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.


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*


  • Azetidines
  • Benzyl Compounds
  • Sphingosine 1 Phosphate Receptor Modulators
  • siponimod

Associated data