Despite the relative success of immuno-modulatory disease-modifying therapy in relapsing remitting multiple sclerosis, progressive worsening of disability remains a major problem, particularly for those with secondary progressive multiple sclerosis. Various underlying mechanisms are likely to contribute, augmented by comorbidities (such as vascular risk) and ageing. In the phase 2b MS-STAT trial, simvastatin (80 mg) (Sandoz Ltd, Camberley, UK) reduced the mean annualised whole brain atrophy rate by 43% compared to placebo in patients with secondary progressive multiple sclerosis (p = 0.003). We now report the phase 3, MS-STAT2 trial, with confirmed progression of disability as the primary outcome. A multicentre, phase 3, randomised, double-blind, placebo-controlled clinical trial was conducted at 31 UK neuroscience centres and district general hospitals. Secondary progressive multiple sclerosis participants aged 18-65 years were randomised 1 : 1 to oral simvastatin (80 mg), or matched placebo, based on a minimisation algorithm that incorporated the following factors: sex (male/female); age (< or ≥ 45 years); Expanded Disability Status Scale baseline score (≤ 5.5 or ≥ 6); whether participants were taking newly licensed (2017 onward) disease-modifying treatments for secondary progressive multiple sclerosis; and trial site. An independent and secure online randomisation service was used. All participants, site investigators and the trial co-ordinating team were blinded to treatment allocation. The Expanded Disability Status Scale was measured every 6 months and was compared to baseline scores, with remote data collection used when enforced by the COVID-19 pandemic. The primary outcome was time to Expanded Disability Status Scale-confirmed disability progression. Progression of disability was defined as an increase of at least one point on the Expanded Disability Status Scale if the baseline score was < 6, or an increase of 0.5 point if the baseline score was ≥ 6. The initial disability progression event was finalised as confirmed if the increase in Expanded Disability Status Scale score persisted at the next assessments ≥ 6 months later. Follow-up was for 36 months, or 54 months, for those without confirmed disability progression at 36 months who agreed to enter an optional blinded extension. An intention-to-treat analysis was carried out. The study was conducted between 10 May 2018 and 26 July 2024. There were 964 participants randomised, with 482 in the placebo group and 482 in the simvastatin group. 173 (35.9%) participants in the placebo group and 192 (39.8%) participants in the simvastatin group experienced Expanded Disability Status Scale-confirmed disability progression (adjusted hazard ratio = 1.13, 95% confidence interval 0.91 to 1.39, p = 0.263). No material differences in the secondary outcomes were observed. No major safety issues were seen. The MS-STAT2 trial did not demonstrate a treatment effect of simvastatin in slowing disability progression in participants with secondary progressive multiple sclerosis. Despite the favourable outcomes of the previous phase 2b trial, simvastatin use in secondary progressive multiple sclerosis should be confined to existing vascular indications. This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 15/57/143. Multiple sclerosis is a lifelong condition that affects the brain and spinal cord. Many people with multiple sclerosis start with a type called relapsing-remitting multiple sclerosis, which can later become secondary progressive multiple sclerosis. Secondary progressive multiple sclerosis causes steady worsening of disability over time, and currently, there are very few treatment options for people without signs of active inflammation. Simvastatin is a cholesterol-lowering drug (a statin) that is widely used for heart disease. Earlier research (the Simvastatin in Secondary Progressive Multiple Sclerosis phase 2 trial) suggested that high-dose simvastatin might slow brain shrinkage and disability in people with secondary progressive multiple sclerosis. To test this further, researchers ran a large phase 3 clinical trial called Simvastatin in Secondary Progressive Multiple Sclerosis (phase 3 trial), involving 964 participants across the United Kingdom. Half were given simvastatin and half a placebo, and they were followed up while continuing to take these for 3 years. For participants whose disability was stable at 3 years, they could continue in the trial on the same medication for up to 4.5 years if they were happy to do so. The main aim was to see if simvastatin could slow down worsening disability, which was measured using a scale called Expanded Disability Status Scale. The Expanded Disability Status Scale data were mainly collected at face-to-face appointments, but some assessments were conducted by telephone when enforced by the COVID-19 pandemic. The results showed no significant difference between the simvastatin and placebo groups. Simvastatin did not delay disability progression. The trial also looked at other outcomes such as walking speed, hand function, memory and quality of life. Again, there were no meaningful differences. Importantly, simvastatin was generally safe, and side effects were rare. The trial also found that people with higher disability levels faced higher personal and financial costs, and many relied on unpaid care from family or friends. Overall, the Simvastatin in Secondary Progressive Multiple Sclerosis phase 3 trial provides clear evidence that simvastatin does not have a therapeutic effect in slowing disability progression in people with secondary progressive multiple sclerosis. It also offers valuable insights for future research into progressive multiple sclerosis and highlights the need for new treatments that target the disease’s underlying causes.
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arXiv · 2023-07-20
arXiv · 2024-09-24