillert, T. Olddon, Charles W. Martin, Egemen İdıman, Basil Sharrack, Gavin Giovannoni, Carolyn Young, Tetyana Nehrych, Sergii Moskovko, Tetyana Kobys, AIpatov, K. Loganovskyi, Nadia Abou‐Zeid, Douglas Jeffery, Bhupesh Dihenia, Adam Carpenter, Stephen Flitman, Suzanne Gazda, Andrew Goodman, Brian Green, Sachin Gupta, J. Herbert, B.P. Hughes, Alice K. Jacobs, B. Khatri, S. Lynch, Tasha Miller, Clyde Markowitz, Richard M. Murray, Gabriel Pardo, G. Parry, G. Gottschalk, Howard Rossman, S. Scaberry, Florian P. Thomas, Anthony P. Turel, Gregory J. Anderson, CTwyman, D. Wyn,

Toxin Mechanisms and Immunotoxins

In Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod's potential effects on inflammation and neurodegeneration.1106 RRMS patients were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM.Compared with placebo, laquinimod-treated patients showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p<0.05). By month 24, MTR decreased significantly in NABT (p=0.015), WM (p=0.011) and GM (p=0.034) in placebo-treated patients, but not in laquinimod-treated patients. WM NAA/Cr tended to increase with laquinimod and decrease with placebo at 24 months (p=0.179).Oral laquinimod may reduce (at least in the initial phase of treatment) some of the more destructive pathological processes in RRMS patients.The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.