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
Authors: Blackstone James , Williams Thomas , Nicholas Jennifer M , Bordea Ekaterina , De Angelis Floriana , Bianchi Alessia , Calvi Alberto , Doshi Anisha , John Nevin , Apap Mangion Sean , Wade Charles , Merry Rachel , Barton Gil , Lyle Dawn , Jarman Elisabeth , Mahad Don , Shehu Abdullah , Arun Tarunya , McDonnell Gavin , Geraldes Ruth , Craner Matthew , Hillier Charles , Ganesalingam Jeban , Fisniku Leonora , Hobart Jeremy , Spilker Cord , Robertson Neil , Kalra Seema , Pluchino Stefano , Harikrishnan Sreedharan , Mattoscio Miriam , Harrower Timothy , Young Carolyn , Lee Martin , Chhetri Suresh , Ahmed Fayyaz , Rog David , Silber Eli , Gallagher Paul , Duddy Martin , Straukiene Agne , Nicholas Richard , Rice Claire , Nixon Stuart J , Beveridge Judy , Hawton Annie , Tebbs Susan , Braisher Marie , Giovannoni Gavin , Ciccarelli Olga , Greenwood John , Thompson Alan J , Hunter Rachael , Pavitt Sue , Pearson Owen , Evangelou Nikos , Sharrack Basil , Galea Ian , Chandran Siddharthan , Ford Helen L , Frost Chris , Chataway Jeremy 
Published: September 2024

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.