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1. Comparative effectiveness of autologous hematopoietic stem cell transplant vs Fingolimod, Natalizumab, and Ocrelizumab in highly active relapsing-remitting multiple sclerosis

Author

Kalincik, Tomas, Sharmin, Sifat, Roos, Izanne, Freedman, Mark S., Atkins, Harold, Burman, Joachim, Massey, Jennifer, Sutton, Ian, Withers, Barbara, Macdonell, Richard, Grigg, Andrew, Torkildsen, Øivind, Bo, Lars, Lehmann, Anne Kristine, Havrdova, Eva Kubala, Krasulova, Eva, Trněný, Marek, Kozak, Tomas, van der Walt, Anneke, Butzkueven, Helmut, McCombe, Pamela, Skibina, Olga, Lechner-Scott, Jeannette, Willekens, Barbara, Cartechini, Elisabetta, Ozakbas, Serkan, Alroughani, Raed, Kuhle, Jens, Patti, Francesco, Duquette, Pierre, Lugaresi, Alessandra, Khoury, Samia J., Slee, Mark, Turkoglu, Recai, Hodgkinson, Suzanne, John, Nevin, Maimone, Davide, Sa, Maria Jose, van Pesch, Vincent, Gerlach, Oliver, Laureys, Guy, Van Hijfte, Liesbeth, Karabudak, Rana, Spitaleri, Daniele, Csepany, Tunde, Gouider, Riadh, Castillo-Triviño, Tamara, Taylor, Bruce, Sharrack, Basil, Snowden, John A., Horakova, Dana, Buzzard, Katherine, Terzi, Murat, Prat, Alexandre, Girard, Marc, Grammond, Pierre, Barnett, Michael, Stewart, Grace, Onofrj, Marco, Izquierdo, Guillermo, Eichau, Sara, Grand'Maison, Francois, Prevost, Julie, Van Wijmeersch, Bart, Amato, Maria Pia, Shaygannejad, Vahid, Boz, Cavit, Bolaños, Ricardo Fernandez, Soysal, Aysun, Ramo-Tello, Cristina, Solaro, Claudio, Gobbi, Claudio, Cabrera-Gomez, Jose Antonio, Roullet, Etienne, Zwanikken, Cees, Den braber-Moerland, Leontien, Deri, Norma, Saladino, Maria Laura, Cristiano, Edgardo, Rojas, Juan Ignacio, Vrech, Carlos, Shaw, Cameron, Shuey, Neil, Boggild, Mike, Tan, Ik Lin, Hardy, Todd, Decoo, Danny, Moore, Fraser, Oh, Jiwon, Lalive, Patrice, Ampapa, Radek, Petersen, Thor, Oreja-Guevara, Celia, Perez Sempere, Angel, Dominguez, Jose Andres, Besora, Sarah, Hughes, Stella, Gray, Orla, Grigoriadis, Nikolaos, Piroska, Imre, Rozsa, Csilla, Kasa, Krisztian, Simo, Magdolna, Kovacs, Krisztina, Sas, Attila, Dobos, Eniko, Rajda, Cecilia, McGuigan, Chris, Mason, Deborah, Schepel, Jan, Alkhaboori, Jabir, Rio, Maria Edite, Mihaela, Simu, Al-Harbi, Talal, Altintas, Ayse, Kister, Ilya, Marriott, Mark, Kilpatrick, Trevor, King, John, Nguyen, Ai-Lan, Dwyer, Chris, Monif, Mastura, Taylor, Lisa, Diamanti, Matteo, Chisari, Clara, Toscano, Simona, Salvatore, Lo Fermo, Larochelle, Catherine, De Luca, Giovanna, Di Tommaso, Valeria, Travaglini, Daniela, Pietrolongo, Erika, di Ioia, Maria, Farina, Deborah, Mancinelli, Luca, Hupperts, Raymond, Olascoaga, Javier, Saiz, Albert, Zivadinov, Robert, Benedict, Ralph, Verheul, Freek, Fabis-Pedrini, Marzena, Mrabet, Saloua, Garber, Justin, Sanchez-Menoyo, Jose Luis, Aguera-Morales, Eduardo, Blanco, Yolanda, Al-Asmi, Abdullah, Weinstock-Guttman, Bianca, Fragoso, Yara, de Gans, Koen, and Kermode, Allan

Subjects
Human medicine
Abstract

you are agreeing to our Cookie Policy | Continue JAMA Network HomeJAMA Neurology This Issue Views 2,357 Citations 0 60 Full Text Share Comment Original Investigation May 15, 2023 Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis Tomas Kalincik, MD, PhD1,2; Sifat Sharmin, PhD1,2; Izanne Roos, MBChB, PhD1,2; Mark S. Freedman, MD3; Harold Atkins, MD4; Joachim Burman, MD, PhD5; Jennifer Massey, MBBS, PhD6,7; Ian Sutton, MBBS, PhD6,8; Barbara Withers, MD, PhD7,9; Richard Macdonell, MD, PhD10,11; Andrew Grigg, MD, PhD11,12; Øivind Torkildsen, MD, PhD13; Lars Bo, MD, PhD13; Anne Kristine Lehmann, MD, PhD14; Eva Kubala Havrdova, MD, PhD15; Eva Krasulova, MD, PhD15; Marek Trněný, MD, PhD16; Tomas Kozak, MD, PhD17; Anneke van der Walt, MBBS, PhD18,19; Helmut Butzkueven, MBBS, PhD18,19; Pamela McCombe, MBBS20,21; Olga Skibina, MBBS18,22,23; Jeannette Lechner-Scott, MD, PhD24,25; Barbara Willekens, MD, PhD26,27; Elisabetta Cartechini, MD28; Serkan Ozakbas, MD29; Raed Alroughani, MD30; Jens Kuhle, MD, PhD31; Francesco Patti, MD32,33; Pierre Duquette, MD34; Alessandra Lugaresi, MD, PhD35,36; Samia J. Khoury, MD, PhD37; Mark Slee, MD, PhD38; Recai Turkoglu, MD39; Suzanne Hodgkinson, MD40; Nevin John, MD, PhD41,42; Davide Maimone, MD43; Maria Jose Sa, MD44; Vincent van Pesch, MD, PhD45,46; Oliver Gerlach, MD, PhD47,48; Guy Laureys, MD49; Liesbeth Van Hijfte, MD49; Rana Karabudak, MD50; Daniele Spitaleri, MD51; Tunde Csepany, MD, PhD52; Riadh Gouider, MD53,54; Tamara Castillo-Triviño, MD55; Bruce Taylor, MD, PhD56,57; Basil Sharrack, MD, PhD58; John A. Snowden, MD, PhD59; and the MSBase Study Group Collaborators; and the MSBase Study Group Authors Author Affiliations JAMA Neurol. 2023;80(7):702-713. doi:10.1001/jamaneurol.2023.1184 editorial comment iconEditorial Comment Key Points Question What is the comparative effectiveness of autologous hematopoietic stem cell transplant (AHSCT) vs individual most potent disease-modifying therapies for relapsing-remitting multiple sclerosis (MS), such as natalizumab or ocrelizumab? Findings In this observational comparative effectiveness study of 4915 individuals using a composite cohort from specialized MS centers and the MSBase international registry, the effectiveness of AHSCT was compared with 1 medium-efficacy and 2 high-efficacy disease-modifying therapies (fingolimod, natalizumab, and ocrelizumab) in patients with relapsing-remitting MS, high frequency of relapses, and moderate disability. Over 5 years, AHSCT was associated with substantially lower relapse rate than fingolimod and marginally lower relapse rate than natalizumab and was also associated with a higher rate of recovery from disability compared with fingolimod and natalizumab, but no evidence of difference in clinical outcomes between AHSCT and ocrelizumab was found at 3-year follow-up. Meaning The results indicate that in relapsing-remitting MS, the clinical effectiveness of AHSCT is considerably superior to fingolimod and marginally superior to natalizumab. Abstract Importance Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Published
2023

2. The risk of secondary progressive multiple sclerosis is geographically determined but modifiable

Author

Sharmin, Sifat, Roos, Izanne, Simpson-Yap, Steve, Malpas, Charles, Sánchez, Marina M., Ozakbas, Serkan, Horakova, Dana, Havrdova, Eva K., Patti, Francesco, Alroughani, Raed, Izquierdo, Guillermo, Eichau, Sara, Boz, Cavit, Zakaria, Magd, Onofrj, Marco, Lugaresi, Alessandra, Weinstock-Guttman, Bianca, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Terzi, Murat, Amato, Maria Pia, Karabudak, Rana, Grand'Maison, Francois, Khoury, Samia J., Grammond, Pierre, Lechner-Scott, Jeannette, Buzzard, Katherine, Skibina, Olga, van der Walt, Anneke, Butzkueven, Helmut, Turkoglu, Recai, Altintas, Ayse, Maimone, Davide, Kermode, Allan, Shalaby, Nevin, Pesch, Vincent V., Butler, Ernest, Sidhom, Youssef, Gouider, Riadh, Mrabet, Saloua, Gerlach, Oliver, Soysal, Aysun, Barnett, Michael, Kuhle, Jens, Hughes, Stella, Sa, Maria J., Hodgkinson, Suzanne, Oreja-Guevara, Celia, Ampapa, Radek, Petersen, Thor, Ramo-Tello, Cristina, Spitaleri, Daniele, McCombe, Pamela, Taylor, Bruce, Prevost, Julie, Foschi, Matteo, Slee, Mark, McGuigan, Chris, Laureys, Guy, Hijfte, Liesbeth V., de Gans, Koen, Solaro, Claudio, Oh, Jiwon, Macdonell, Richard, Aguera-Morales, Eduardo, Singhal, Bhim, Gray, Orla, Garber, Justin, Wijmeersch, Bart V., Simu, Mihaela, Triviño, Tamara C., Sanchez-Menoyo, Jose L., Khurana, Dheeraj, Al-Asmi, Abdullah, Al-Harbi, Talal, Deri, Norma, Lalive, Patrice H., Sinnige, L.G.F., Shaw, Cameron, Shuey, Neil, Csepany, Tunde, Sempere, Angel P., Moore, Fraser, Decoo, Danny, Willekens, Barbara, Gobbi, Claudio, Massey, Jennifer, Hardy, Todd, Parratt, John, Kalincik, Tomas, and MSBase investigators

Subjects
Human medicine
Abstract

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis which is characterised by steady accrual of irreversible disability.

Published
2023

3. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Rojas, Juan Ignacio, Gray, Orla, Khurana, Dheeraj, Van Wijmeersch, Bart, Grigoriadis, Nikolaos, Inshasi, Jihad, Oh, Jiwon, Aguera-Morales, Eduardo, Fragoso, Yara, Moore, Fraser, Shaw, Cameron, Baghbanian, Seyed Mohammad, Shuey, Neil, Willekens, Barbara, Hardy, Todd A., Decoo, Danny, Sempere, Angel Perez, Field, Deborah, Wynford-Thomas, Ray, Cunniffe, Nick G., Roos, Izanne, Malpas, Charles B., Coles, Alasdair J., Kalincik, Tomas, Brown, J. William L., MSBase Study Grp, MSBase Study Grp, Shaygannejad, Vahid, Daruwalla, Cyrus, ÖZAKBAŞ, SERKAN, Havrdova, Eva Kubala, Horakova, Dana, Alroughani, Raed, BOZ, CAVİT, Patti, Francesco, Onofrj, Marco, Lugaresi, Alessandra, Eichau, Sara, Girard, Marc, Prat, Alexandre, Duquette, Pierre, Yamout, Bassem, Khoury, Samia J., Sajedi, Seyed Aidin, Turkoglu, Recai, Altintas, Ayse, Skibina, Olga, Buzzard, Katherine, Grammond, Pierre, Karabudak, Rana, van der Walt, Anneke, Butzkueven, Helmut, Maimone, Davide, Lechner-Scott, Jeannette, Soysal, Aysun, John, Nevin, Prevost, Julie, Spitaleri, Daniele, Ramo-Tello, Cristina, Gerlach, Oliver, Iuliano, Gerardo, Foschi, Matteo, Ampapa, Radek, van Pesch, Vincent, Barnett, Michael, Shalaby, Nevin, D'hooghe, Marie, Kuhle, Jens, Sa, Maria Jose, Fabis-Pedrini, Marzena, Kermode, Allan, Mrabet, Saloua, Gouider, Riadh, Hodgkinson, Suzanne, Laureys, Guy, Van Hijfte, Liesbeth, Macdonell, Richard, Oreja-Guevara, Celia, Cristiano, Edgardo, McCombe, Pamela, Sanchez-Menoyo, Jose Luis, Singhal, Bhim, Blanco, Yolanda, Hughes, Stella, Garber, Justin, Solaro, Claudio, McGuigan, Chris, Taylor, Bruce, de Gans, Koen, Habek, Mario, Al-Asmi, Abdullah, Mihaela, Simu, Castillo Trivino, Tamara, Al-Harbi, Talal, MSBase Study Group, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Faculty of Medicine and Pharmacy, Daruwalla, Cyrus [0000-0002-2329-5329], Shaygannejad, Vahid [0000-0001-5511-509X], Horakova, Dana [0000-0003-1915-0036], Alroughani, Raed [0000-0001-5436-5804], Patti, Francesco [0000-0002-6923-0846], Lugaresi, Alessandra [0000-0003-2902-5589], Eichau, Sara [0000-0001-9159-3128], Duquette, Pierre [0000-0001-7231-1754], Sajedi, Seyed Aidin [0000-0002-6704-9787], van der Walt, Anneke [0000-0002-4278-7003], Lechner-Scott, Jeannette [0000-0002-3850-447X], Barnett, Michael [0000-0002-2156-8864], Oreja-Guevara, Celia [0000-0002-9221-5716], Habek, Mario [0000-0002-3360-1748], Castillo Triviño, Tamara [0000-0002-9249-3185], Inshasi, Jihad [0000-0001-5892-751X], Oh, Jiwon [0000-0001-5519-6088], Fragoso, Yara [0000-0001-8726-089X], Baghbanian, Seyed Mohammad [0000-0002-8138-7504], Hardy, Todd A [0000-0003-4145-3172], Decoo, Danny [0000-0001-7689-3114], Roos, Izanne [0000-0003-0371-3666], Kalincik, Tomas [0000-0003-3778-1376], Brown, J William L [0000-0002-7737-5834], Apollo - University of Cambridge Repository, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire

Subjects
Neuroscience(all), Multiple sclerosis, prognosis, multiple sclerosis, Prognosis, Multiple Sclerosis, Relapsing-Remitting, Neurology, Recurrence, Medicine and Health Sciences, Humans, Human medicine, Neurology (clinical)
Abstract

Background: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. Objective: To determine whether early non-disabling relapses predict disability accumulation in RRMS. Methods: We redefined mild relapses in MSBase as ‘non-disabling’, and moderate or severe relapses as ‘disabling’. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. Results: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated ( n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00–1.68) or given platform DMTs ( n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15–1.54), but not if given high-efficacy DMTs ( n = 572 vs 3534; HR = 0.90, 95% CI = 0.71–1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. Conclusion: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Published
2023

4. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

Author

Ludwig Kappos, Amit Bar-Or, Bruce A C Cree, Robert J Fox, Gavin Giovannoni, Ralf Gold, Patrick Vermersch, Douglas L Arnold, Sophie Arnould, Tatiana Scherz, Christian Wolf, Erik Wallström, Frank Dahlke, Anat Achiron, Lutz Achtnichts, Kadriye Agan, Gulsen Akman-Demir, Alison B Allen, Jack P Antel, Alfredo Rodriguez Antiguedad, Michelle Apperson, Angela M Applebee, Guillermo Izquierdo Ayuso, Masayuki Baba, Ovidiu Bajenaru, Rodica Balasa, Belgin Petek Balci, Michael Barnett, Ann Bass, Veit U Becker, Mihaela Bejinariu, Florian Then Bergh, Arnfin Bergmann, Evanthia Bernitsas, Achim Berthele, Virender Bhan, Felix Bischof, Randall John Bjork, Gregg Blevins, Matthias Boehringer, Thomas Boerner, Robert Bonek, James D Bowen, Allen Bowling, Alexey N Boyko, Cavit Boz, Vera Bracknies, Stefan Braune, Vincenzo Brescia Morra, Bruno Brochet, Waldemar Brola, Paul Kenneth Brownstone, Miroslav Brozman, Donald Brunet, Ioan Buraga, Margaret Burnett, Mathias Buttmann, Helmut Butzkueven, Jonathan Cahill, Jonathan C Calkwood, William Camu, Mark Cascione, Giovani Castelnovo, Diego Centonze, Joao Cerqueira, Andrew Chan, Andrea Cimprichova, Stanley Cohan, Giancarlo Comi, Jill Conway, Joanna A Cooper, John Corboy, Jorge Correale, Brian Costell, David A Cottrell, Patricia K Coyle, Matthew Craner, Liying Cui, Luis Cunha, Anna Czlonkowska, Ana Martins da Silva, Joao de Sa, Jérôme de Seze, Marc Debouverie, Jan Debruyne, Danny Decoo, Gilles Defer, Tobias Derfuss, Norma H Deri, Bhupesh Dihenia, Peter Dioszeghy, Vladimir Donath, Benedicte Dubois, Martin Duddy, Pierre Duquette, Gilles Edan, Husnu Efendi, Stanton Elias, Peter J Emrich, Bonaventura Casanova Estruch, Evgeniy P Evdoshenko, Juergen Faiss, Alexander S Fedyanin, Wolfgang Feneberg, Jiske Fermont, Oscar Fernandez Fernandez, Francisco Coret Ferrer, Katharina Fink, Helen Ford, Corey Ford, Ada Francia, Mark Freedman, Benjamin Frishberg, Simonetta Galgani, George P Garmany, Klaus Gehring, Jeffrey Gitt, Claudio Gobbi, Lawrence P Goldstick, Rafael Arroyo Gonzalez, Francois Grandmaison, Nikolaos Grigoriadis, Olga Grigorova, Luigi Maria Edoardo Grimaldi, Jeffrey Gross, Katrin Gross-Paju, Mark Gudesblatt, Daniel Guillaume, Judith Haas, Viera Hancinova, Anca Hancu, Orla Hardiman, Arndt Harmjanz, Fedor R Heidenreich, G J D Hengstman, Joseph Herbert, Mark Herring, Suzanne Hodgkinson, Olaf M Hoffmann, Werner E Hofmann, William D Honeycutt, Le Hanh Hua, Dehui Huang, Yining Huang, DeRen Huang, Raymond Hupperts, Piroska Imre, Alan Keith Jacobs, Gabor Jakab, Elzbieta Jasinska, Kenichi Kaida, Jolanta Kalnina, Ara Kaprelyan, Guntis Karelis, Dimitrios Karussis, Amos Katz, Farit A Khabirov, Bhupendra Khatri, Takashi Kimura, Ilya Kister, Rasa Kizlaitiene, Eleonora Klimova, Juergen Koehler, Aparna Komatineni, Anselm Kornhuber, Krisztina Kovacs, Agnes Koves, Wojciech Kozubski, Georgi Krastev, Lauren B Krupp, Egon Kurca, Christoph Lassek, Guy Laureys, Liesly Lee, Eckart Lensch, Fritz Leutmezer, Hongzeng Li, Ralf A Linker, Michael Linnebank, Petra Liskova, Cristina Llanera, Jiahong Lu, Andreas Lutterotti, Jan Lycke, Richard Macdonell, Maciej Maciejowski, Mathias Maeurer, Rim V Magzhanov, Eva-Maria Maida, Lina Malciene, Yang Mao-Draayer, Girolama Alessandra Marfia, Clyde Markowitz, Vasileios Mastorodimos, Klotild Matyas, Jose Meca-Lallana, Juan Antonio Garcia Merino, Ioan Gheorghe Mihetiu, Ivan Milanov, Aaron E Miller, Andrejs Millers, Massimiliano Mirabella, Masanori Mizuno, Xavier Montalban, Lilina Montoya, Masahiro Mori, Stefanie Mueller, Jin Nakahara, Yuji Nakatsuji, Scott Newsome, Richard Nicholas, A Scott Nielsen, Esmaeil Nikfekr, Ugo Nocentini, Chiyoko Nohara, Kyoichi Nomura, Miroslav M Odinak, Tomas Olsson, B W van Oosten, Celia Oreja-Guevara, Patrick Oschmann, James Overell, Andrew Pachner, Gyula Panczel, Massimo Pandolfo, Caroline Papeix, Liliana Patrucco, Jean Pelletier, Raul Piedrabuena, Misha Pless, Udo Polzer, Krisztian Pozsegovits, Daiva Rastenyte, Sebastian Rauer, Gerd Reifschneider, Roberto Rey, Syed A Rizvi, Derrick Robertson, Jose Martinez Rodriguez, David Rog, Homayoun Roshanisefat, Vernon Rowe, Csilla Rozsa, Susan Rubin, Stanislaw Rusek, Francesco Saccà, Takahiko Saida, Antonio Vasco Salgado, Victoria Eugenia Fernandez Sanchez, Kalina Sanders, Maria Satori, Denis V Sazonov, Elio Angelo Scarpini, Eugen Schlegel, Myriam Schluep, Stephan Schmidt, Erich Scholz, H M Schrijver, Matthias Schwab, Raymond Schwartz, James Scott, Krzysztof Selmaj, Stuart Shafer, Basil Sharrack, Ivan A Shchukin, Yuko Shimizu, Penko Shotekov, Arno Siever, Karl-Otto Sigel, Scott Silliman, Magdolna Simo, Mihaela Simu, Vladimiro Sinay, Antonio Escartin Siquier, Aksel Siva, Ondrej Skoda, Andrew Solomon, Martin Stangel, Dusan Stefoski, Brian Steingo, Igor D Stolyarov, Pavel Stourac, Katrin Strassburger-Krogias, Erik Strauss, Olaf Stuve, Ivaylo Tarnev, Antonios Tavernarakis, Cristina Ramo Tello, Murat Terzi, Veronika Ticha, Marina Ticmeanu, Klaus Tiel-Wilck, Toomas Toomsoo, Niall Tubridy, Mark J Tullman, Hayrettin Tumani, Peter Turcani, Ben Turner, Antonio Uccelli, Francisco Javier Olascoaga Urtaza, Marta Vachova, Attila Valikovics, Silke Walter, Bart Van Wijmeersch, Ludo Vanopdenbosch, Joerg R Weber, Sara Weiss, Robert Weissert, Timothy West, Heinz Wiendl, Sandrine Wiertlewski, Brigitte Wildemann, Barbara Willekens, L H Visser, Galina Vorobeychik, Xianhao Xu, Takashi Yamamura, Yi N Yang, Sergio Martinez Yelamos, Michael Yeung, Alan Zacharias, Marvin Zelkowitz, Uwe Zettl, Meini Zhang, Hongyu Zhou, Ulf Zieman, Tjalf Ziemssen, Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, University of Basel, Basel, Center for Neuroinflammation and Neurotherapeutics, and Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, Mellen Centre for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, Department of Neurology St. Josef-Hospital, Ruhr University Bochum, Germany, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Montreal Neurological Institute, McGill University, Montreal, QC, Canada, NeuroRx Research, Montreal, QC, Novartis Pharma AG, Lycalis, Brussels, 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), 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), Kappos, Ludwig, Bar-Or, Amit, Cree, Bruce A C, Fox, Robert J, Giovannoni, Gavin, Gold, Ralf, Vermersch, Patrick, Arnold, Douglas L, Arnould, Sophie, Scherz, Tatiana, Wolf, Christian, Wallström, Erik, Dahlke, Frank, Achiron, Anat, Achtnichts, Lutz, Agan, Kadriye, Akman-Demir, Gulsen, Allen, Alison B, Antel, Jack P, Antiguedad, Alfredo Rodriguez, Apperson, Michelle, Applebee, Angela M, Ayuso, Guillermo Izquierdo, Baba, Masayuki, Bajenaru, Ovidiu, Balasa, Rodica, Balci, Belgin Petek, Barnett, Michael, Bass, Ann, Becker, Veit U, Bejinariu, Mihaela, Bergh, Florian Then, Bergmann, Arnfin, Bernitsas, Evanthia, Berthele, Achim, Bhan, Virender, Bischof, Felix, Bjork, Randall John, Blevins, Gregg, Boehringer, Matthia, Boerner, Thoma, Bonek, Robert, Bowen, James D, Bowling, Allen, Boyko, Alexey N, Boz, Cavit, Bracknies, Vera, Braune, Stefan, Brescia Morra, Vincenzo, Brochet, Bruno, Brola, Waldemar, Brownstone, Paul Kenneth, Brozman, Miroslav, Brunet, Donald, Buraga, Ioan, Burnett, Margaret, Buttmann, Mathia, Butzkueven, Helmut, Cahill, Jonathan, Calkwood, Jonathan C, Camu, William, Cascione, Mark, Castelnovo, Giovani, Centonze, Diego, Cerqueira, Joao, Chan, Andrew, Cimprichova, Andrea, Cohan, Stanley, Comi, Giancarlo, Conway, Jill, Cooper, Joanna A, Corboy, John, Correale, Jorge, Costell, Brian, Cottrell, David A, Coyle, Patricia K, Craner, Matthew, Cui, Liying, Cunha, Lui, Czlonkowska, Anna, da Silva, Ana Martin, de Sa, Joao, de Seze, Jérôme, Debouverie, Marc, Debruyne, Jan, Decoo, Danny, Defer, Gille, Derfuss, Tobia, Deri, Norma H, Dihenia, Bhupesh, Dioszeghy, Peter, Donath, Vladimir, Dubois, Benedicte, Duddy, Martin, Duquette, Pierre, Edan, Gille, Efendi, Husnu, Elias, Stanton, Emrich, Peter J, Estruch, Bonaventura Casanova, Evdoshenko, Evgeniy P, Faiss, Juergen, Fedyanin, Alexander S, Feneberg, Wolfgang, Fermont, Jiske, Fernandez, Oscar Fernandez, Ferrer, Francisco Coret, Fink, Katharina, Ford, Helen, Ford, Corey, Francia, Ada, Freedman, Mark, Frishberg, Benjamin, Galgani, Simonetta, Garmany, George P, Gehring, Klau, Gitt, Jeffrey, Gobbi, Claudio, Goldstick, Lawrence P, Gonzalez, Rafael Arroyo, Grandmaison, Francoi, Grigoriadis, Nikolao, Grigorova, Olga, Grimaldi, Luigi Maria Edoardo, Gross, Jeffrey, Gross-Paju, Katrin, Gudesblatt, Mark, Guillaume, Daniel, Haas, Judith, Hancinova, Viera, Hancu, Anca, Hardiman, Orla, Harmjanz, Arndt, Heidenreich, Fedor R, Hengstman, G J D, Herbert, Joseph, Herring, Mark, Hodgkinson, Suzanne, Hoffmann, Olaf M, Hofmann, Werner E, Honeycutt, William D, Hua, Le Hanh, Huang, Dehui, Huang, Yining, Huang, Deren, Hupperts, Raymond, Imre, Piroska, Jacobs, Alan Keith, Jakab, Gabor, Jasinska, Elzbieta, Kaida, Kenichi, Kalnina, Jolanta, Kaprelyan, Ara, Karelis, Gunti, Karussis, Dimitrio, Katz, Amo, Khabirov, Farit A, Khatri, Bhupendra, Kimura, Takashi, Kister, Ilya, Kizlaitiene, Rasa, Klimova, Eleonora, Koehler, Juergen, Komatineni, Aparna, Kornhuber, Anselm, Kovacs, Krisztina, Koves, Agne, Kozubski, Wojciech, Krastev, Georgi, Krupp, Lauren B, Kurca, Egon, Lassek, Christoph, Laureys, Guy, Lee, Liesly, Lensch, Eckart, Leutmezer, Fritz, Li, Hongzeng, Linker, Ralf A, Linnebank, Michael, Liskova, Petra, Llanera, Cristina, Lu, Jiahong, Lutterotti, Andrea, Lycke, Jan, Macdonell, Richard, Maciejowski, Maciej, Maeurer, Mathia, Magzhanov, Rim V, Maida, Eva-Maria, Malciene, Lina, Mao-Draayer, Yang, Marfia, Girolama Alessandra, Markowitz, Clyde, Mastorodimos, Vasileio, Matyas, Klotild, Meca-Lallana, Jose, Merino, Juan Antonio Garcia, Mihetiu, Ioan Gheorghe, Milanov, Ivan, Miller, Aaron E, Millers, Andrej, Mirabella, Massimiliano, Mizuno, Masanori, Montalban, Xavier, Montoya, Lilina, Mori, Masahiro, Mueller, Stefanie, Nakahara, Jin, Nakatsuji, Yuji, Newsome, Scott, Nicholas, Richard, Nielsen, A Scott, Nikfekr, Esmaeil, Nocentini, Ugo, Nohara, Chiyoko, Nomura, Kyoichi, Odinak, Miroslav M, Olsson, Toma, van Oosten, B W, Oreja-Guevara, Celia, Oschmann, Patrick, Overell, Jame, Pachner, Andrew, Panczel, Gyula, Pandolfo, Massimo, Papeix, Caroline, Patrucco, Liliana, Pelletier, Jean, Piedrabuena, Raul, Pless, Misha, Polzer, Udo, Pozsegovits, Krisztian, Rastenyte, Daiva, Rauer, Sebastian, Reifschneider, Gerd, Rey, Roberto, Rizvi, Syed A, Robertson, Derrick, Rodriguez, Jose Martinez, Rog, David, Roshanisefat, Homayoun, Rowe, Vernon, Rozsa, Csilla, Rubin, Susan, Rusek, Stanislaw, Saccà, Francesco, Saida, Takahiko, Salgado, Antonio Vasco, Sanchez, Victoria Eugenia Fernandez, Sanders, Kalina, Satori, Maria, Sazonov, Denis V, Scarpini, Elio Angelo, Schlegel, Eugen, Schluep, Myriam, Schmidt, Stephan, Scholz, Erich, Schrijver, H M, Schwab, Matthia, Schwartz, Raymond, Scott, Jame, Selmaj, Krzysztof, Shafer, Stuart, Sharrack, Basil, Shchukin, Ivan A, Shimizu, Yuko, Shotekov, Penko, Siever, Arno, Sigel, Karl-Otto, Silliman, Scott, Simo, Magdolna, Simu, Mihaela, Sinay, Vladimiro, Siquier, Antonio Escartin, Siva, Aksel, Skoda, Ondrej, Solomon, Andrew, Stangel, Martin, Stefoski, Dusan, Steingo, Brian, Stolyarov, Igor D, Stourac, Pavel, Strassburger-Krogias, Katrin, Strauss, Erik, Stuve, Olaf, Tarnev, Ivaylo, Tavernarakis, Antonio, Tello, Cristina Ramo, Terzi, Murat, Ticha, Veronika, Ticmeanu, Marina, Tiel-Wilck, Klau, Toomsoo, Tooma, Tubridy, Niall, Tullman, Mark J, Tumani, Hayrettin, Turcani, Peter, Turner, Ben, Uccelli, Antonio, Urtaza, Francisco Javier Olascoaga, Vachova, Marta, Valikovics, Attila, Walter, Silke, Van Wijmeersch, Bart, Vanopdenbosch, Ludo, Weber, Joerg R, Weiss, Sara, Weissert, Robert, West, Timothy, Wiendl, Heinz, Wiertlewski, Sandrine, Wildemann, Brigitte, Willekens, Barbara, Visser, L H, Vorobeychik, Galina, Xu, Xianhao, Yamamura, Takashi, Yang, Yi N, Yelamos, Sergio Martinez, Yeung, Michael, Zacharias, Alan, Zelkowitz, Marvin, Zettl, Uwe, Zhang, Meini, Zhou, Hongyu, Zieman, Ulf, Ziemssen, Tjalf, and EXPAND Clinical Investigators

Subjects
Adult, Male, 0301 basic medicine, Relative risk reduction, medicine.medical_specialty, Adolescent, Placebo, law.invention, Cohort Studies, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Multiple Sclerosis, Chronic Progressive / drug therapy, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, Benzyl Compounds, Clinical endpoint, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, Settore MED/36 - DIAGNOSTICA PER IMMAGINI E RADIOTERAPIA, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Hazard ratio, General Medicine, Middle Aged, Multiple Sclerosis, Chronic Progressive, Fingolimod, Treatment Outcome, Settore M-EDF/01 - METODI E DIDATTICHE DELLE ATTIVITÀ MOTORIE, 030104 developmental biology, Siponimod, chemistry, Disease Progression, Azetidines, Female, Settore MED/26 - Neurologia, Human medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, medicine.drug
Abstract

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

Published
2018

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