Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses

Ralph H B Benedict; Davorka Tomic; Bruce A Cree; Robert Fox; Gavin Giovannoni; Amit Bar-Or; Ralf Gold; Patrick Vermersch; Harald Pohlmann; Ian Wright; Göril Karlsson; Frank Dahlke; Christian Wolf; Ludwig Kappos

doi:10.1212/WNL.0000000000011275

Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses

Neurology. 2021 Jan 19;96(3):e376-e386. doi: 10.1212/WNL.0000000000011275. Epub 2020 Dec 16.

Affiliations

¹ From the Department of Neurology (R.H.B.B.), University at Buffalo, NY; Novartis Pharma AG (D.T., H.P., G.K., F.D.), Basel, Switzerland; Weill Institute for Neurosciences (B.A.C.), Department of Neurology, University of California San Francisco; Mellen Center for Treatment and Research in Multiple Sclerosis (R.F.), Neurological Institute, Cleveland Clinic, OH; Blizard Institute (GG), Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK; Department of Neurology (A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Neurology (R.G.), St. Josef-Hospital/Ruhr-University Bochum, Germany; Department of Neurology (P.V.), University of Lille, INSERM U1172, CHU Lille, FHU Imminent, France; Novartis Ireland Ltd (I.W.), Dublin; Lycalis sprl (C.W.), Brussels, Belgium; and Neurologic Clinic and Policlinic (G.K., L.K.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel, Switzerland. benedict@buffalo.edu.
² From the Department of Neurology (R.H.B.B.), University at Buffalo, NY; Novartis Pharma AG (D.T., H.P., G.K., F.D.), Basel, Switzerland; Weill Institute for Neurosciences (B.A.C.), Department of Neurology, University of California San Francisco; Mellen Center for Treatment and Research in Multiple Sclerosis (R.F.), Neurological Institute, Cleveland Clinic, OH; Blizard Institute (GG), Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK; Department of Neurology (A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Neurology (R.G.), St. Josef-Hospital/Ruhr-University Bochum, Germany; Department of Neurology (P.V.), University of Lille, INSERM U1172, CHU Lille, FHU Imminent, France; Novartis Ireland Ltd (I.W.), Dublin; Lycalis sprl (C.W.), Brussels, Belgium; and Neurologic Clinic and Policlinic (G.K., L.K.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel, Switzerland.

PMID: 33328324
DOI: 10.1212/WNL.0000000000011275

Abstract

Objective: To investigate the effects of siponimod on cognitive processing speed in patients with secondary progressive (SP) multiple sclerosis (MS), by means of a predefined exploratory and post hoc analysis of the Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND) study, a randomized controlled trial comparing siponimod and placebo.

Methods: EXPAND was a double-blind, placebo-controlled phase 3 trial involving 1,651 patients with SPMS randomized (2:1) to either siponimod 2 mg/d or placebo. Cognitive function was assessed with the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Brief Visuospatial Memory Test-Revised (BVMT-R) administered at baseline, 6-month intervals, and end of treatment.

Results: Between-group differences in mean change from baseline in SDMT scores were significantly better in siponimod- vs placebo-treated patients at month 12 (difference 1.08 [95% confidence interval 0.23-1.94]; p = 0.0132), month 18 (1.23 [0.25-2.21); p = 0.0135), and month 24 (2.30 [1.11-3.50]; p = 0.0002). Siponimod-treated patients were at significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR] 0.79 [0.65-0.96]; p = 0.0157), while their chance for having a 4-point sustained increase in SDMT score was higher (HR 1.28 [1.05-1.55]; p = 0.0131). PASAT and BVMT-R scores did not differ significantly between the 2 treatment groups (all p > 0.28).

Conclusion: Siponimod had a significant benefit on SDMT in patients with SPMS. Siponimod-treated patients were at significantly lower risk for having a ≥4-point decrease in SDMT score and had a significantly higher chance for having a ≥4-point increase in SDMT score, a magnitude of change accepted as clinically meaningful.

Clinicaltrialsgov identifier: NCT01665144.

Classification of evidence: This study provides Class II evidence that, for patients with SPMS, siponimod had a significant benefit on cognitive processing speed.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Azetidines / pharmacology
Azetidines / therapeutic use*
Benzyl Compounds / pharmacology
Benzyl Compounds / therapeutic use*
Cognition / drug effects*
Double-Blind Method
Female
Humans
Male
Middle Aged
Multiple Sclerosis, Chronic Progressive / drug therapy*
Multiple Sclerosis, Chronic Progressive / psychology
Neuropsychological Tests
Sphingosine 1 Phosphate Receptor Modulators / pharmacology
Sphingosine 1 Phosphate Receptor Modulators / therapeutic use*

Substances

Azetidines
Benzyl Compounds
Sphingosine 1 Phosphate Receptor Modulators
siponimod

Associated data

ClinicalTrials.gov/NCT01665144