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

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) receptor1,5 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.

Ludwig Kappos | Margaret Burnett | Gavin Giovannoni | Bart Van Wijmeersch | Murat Terzi | Richard Nicholas | Xavier Montalban | Amit Bar-Or | Daniel Guillaume | Gilles Edan | Achim Berthele | Antonio Uccelli | Anat Achiron | Scott Silliman | Florian Then Bergh | Bruno Brochet | Martin Duddy | Myriam Schluep | Helmut Butzkueven | Takashi Yamamura | Marc Debouverie | Mark Herring | Jean Pelletier | Georgi Krastev | Gilles Defer | Amos Katz | Tomas Olsson | Jack P Antel | Joseph Herbert | Toomas Toomsoo | David Rog | Basil Sharrack | Hongzeng Li | Ralf Gold | Corey Ford | Matthias Schwab | Niall Tubridy | Tjalf Ziemssen | Judith Haas | Andreas Lutterotti | Douglas L Arnold | Anna Czlonkowska | Stephan Schmidt | Allen Bowling | Suzanne Hodgkinson | Robert J Fox | Erik Strauss | Sebastian Rauer | Andrew Solomon | Wojciech Kozubski | Francesco Saccà | Frank Dahlke | Jiahong Lu | Katrin Gross-Paju | Giancarlo Comi | Orla Hardiman | Klaus Gehring | Patrick Vermersch | Liying Cui | Heinz Wiendl | Caroline Papeix | Xianhao Xu | Takahiko Saida | Robert Weissert | Brigitte Wildemann | Patrick Oschmann | Michael Barnett | Matthew Craner | Wolfgang Feneberg | Hongyu Zhou | Arnfin Bergmann | Martin Stangel | Stefan Braune | Cavit Boz | Masahiro Mori | D. Centonze | G. Marfia | D. Arnold | X. Montalban | L. Kappos | P. Vermersch | M. Duddy | E. Nikfekr | Erik Strauss | A. Bar-Or | O. Hardiman | A. Nielsen | B. Sharrack | G. Comi | J. Correale | M. Freedman | Aaron E Miller | A. Achiron | M. Pless | E. Scarpini | B. Brochet | J. Herbert | Georgi Krastev | L. Grimaldi | T. Olsson | A. Lutterotti | T. Derfuss | H. Wiendl | R. Gold | M. Buttmann | D. Rastenytė | T. Ziemssen | P. Oschmann | H. Butzkueven | N. Tubridy | F. Dahlke | L. Krupp | G. Edan | G. Giovannoni | K. Selmaj | R. Fox | Y. Nakatsuji | J. Antel | A. Applebee | L. Cui | F. Leutmezer | J. Bowen | S. Galgani | M. Schluep | Y. Shimizu | K. Kaida | W. Feneberg | T. Yamamura | W. Kozubski | O. Stuve | M. Barnett | S. Elias | M. Mirabella | A. Chan | D. Karussis | U. Nocentini | V. Morra | D. Cottrell | U. Zettl | A. Hâncu | D. Rog | C. Boz | M. Brozman | Yining Huang | T. Toomsoo | R. Magzhanov | N. Grigoriadis | A. Członkowska | R. Nicholas | H. Tumani | S. Silliman | A. Tavernarakis | W. Camu | D. Decoo | J. Weber | A. Uccelli | M. Mori | C. Gobbi | C. Oreja-Guevara | C. Ford | J. Debruyne | P. Turčáni | J. Nakahara | R. Linker | Y. Mao-Draayer | A. Katz | P. Duquette | I. Kister | S. Schmidt | B. Cree | H. Ford | B. Khatri | G. Defer | Christoph Lassek | A. Francia | S. Newsome | Deren Huang | J. Cerqueira | J. Cahill | S. Rizvi | F. Heidenreich | P. Coyle | M. Burnett | I. Milanov | R. Hupperts | L. Patrucco | M. Debouverie | A. Berthele | B. Dubois | J. Pelletier | G. Akman-Demir | A. Siva | V. Sinay | M. Schwab | N. Deri | R. Macdonell | B. Turner | A. Boyko | E. Evdoshenko | E. Bernitsas | C. Papeix | M. Stangel | R. Kizlaitienė | B. Wildemann | M. Gudesblatt | O. Bajenaru | Liesly Lee | B. Dihenia | S. Wiertlewski | B. Wijmeersch | G. Vorobeychik | J. Lycke | F. Bergh | S. Hodgkinson | P. Lišková | Massimiliano Mirabella | Nikolaos Grigoriadis | Dimitrios Karussis | Gregg Blevins | Virender Bhan | Syed A Rizvi | Michael Linnebank | S. Cohan | J. Overell | Diego Centonze | Aksel Siva | James D Bowen | Hayrettin Tumani | Christian Wolf | Krzysztof Selmaj | Tobias Derfuss | V. Bhan | Jin Nakahara | Michelle Apperson | Patricia K Coyle | S. Walter | Celia Oreja-Guevara | Ilya Kister | Andrew Chan | M. Linnebank | Pierre Duquette | Jan Lycke | G. Blevins | L. Achtnichts | E. Kurča | M. Boehringer | F. Khabirov | Dehui Huang | C. Rózsa | K. Mátyás | M. Apperson | A. Valikovics | O. Škoda | Masanori Mizuno | Liesly Lee | Husnu Efendi | Ada Francia | Stefanie Mueller | B. Frishberg | Richard Macdonell | J. Koehler | D. Brunet | A. Harmjanz | M. Maciejowski | P. Diószeghy | W. Brola | F. Saccà | Stefanie Mueller | Lutz Achtnichts | Claudio Gobbi | G. Laureys | M. Terzi | M. Simó | A. Bass | B. Willekens | L. Vanopdenbosch | E. Klímová | M. Vachová | Dusan Stefoski | F. Bischof | Daiva Rastenyte | Ugo Nocentini | A. 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