Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension
2018; Elsevier BV; Volume: 17; Issue: 5 Linguagem: Inglês
10.1016/s1474-4422(18)30069-3
ISSN1474-4465
AutoresRaju Kapoor, Pei‐Ran Ho, Nolan Campbell, Ih Chang, Aaron Deykin, Fiona Forrestal, Nisha Lucas, Bei Yu, Douglas L. Arnold, Mark S. Freedman, Myla Goldman, Hans-Peter Hartung, Eva Havrdová, Douglas Jeffery, A Miller, Finn Sellebjerg, Diego Cadavid, Dan Mikol, Deborah Steiner, E Bartholomé, Marie D’hooghe, Massimo Pandolfo, Bart Van Wijmeersch, Virender Bhan, Gregg Blevins, Donald Brunet, Virginia Devonshire, Pierre Duquette, Mark S. Freedman, François Grand’Maison, François Jacques, Yves Lapierre, Liesly Lee, Sarah A. Morrow, Michael Yeung, Michal Dufek, Eva Havrdová, Petr Kaňovský, Ivana Štětkářová, Marika Talábová, Jette Lautrup Frederiksen, Matthias Kant, Thor Petersen, Mads Ravnborg, Finn Sellebjerg, Laura Airas, Irina Elovaara, Juha-Pekka Erälinna, Taneli Sarasoja, Abdullatif Al Khedr, David Brassat, Bruno Brochet, William Camu, Marc Debouverie, David Laplaud, Christine Lebrun‐Frénay, Jean Pelletier, Patrick Vermersch, Sandra Vukusi, Karl Baum, Achim Berthele, Juergen Faiss, Peter Flachenecker, Reinhard Hohlfeld, Markus Krumbholz, Christoph Lassek, Markus Maeurer, Sven G. Meuth, Tjalf Ziemssen, Orla Hardiman, Christopher McGuigan, Anat Achiron, Dimitrios Karussis, Roberto Bergamaschi, Vincenzo Brescia Morra, Giancarlo Comi, Salvatore Cottone, Luigi M.E. Grimaldi, Gianluigi Mancardi, Luca Massacesi, Ugo Nocentini, Marco Salvetti, Elio Scarpini, Patrizia Sola, Gioacchino Tedeschi, Maria Trojano, Mauro Zaffaroni, Stephan Frequin, Raymond Hupperts, Joep Killestein, Hans M. Schrijver, Ronald Van Dijl, Erik van Munster, Maciej Czarnecki, Wiesław Drozdowski, Waldemar Fryze, Hanka Hertmanowska, Jan Ilkowski, Anna Kamińska, Gabriela Kłodowska-Duda, Maciej Maciejowski, Ewa Motta, Ryszard Podemski, Andrzej Potemkowski, Teresa Róg, Krzysztof Selmaj, Z Stelmasiak, Adam Stȩpień, Andrzej Tutaj, Jacek Zaborski, Alexey Boyко, Zanna Chefranova, Evgeny Evdoshenko, Ф. А. Хабиров, С А Сиверцева, E Z Yakupov, José Carlos Álvarez Cermeño, Antonio Escartín, Óscar Fernández Fernández, Antonio García‐Merino, Miguel Ángel Hernández Pérez, Guillermo Izquierdo Ayuso, José Meca Lallana, Xavier Montalbán, Celia Oreja‐Guevara, Albert Saiz Hinarejos, Martin Gunnarsson, Jan Lycke, Claes Martin, Fredrik Piehl, Homayoun Roshanisefat, Peter Sundström, Martin Duddy, Bruno Gran, Timothy Harrower, Jeremy Hobart, Raju Kapoor, Martin L. Lee, Paul Mattison, Richard Nicholas, Owen Pearson, Waqar Rashid, David Rog, Basil Sharrack, Eli Silber, Ben Turner, Anna Williams, John Woolmore, Carolyn Young, Daniel S. Bandari, Joseph R. Berger, Ann Camac, Stanley Cohan, Jill Ker Conway, Keith R. Edwards, Michelle Fabian, Jack Florin, Steven Freedman, Dennis Garwacki, Myla Goldman, Daniel M. Harrison, Craig Herrman, DeRen Huang, Adil Javed, Douglas Jeffery, Stephen Kamin, George Katsamakis, Bhupendra Khatri, Annette Langer-Gould, Sharon Lynch, David H. Mattson, Tamara Miller, Augusto Miravalle, Harold Moses, Suraj Muley, James Napier, A. Scott Nielsen, Andrew R. Pachner, Gabriel Pardo, MaryAnn Picone, Derrick Robertson, Walter Royal, Christopher A. Sheppard, Ben Thrower, Cary Twyman, Emmanuelle Waubant, Jeanette Wendt, Vijayshree Yadav, Rana Zabad, Greg Zarelli,
Tópico(s)Autoimmune and Inflammatory Disorders Research
ResumoBackground Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding Biogen.
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