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.

James Blackstone ORCID logo ; Thomas Williams ; Jennifer M Nicholas ORCID logo ; Ekaterina Bordea ; Floriana De Angelis ; Alessia Bianchi ; Alberto Calvi ; Anisha Doshi ; Nevin John ; Sean Apap Mangion ; +52 more... Charles Wade ; Rachel Merry ; Gil Barton ; Dawn Lyle ; Elisabeth Jarman ; Don Mahad ; Abdullah Shehu ; Tarunya Arun ; Gavin McDonnell ; Ruth Geraldes ; Matthew Craner ; Charles Hillier ; Jeban Ganesalingam ; Leonora Fisniku ; Jeremy Hobart ; Cord Spilker ; Neil Robertson ; Seema Kalra ; Stefano Pluchino ; Sreedharan Harikrishnan ; Miriam Mattoscio ; Timothy Harrower ; Carolyn Young ; Martin Lee ; Suresh Chhetri ; Fayyaz Ahmed ; David Rog ; Eli Silber ; Paul Gallagher ; Martin Duddy ; Agne Straukiene ; Richard Nicholas ; Claire Rice ; Stuart J Nixon ; Judy Beveridge ; Annie Hawton ; Susan Tebbs ; Marie Braisher ; Gavin Giovannoni ORCID logo ; Olga Ciccarelli ; John Greenwood ; Alan J Thompson ; Rachael Hunter ORCID logo ; Sue Pavitt ; Owen Pearson ; Nikos Evangelou ; Basil Sharrack ; Ian Galea ORCID logo ; Siddharthan Chandran ORCID logo ; Helen L Ford ORCID logo ; Chris Frost ORCID logo ; Jeremy Chataway ORCID logo ; (2024) 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. BMJ open, 14 (9). e086414-. ISSN 2044-6055 DOI: 10.1136/bmjopen-2024-086414
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INTRODUCTION: 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. METHODS AND ANALYSIS: 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. ETHICS AND DISSEMINATION: 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. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

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