The phase 3 MS-STAT2 trial, a large-scale study evaluating the effectiveness of simvastatin in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS), has yielded negative results. The trial found that simvastatin, a commonly used high-cholesterol drug, did not significantly reduce disability progression compared to placebo in patients with non-active SPMS.
The multicenter, placebo-controlled, double-blind trial, involved 964 patients with non-active SPMS who were randomized to receive either simvastatin 80 mg (n = 482) or placebo (n = 482) and followed for a 54-month treatment period. The primary outcome was confirmed disability progression up to 48 months post-randomization, assessed using the Expanded Disability Status Scale (EDSS).
Primary Outcome
The primary outcome did not significantly differ between the simvastatin and placebo groups. Across 365 progression events, the estimated hazard ratio was 1.13 (95% CI, 0.91-1.39; P = 0.26) on the cumulative incidence of confirmed EDSS progression. Progression was defined as a 1-point increase if the EDSS score at baseline was less than 6, or a 0.5-point increase if the EDSS score at baseline was at least 6.
Secondary Outcomes
Certain secondary outcomes, including a multi-component measure of confirmed disability progression up to 36 months (incorporating EDSS, 25-foot walk, and 9-hole peg test), showed an odds ratio of 1.17 (95% CI, 0.89-1.53; P = 0.26). The relapse rate revealed an incidence rate ratio of 1.43 (95% CI, 1.01-2.01; P = 0.04).
Safety and Tolerability
Simvastatin was found to be safe and well-tolerated. There were no suspected unexpected serious adverse reactions related to the treatment. One patient in the simvastatin group experienced rhabdomyolysis, which resolved upon stopping the medication. There were 9 deaths during the trial, but none were related to the treatment, and the number of deaths was evenly distributed between the placebo (n = 4) and simvastatin (n = 5) groups.
Impact of COVID-19 Pandemic
The study took place during the COVID-19 pandemic, and a separate analysis was conducted to assess the treatment effect of simvastatin during different pandemic periods. The analysis found no evidence of a difference in treatment effect between the pre-COVID-19 restrictions, during COVID-19 restrictions, and after COVID-19 restrictions periods (P = 0.22).
Previous MS-STAT Trial
MS-STAT2 was a follow-up to the phase 2b MS-STAT trial, which suggested the potential of simvastatin in SPMS. The earlier trial, conducted from 2008 to 2011, randomized 140 patients with SPMS to either simvastatin (n = 70) or placebo (n = 70). The annualized atrophy rate was significantly lower in the simvastatin group (0.288% per year) compared to the placebo group (0.584% per year). The adjusted difference in atrophy rate between the groups was -0.254% per year (95% CI, -0.422 to -0.087; P = 0.003), representing a 43% reduction in the annualized rate.
Implications for Future Research
Despite the negative results, researchers emphasize the trial's importance in advancing the understanding of progressive MS and demonstrating the feasibility of conducting large-scale clinical trials in this patient population. The MS-STAT2 trial provides a definitive answer regarding simvastatin's lack of benefit in SPMS and paves the way for future research focused on emerging treatments.
