Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND)

a double-blind, randomised, phase 3 study

EXPAND Clinical Investigators

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1263-1273
Number of pages11
JournalThe Lancet
Volume391
Issue number10127
DOIs
Publication statusPublished - 2018 Mar 31

Fingerprint

Chronic Progressive Multiple Sclerosis
Placebos
1-(4-(1-((E)-4-cyclohexyl-3-trifluoromethylbenzyloxyimino)-ethyl)-2-ethylbenzyl)-azetidine-3-carboxylic acid
Bradycardia
Safety
Multiple Sclerosis
Consent Forms
Lymphopenia
Macular Edema

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: The Lancet, Vol. 391, No. 10127, 31.03.2018, p. 1263-1273.

Research output: Contribution to journalArticle

@article{e4b6e8cf2b5d496cacce44b22ed70c1e,
title = "Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study",
abstract = "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.",
author = "{EXPAND Clinical Investigators} and Ludwig Kappos and Amit Bar-Or and Cree, {Bruce A.C.} and Fox, {Robert J.} and Gavin Giovannoni and Ralf Gold and Patrick Vermersch and Arnold, {Douglas L.} and Sophie Arnould and Tatiana Scherz and Christian Wolf and Erik Wallstr{\"o}m and Frank Dahlke and Anat Achiron and Lutz Achtnichts and Kadriye Agan and Gulsen Akman-Demir and Allen, {Alison B.} and Antel, {Jack P.} and Antiguedad, {Alfredo Rodriguez} and Michelle Apperson and Applebee, {Angela M.} and Ayuso, {Guillermo Izquierdo} and Masayuki Baba and Ovidiu Bajenaru and Rodica Balasa and Balci, {Belgin Petek} and Michael Barnett and Ann Bass and Becker, {Veit U.} and Mihaela Bejinariu and Bergh, {Florian Then} and Arnfin Bergmann and Evanthia Bernitsas and Achim Berthele and Virender Bhan and Felix Bischof and Bjork, {Randall John} and Gregg Blevins and Matthias Boehringer and Thomas Boerner and Robert Bonek and Bowen, {James D.} and Allen Bowling and Boyko, {Alexey N.} and Cavit Boz and Vera Bracknies and Stefan Braune and {Brescia Morra}, Vincenzo and Jin Nakahara",
year = "2018",
month = "3",
day = "31",
doi = "10.1016/S0140-6736(18)30475-6",
language = "English",
volume = "391",
pages = "1263--1273",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "10127",

}

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

AU - Brescia Morra, Vincenzo

AU - Nakahara, Jin

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

UR - http://www.scopus.com/inward/citedby.url?scp=85044304126&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(18)30475-6

DO - 10.1016/S0140-6736(18)30475-6

M3 - Article

VL - 391

SP - 1263

EP - 1273

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10127

ER -