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

Artikel i vetenskaplig tidskrift
Författare 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
Jan Lycke
Publicerad i The Lancet
Volym 391
Sidor 1263-1273
ISSN 0140-6736
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi
Sidor 1263-1273
Språk en
Länkar https://doi.org/10.1016/S0140-6736(...
Ämneskategorier Neurologi

Sammanfattning

© 2018 Elsevier Ltd 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 treatme nt 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.

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