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Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23.

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

Collaborators (315)

Achiron A, Achtnichts L, Agan K, Akman-Demir G, Allen AB, Antel JP, Antiguedad AR, Apperson M, Applebee AM, Ayuso GI, Baba M, Bajenaru O, Balasa R, Balci BP, Barnett M, Bass A, Becker VU, Bejinariu M, Bergh FT, Bergmann A, Bernitsas E, Berthele A, Bhan V, Bischof F, Bjork RJ, Blevins G, Boehringer M, Boerner T, Bonek R, Bowen JD, Bowling A, Boyko AN, Boz C, Bracknies V, Braune S, Brescia Morra V, Brochet B, Brola W, Brownstone PK, Brozman M, Brunet D, Buraga I, Burnett M, Buttmann M, Butzkueven H, Cahill J, Calkwood JC, Camu W, Cascione M, Castelnovo G, Centonze D, Cerqueira J, Chan A, Cimprichova A, Cohan S, Comi G, Conway J, Cooper JA, Corboy J, Correale J, Costell B, Cottrell DA, Coyle PK, Craner M, Cui L, Cunha L, Czlonkowska A, da Silva AM, de Sa J, de Seze J, Debouverie M, Debruyne J, Decoo D, Defer G, Derfuss T, Deri NH, Dihenia B, Dioszeghy P, Donath V, Dubois B, Duddy M, Duquette P, Edan G, Efendi H, Elias S, Emrich PJ, Estruch BC, Evdoshenko EP, Faiss J, Fedyanin AS, Feneberg W, Fermont J, Fernandez OF, Ferrer FC, Fink K, Ford H, Ford C, Francia A, Freedman M, Frishberg B, Galgani S, Garmany GP, Gehring K, Gitt J, Gobbi C, Goldstick LP, Gonzalez RA, Grandmaison F, Grigoriadis N, Grigorova O, Grimaldi LME, Gross J, Gross-Paju K, Gudesblatt M, Guillaume D, Haas J, Hancinova V, Hancu A, Hardiman O, Harmjanz A, Heidenreich FR, Hengstman GJD, Herbert J, Herring M, Hodgkinson S, Hoffmann OM, Hofmann WE, Honeycutt WD, Hua LH, Huang D, Huang Y, Huang D, Hupperts R, Imre P, Jacobs AK, Jakab G, Jasinska E, Kaida K, Kalnina J, Kaprelyan A, Karelis G, Karussis D, Katz A, Khabirov FA, Khatri B, Kimura T, Kister I, Kizlaitiene R, Klimova E, Koehler J, Komatineni A, Kornhuber A, Kovacs K, Koves A, Kozubski W, Krastev G, Krupp LB, Kurca E, Lassek C, Laureys G, Lee L, Lensch E, Leutmezer F, Li H, Linker RA, Linnebank M, Liskova P, Llanera C, Lu J, Lutterotti A, Lycke J, Macdonell R, Maciejowski M, Maeurer M, Magzhanov RV, Maida EM, Malciene L, Mao-Draayer Y, Marfia GA, Markowitz C, Mastorodimos V, Matyas K, Meca-Lallana J, Merino JAG, Mihetiu IG, Milanov I, Miller AE, Millers A, Mirabella M, Mizuno M, Montalban X, Montoya L, Mori M, Mueller S, Nakahara J, Nakatsuji Y, Newsome S, Nicholas R, Nielsen AS, Nikfekr E, Nocentini U, Nohara C, Nomura K, Odinak MM, Olsson T, van Oosten BW, Oreja-Guevara C, Oschmann P, Overell J, Pachner A, Panczel G, Pandolfo M, Papeix C, Patrucco L, Pelletier J, Piedrabuena R, Pless M, Polzer U, Pozsegovits K, Rastenyte D, Rauer S, Reifschneider G, Rey R, Rizvi SA, Robertson D, Rodriguez JM, Rog D, Roshanisefat H, Rowe V, Rozsa C, Rubin S, Rusek S, Saccà F, Saida T, Salgado AV, Sanchez VEF, Sanders K, Satori M, Sazonov DV, Scarpini EA, Schlegel E, Schluep M, Schmidt S, Scholz E, Schrijver HM, Schwab M, Schwartz R, Scott J, Selmaj K, Shafer S, Sharrack B, Shchukin IA, Shimizu Y, Shotekov P, Siever A, Sigel KO, Silliman S, Simo M, Simu M, Sinay V, Siquier AE, Siva A, Skoda O, Solomon A, Stangel M, Stefoski D, Steingo B, Stolyarov ID, Stourac P, Strassburger-Krogias K, Strauss E, Stuve O, Tarnev I, Tavernarakis A, Tello CR, Terzi M, Ticha V, Ticmeanu M, Tiel-Wilck K, Toomsoo T, Tubridy N, Tullman MJ, Tumani H, Turcani P, Turner B, Uccelli A, Urtaza FJO, Vachova M, Valikovics A, Walter S, Van Wijmeersch B, Vanopdenbosch L, Weber JR, Weiss S, Weissert R, Vermersch P, West T, Wiendl H, Wiertlewski S, Wildemann B, Willekens B, Visser LH, Vorobeychik G, Xu X, Yamamura T, Yang YN, Yelamos SM, Yeung M, Zacharias A, Zelkowitz M, Zettl U, Zhang M, Zhou H, Zieman U, Ziemssen T.

Author information

1
Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland. Electronic address: ludwig.kappos@usb.ch.
2
Center for Neuroinflammation and Neurotherapeutics, and Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
3
UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
4
Mellen Centre for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
5
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
6
Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany.
7
University of Lille, CHU Lille, LIRIC-INSERM U995, Lille, France.
8
Montreal Neurological Institute, McGill University, Montreal, QC, Canada; NeuroRx Research, Montreal, QC, Canada.
9
Novartis Pharma AG, Basel, Switzerland.
10
Lycalis, Brussels, Belgium.

Erratum in

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.

PMID:
29576505
DOI:
10.1016/S0140-6736(18)30475-6
[Indexed for MEDLINE]

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