Article
作者: Blackstone, James ; Calvi, Alberto ; Barton, Gil ; Kalra, Seema ; Merry, Rachel ; Thompson, Alan J ; Sharrack, Basil ; Mahad, Don ; Rog, David ; Wade, Charles ; John, Nevin ; Arun, Tarunya ; Spilker, Cord ; Ciccarelli, Olga ; Chataway, Jeremy ; Bordea, Ekaterina ; Lyle, Dawn ; Doshi, Anisha ; Hillier, Charles ; Nicholas, Jennifer M ; Lee, Martin ; Silber, Eli ; Robertson, Neil ; Harikrishnan, Sreedharan ; Nicholas, Richard ; Williams, Thomas ; Geraldes, Ruth ; Galea, Ian ; Apap Mangion, Sean ; Duddy, Martin ; De Angelis, Floriana ; Ganesalingam, Jeban ; Young, Carolyn ; Ford, Helen L ; Nixon, Stuart J ; Hobart, Jeremy ; Braisher, Marie ; Ahmed, Fayyaz ; Frost, Chris ; Bianchi, Alessia ; Hunter, Rachael ; McDonnell, Gavin ; Beveridge, Judy ; Pluchino, Stefano ; Evangelou, Nikos ; Jarman, Elisabeth ; Harrower, Timothy ; Giovannoni, Gavin ; Greenwood, John ; Tebbs, Susan ; Hawton, Annie ; Chhetri, Suresh ; Rice, Claire ; Shehu, Abdullah ; Straukiene, Agne ; Gallagher, Paul ; Pearson, Owen ; Chandran, Siddharthan ; Pavitt, Sue ; Craner, Matthew ; Mattoscio, Miriam ; Fisniku, Leonora
INTRODUCTIONThere 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 ANALYSISMS-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 DISSEMINATIONThe 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 NUMBERSNCT03387670; ISRCTN82598726.