1. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND)
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Raju Kapoor, Pei-Ran Ho, Nolan Campbell, Ih Chang, Aaron Deykin, Fiona Forrestal, Nisha Lucas, Bei Yu, Douglas L Arnold, Mark S Freedman, Myla D Goldman, Hans-Peter Hartung, Eva Kubala Havrdová, Douglas Jeffery, Aaron Miller, Finn Sellebjerg, Diego Cadavid, Dan Mikol, Deborah Steiner, Emmanuel Bartholomé, Marie D'Hooghe, Massimo Pandolfo, Bart Van Wijmeersch, Virender Bhan, Gregg Blevins, Donald Brunet, Virginia Devonshire, Pierre Duquette, Mark Freedman, François Grand'Maison, François Jacques, Yves Lapierre, Liesly Lee, Sarah Morrow, Michael Yeung, Michal Dufek, Petr Kanovsky, Ivana Stetkarova, Marika Talabova, Jette Frederiksen, Matthias Kant, Thor Petersen, Mads Ravnborg, Laura Airas, Irina Elovaara, Juha-Pekka Eralinna, Taneli Sarasoja, Abdullatif Al Khedr, David Brassat, Bruno Brochet, William Camu, Marc Debouverie, David Laplaud, Christine Lebrun Frenay, Jean Pelletier, Patrick Vermersch, Sandra Vukusi, Karl Baum, Achim Berthele, Juergen Faiss, Peter Flachenecker, Reinhard Hohlfeld, Markus Krumbholz, Christoph Lassek, Mathias Maeurer, Sven Meuth, Tjalf Ziemssen, Orla Hardiman, Christopher McGuigan, Anat Achiron, Dimitrios Karussis, Roberto Bergamaschi, Vincenzo Brescia Morra, Giancarlo Comi, Salvatore Cottone, Luigi Grimaldi, Giovanni Luigi Mancardi, Luca Massacesi, Ugo Nocentini, Marco Salvetti, Elio Scarpini, Patrizia Sola, Gioacchino Tedeschi, Maria Trojano, Mauro Zaffaroni, Stephan Frequin, Raymond Hupperts, Joep Killestein, Hans Schrijver, Ronald Van Dijl, Erik van Munster, Maciej Czarnecki, Wieslaw Drozdowski, Waldemar Fryze, Hanka Hertmanowska, Jan Ilkowski, Anna Kaminska, Gabriela Klodowska-Duda, Maciej Maciejowski, Ewa Motta, Ryszard Podemski, Andrzej Potemkowski, Teresa Rog, Krzysztof Selmaj, Zbigniew Stelmasiak, Adam Stepien, Andrzej Tutaj, Jacek Zaborski, Alexey Boyko, Zanna Chefranova, Evgeny Evdoshenko, Farit Khabirov, Stella Sivertseva, Eduard Yakupov, Jose Carlos Alvarez Cermeño, Antonio Escartin, Oscar Fernandez Fernandez, Antonio Garcia-Merino, Miguel Angel Hernandez Perez, Guillermo Izquierdo Ayuso, José Meca Lallana, Xavier Montalban Gairin, Celia Oreja-Guevara, Albert Saiz Hinarejos, Martin Gunnarsson, Jan Lycke, Claes Martin, Fredrik Piehl, Homayoun Roshanisefat, Peter Sundstrom, Martin Duddy, Bruno Gran, Timothy Harrower, Jeremy Hobart, Martin Lee, Paul Mattison, Richard Nicholas, Owen Pearson, Waqar Rashid, David Rog, Basil Sharrack, Eli Silber, Ben Turner, Anna Williams, John Woolmore, Carolyn Young, Daniel Bandari, Joseph Berger, Ann Camac, Stanley Cohan, Jill Conway, Keith Edwards, Michelle Fabian, Jack Florin, Steven Freedman, Dennis Garwacki, Myla Goldman, Daniel Harrison, Craig Herrman, Deren Huang, Adil Javed, Stephen Kamin, George Katsamakis, Bhupendra Khatri, Annette Langer-Gould, Sharon Lynch, David Mattson, Tamara Miller, Augusto Miravalle, Harold Moses, Suraj Muley, James Napier, Allen Nielsen, Andrew Pachner, Gabriel Pardo, MaryAnn Picone, Derrick Robertson, Walter Royal, Christopher Sheppard, Ben Thrower, Cary Twyman, Emmanuelle Waubant, Jeanette Wendt, Vijayshree Yadav, Rana Zabad, Greg Zarelli, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, University College London Hospitals NHS Foundation Trust [London, UK] (UCLH), Biogen Inc. [Cambridge, MA, USA], Montreal Neurological Institute, Montreal, QC, Canada, NeuroRx Research, Montreal, QC, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, University of Virginia, Charlottesville, VA, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], First Faculty of Medicine-Charles University in Prague and General University Hospital in Prague, Piedmont HealthCare, Mooresville, NC, Icahn School of Medicine at Mount Sinai, New York, NY, University of Copenhagen = Københavns Universitet (UCPH), AP-HM, CHU Timone, Pole de Neurosciences Cliniques, Department of Neurology, Marseille, France., Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,0301 basic medicine ,Outcome Assessment ,secondary progressive multiple sclerosis, natalizumab ,Placebo-controlled study ,multicenter ,Severity of Illness Index ,law.invention ,chemistry.chemical_compound ,0302 clinical medicine ,Natalizumab ,Randomized controlled trial ,law ,Outcome Assessment, Health Care ,ComputingMilieux_MISCELLANEOUS ,education.field_of_study ,Progressive multifocal leukoencephalopathy ,Multiple Sclerosis, Chronic Progressive ,Middle Aged ,Chronic Progressive ,Research Design ,Disease Progression ,Female ,Settore MED/26 - Neurologia ,medicine.drug ,Adult ,medicine.medical_specialty ,Multiple Sclerosis ,Adolescent ,Population ,Clinical Neurology ,Double-Blind Method ,Hand ,Humans ,Immunologic Factors ,Young Adult ,interferon beta 1b ,03 medical and health sciences ,Internal medicine ,medicine ,education ,Expanded Disability Status Scale ,business.industry ,Multiple sclerosis ,ms ,medicine.disease ,Health Care ,030104 developmental biology ,Siponimod ,chemistry ,brain atrophy ,Neurology (clinical) ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030217 neurology & neurosurgery - Abstract
BACKGROUND: 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.
- Published
- 2018
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