Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.

There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. NCT03387670; ISRCTN82598726.

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© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.

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Competing interests: JC has received support in the last 3 years from the Health Technology Assessment (HTA) Programme (National Institute for Health Research, NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS 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, Janssen, Lucid, Merck, NervGen, Novartis and Roche. OC declares being NIHR Research Professor (RP-2017-08-ST2-004); over the last 2 years, member of independent DSMB for Novartis; she gave a teaching talk in a Merck local symposium and 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, the Rosetree Trust, the US National MS Society and the NIHR-HTA. HLF has received honoraria for advisory boards and/or educational activities from Biogen, Merck, Novartis and Roche. HLF has research grant support from the NIHR Health Technology Assessment Programme and EME, UK MS Society and the Horne Family Charitable Trust. 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 that in the last 2 years he has received compensation for serving as a consultant or speaker or research support from Astoria Biologica, Aurinia Pharmaceuticals, Biogen, BMS-Celgene, GlaxoSmithKline, Janssens/J&J, Japanese Tobacco, Merck KGaA/EMD Serono, Moderna, Novartis, Sandoz, Sanofi, Roche/Genentech, Vir Biotechnology and Viracta. NJ is a principal investigator on commercial MS trials sponsored by Roche, Novartis and Biogen. He has received speakers honoraria from Merck and travel congress sponsorship from Novartis. MM has received travel support, speaker honoraria and consultation fees from Genzyme, Merck-Sereno, Novartis, Roche, the MS Academy and the Italian Multiple Sclerosis Foundation (FISM). RN attended paid advisory board for Novartis and Roche. SPavitt was MRC/National Institute for Health Research (NIHR)—Efficacy & Mechanism Evaluation Board Member from 2012–2018. SPluchino is founder, CSO and shareholder (>5%) of CITC and Chair of the Scientific Advisory Board at ReNeuron plc. CR declares research funding from Sanofi. DR declares consulting and/or speaker fees received from Biogen, Celgene, Janssen, MedDay, Merck, Novartis, Roche, Sanofi Genzyme and Teva. Additionally, research support paid to an institutional fund from Actelion, Biogen, GW Pharmaceuticals, Merck Serono, Mitsubishi, Novartis, Sanofi Genzyme, Teva and TG Therapeutics. AJT receives a fee from being Co-Chair, UCL-Eisai Steering Committee drug discovery collaboration; Member, National MS 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. He receives no fee from being: Chair (Scientific Ambassadors), ‘Stop MS’ Appeal Board, UK MS Society; Research & academic counsellor, Fundació Privada Cemcat; Ambassador, European Brain Council. AJT additionally holds a patent for the MSIS-29 Impact Scale.