Effect of repurposed simvastatin on disability progression in secondary progressive multiple sclerosis (MS-STAT2): a phase 3, randomised, double-blind, placebo-controlled trial
- PMID: 41045938
- DOI: 10.1016/S0140-6736(25)01039-6
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.
Funding: National Institute for Health and Care Research Health Technology Assessment Programme, UK Multiple Sclerosis Society, and the US National Multiple Sclerosis Society.
Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of interests In the last 3 years, JC has received support from the Health Technology Assessment (HTA) Programme (National Institute for Health and Care Research; NIHR), the UK MS Society, the US National MS Society, and the Rosetrees Trust. He is supported in part by the National Institute for Health and Care Research, University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in multiple sclerosis funded by MS Canada. A local principal investigator for commercial trials funded by: Ionis and Roche; and has taken part in advisory boards/consultancy for: Biogen, Contineum Therapeutics, FSD Pharma, InnoCare, Pheno Therapeutics, and Roche. OC declares being NIHR Research Professor (RP-2017-08-ST2-004); over the past 2 years, member of independent data safety and monitoring board for Novartis; has received consulting fees or speaker honoraria from Lundbeck, Merck or Biogen; contributed to an advisory board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium; has received research grant support from the UK MS Society, the NIHR UCLH Biomedical Research Centre, and the NIHR; and is vice-president of ECTRIMS (unpaid). HLF has received honoraria for advisory boards or educational activities from Merck, Novartis, and Roche. HLF has research grant support from the NIHR Health Technology Assessment Programme and Efficacy and Mechanisms Evaluation, UK MS Society, and the Horne Family Charitable Trust. She has been a local PI for multiple sclerosis clinical trials of an investigational medicinal product funded by Novartis, Roche, and Biogen Idec. LF has received honoraria for speaking or as an advisory board member from Biogen, Novartis, Merck, Sanofi Genzyme, and Roche and received support for attending educational meetings from Biogen, Novartis, Merck, Sanofi Genzyme, and Teva. GG declares he has received compensation for serving as a consultant, speaker, or research support from Astoria Biologica, Biogen, BMS, Kiniksa, Merck, EMD Serono, Moderna, Sandoz, Sanofi, Roche, Genentech, Viracta, and Zenas BioPharma. IG declares that in the past two years he received research funding from Wessex Medical Research, Independent Research Fund Denmark, UK MS Society, The Binding Site, and NIHR; and conference and travel expenses from Novartis. NJ is a principal investigator on commercial multiple sclerosis trials sponsored by Roche, Sanofi, and Novartis. He has received speakers honoraria from Merck and travel congress sponsorship from Novartis. He has grant support from National Health and Medical Research Council (Australia), paid via his institution. MM has received travel support, speaker honoraria, or consultation fees from Merck-Sereno, Novartis, and Roche. RN receives support from UK MS Society to Imperial College and Swansea university; is a trustee of the Multiple Sclerosis Trials Collaboration charity; and attended paid advisory boards for Novartis and Roche. SPl is founder, chief scientific officer, and shareholder (>5%) of Cambridge Innovation Technologies Consulting and is a consultant for Aspen Therapeutics, Secretome Therapeutics, Macomics, Solute Guard Therapeutics, and Astex Pharmaceutical. DR declares consulting, speaker fees, or support for conference attendance or travel received from Biogen, Celgene, MedDay, Hikma, Janssen, Merck, Neuraxpharm, Novartis, Roche, Sanofi Genzyme, and Teva. Additionally, research support paid to an institutional fund from the UK MS Society. AJT receives a fee from being Co-Chair, University College London (UCL)-Eisai Steering Committee drug discovery collaboration; German Aerospace Center, Heath Research (ERA-NET NEURON); consultancy from Sandoz Global Advisory and Novartis. Member, National Multiple Sclerosis Society (USA) Research Programs Advisory Committee; Clinical Trials Committee, Progressive MS Alliance; Board member, European Charcot Foundation; Editor in Chief, Multiple Sclerosis Journal; Editorial Board Member, The Lancet Neurology. AJT has received fees for academic reviews for Jockey Club College at City University of Hong Kong, Health Research Board Ireland, Sant Pau Biomedical Research Institute. AJT has received support from the UCL/UCLH NIHR Biomedical Research Centre. AJT received travel support from European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), the European Charcot Foundation, Health Research Board Emerging Clinical Scientist Award, Polish Neurological Society, and Armin Curt Farewell Symposium. He receives no fee from being Chair (Scientific Ambassadors), Stop MS Appeal Board, UK MS Society; Research and Academic Counsellor, Fundació Privada Cemcat; Ambassador, European Brain Council. AJT additionally holds a patent for the MSIS-29 Impact Scale. SC is co-founder and director of Pheno Therapeutics and receives consultancy payments for this role. EG is head of clinical trials at the UK MS Society. FDA has received speaker honoraria, travel or conference support, or fees for advisor board participation from Neurology Academy, Coloplast, Janssen, Merck, Novartis, Roche, Sanofi. She is regional coordinator for the Oratorio Hand Trial (Hoffmann-La Roche) and principal investigator for commercial and academic trials (Alithios, O'Hand, Chariot-MS). JBl received salary payments from NIHR HTA programme for this work via his professional role at the UCL Comprehensive Clinical Trials Unit. JH declares research grant support paid to his institution from Roche, Sanofi, Novartis, Merck, Sandoz, and Verge genomics; licences for rating scales paid to his institution; personal consulting fees, honoraria, travel or conference support, or payment for expert testimony from Roche, Sanofi, and Merck. He participates on steering committees for CHARIOT-MS, ATTACK-MS, and for Sanofi. NR has received support for research fellowships or grants from Biogen and Sanofi; conference or travel support from Sanofi and Union Chimique Belge; participation in data monitoring boards from Sanofi and Neuraxpharm. He has personally owned shares is GlaxoSmithKline and AstraZeneca; and is President elect/President of the Association of British Neurologists. AC has received an advanced research contract from BBVA Foundation—Hospital Clinic Barcelona, and a Postdoctoral training fellowship from ECTRIMS. He has also received travel support from Americas Committee for Treatment and Research in Multiple Sclerosis. AB received a research grant from the Italian Society of Neurology, and a Magnetic Resonance Imaging in Multiple Sclerosis–ECTRIMS fellowship; consulting fees from Merck Serono; speaker's honoraria from Merck Serono and Biogen; and travel support from Merck Serono. CR has received research grants from the UK Medical Research Council, Sanofi, Burden Neurological Society, University of Bristol, and Bristol Health Research Charity, and support for clinical research for the OCTOPUS trial (UK MS Society). CR has participated on a data safety monitoring board for the CCMR Two and NEuEoMS trials. Unpaid advisory roles with the UK MS Society, Burden Neurological Institute, Association of British Neurologists, and NICE HTA Assessment Group. CF received grant funding from the NIHR HTA Programme for this work. RG received support for scientific meetings, courses, and honoraria for advisory work, and travel support from Bayer, Biogen, Merck, Novartis, Janssen, UCB, and MIAC. TH held an NIHR Biomedical Research Council Senior Fellowship; received honoraria for various teaching courses from Ispen, and Pfizer; and support for attending ECTRIMS from Sanofi. DM received a development award from the Progressive MS Alliance; and honoraria from University of Calgary for a lecture. OP received travel expenses from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva; participated on advisory boards or acted as speaker for Biogen, Bristol Myers Squibb, Janssen-Cilag, Merck, Neuraxpharm, Novartis, Roche, and Sanofi. MD received consulting fees from Sanofi, Merck, Novartis, Roche, Biogen, and BMS; honoraria from Novartis, Roche, Merck, and Biogen; payment for expert testimony from Biogen; travel support from Novartis, Sanofi, Merck, and Roche; participation on a data monitoring board with Roche and AB Science; leadership role from the UK MS Society as Co-chair UK MS Registers Executive Committee. RH received grants from NIHR DemPRU-QM, NIHR Evidence Synthesis, and NIHR Health Protection Research Unit; received consulting fees from Ministry of Justice, UK Health Security Agency, University of Nottingham, and QuidelOrtho; and leadership role on transforming health and care systems EU funding board as Chair of the Board. NE has received grants from Roche, PCORI, and the UK MS Society; received consulting fees from Merck and Roche; and conference travel support from Novartis and Sanofi. All other authors declare no competing interests.
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