Effect of repurposed simvastatin on disability progression in secondary progressive multiple sclerosis (MS-STAT2): a phase 3, randomised, double-blind, placebo-controlled trial

Abstract

Background: Despite the success of immune modulation in the treatment of relapsing multiple sclerosis, disability progression is a major problem driven by multiple mechanisms. Comorbidities (eg, vascular risk) and ageing are thought to augment these neurodegenerative pathologies. In the phase 2b MS-STAT trial of simvastatin (80 mg) versus placebo in secondary progressive multiple sclerosis (SPMS), the adjusted difference in brain atrophy rate between groups was -0·254% per year: a 43% reduction. In this phase 3 MS-STAT2 trial, we aimed to assess the efficacy of simvastatin versus placebo in slowing the progression of disability in SPMS.

Methods: This phase 3, randomised, double-blind, parallel group, placebo-controlled clinical trial was conducted at 31 neuroscience centres and district general hospitals in the UK. Participants aged 18-65 years with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) of between 4·0 and 6·5 were eligible and randomly assigned (1:1) to oral simvastatin (80 mg) or matched placebo for up to 4·5 years, based on a minimisation algorithm within an independent and secure online randomisation service. All participants, site investigators, and the trial coordinating team were masked to treatment allocation. The primary outcome was time to 6-month EDSS confirmed disability progression (an increase of at least 1 point if EDSS score at baseline visit was less than 6·0 or an increase of 0·5 point if EDSS score at baseline visit was 6·0 or more) assessed in all randomly assigned participants (intention-to-treat analysis) without imputation. This study is registered with ClinicalTrials.gov (NCT03387670) and is on the ISRCTN registry (ISRCTN82598726). The study is completed.

Findings: Between May 10, 2018, and July 26, 2024, 1079 patients were screened for eligibility and 964 participants were randomly assigned, with 482 (50%) in the placebo group and 482 (50%) in the simvastatin group. Of all 964 participants, 704 (73%) were female and 260 (27%) were male, with a mean age of 54 years (SD 7). 173 (36%) of 482 participants in the placebo group and 192 (40%) of 482 participants in the simvastatin group had 6-month confirmed disability progression (adjusted hazard ratio 1·13 [95% CI 0·91 to 1·39], p=0·26). Although no emergent safety issues were seen, there was one serious adverse reaction (rhabdomyolysis) in the simvastatin group. 12 (2%) of 482 participants in the placebo group and five (1%) of 482 participants in the simvastatin group had a cardiovascular serious adverse event.

Interpretation: The MS-STAT2 trial did not show a treatment effect of simvastatin in slowing disability progression in SPMS. Simvastatin use in multiple sclerosis should be confined to existing vascular indications.

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Identifiers

ORCID for Ian Galea: orcid.org/0000-0002-1268-5102

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