TY - JOUR
T1 - Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND)
T2 - a double-blind, randomised, phase 3 study
AU - EXPAND Clinical Investigators
AU - Kappos, Ludwig
AU - Bar-Or, Amit
AU - Cree, Bruce A.C.
AU - Fox, Robert J.
AU - Giovannoni, Gavin
AU - Gold, Ralf
AU - Vermersch, Patrick
AU - Arnold, Douglas L.
AU - Arnould, Sophie
AU - Scherz, Tatiana
AU - Wolf, Christian
AU - Wallström, Erik
AU - Dahlke, Frank
AU - Achiron, Anat
AU - Achtnichts, Lutz
AU - Agan, Kadriye
AU - Akman-Demir, Gulsen
AU - Allen, Alison B.
AU - Antel, Jack P.
AU - Antiguedad, Alfredo Rodriguez
AU - Apperson, Michelle
AU - Applebee, Angela M.
AU - Ayuso, Guillermo Izquierdo
AU - Baba, Masayuki
AU - Bajenaru, Ovidiu
AU - Balasa, Rodica
AU - Balci, Belgin Petek
AU - Barnett, Michael
AU - Bass, Ann
AU - Becker, Veit U.
AU - Bejinariu, Mihaela
AU - Bergh, Florian Then
AU - Bergmann, Arnfin
AU - Bernitsas, Evanthia
AU - Berthele, Achim
AU - Bhan, Virender
AU - Bischof, Felix
AU - Bjork, Randall John
AU - Blevins, Gregg
AU - Boehringer, Matthias
AU - Boerner, Thomas
AU - Bonek, Robert
AU - Bowen, James D.
AU - Bowling, Allen
AU - Boyko, Alexey N.
AU - Boz, Cavit
AU - Bracknies, Vera
AU - Braune, Stefan
A2 - Karelis, Guntis
A2 - Millers, Andrejs
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/3/31
Y1 - 2018/3/31
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044304126&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(18)30475-6
DO - 10.1016/S0140-6736(18)30475-6
M3 - Article
C2 - 29576505
AN - SCOPUS:85044304126
SN - 0140-6736
VL - 391
SP - 1263
EP - 1273
JO - The Lancet
JF - The Lancet
IS - 10127
ER -