Title: MS-STAT2: A phase 3 randomised, double blind, clinical trial investigating the effectiveness of repurposed simvastatin compared to placebo in secondary progressive multiple sclerosis, in slowing the progression of disability
Funder: Department of Health and Social Care

Abstract: HYPOTHESIS:Repurposed Simvastatin(80mg) is a disease modifying treatment for people with progressing SPMS(PwSPMS) AIM:To test the effectiveness of simvastatin(80mg) in a phase 3 double blind, randomised, placebo-controlled trial(1:1) in patients with PwSPMS, over 3yrs, to determine if disability progression can be slowed. SETTING: 24 Neurology outpatient departments have agreed to participate, members of UK MSS-CTN and experienced MS trialists (with contingency Eire site). LITERATURE REVIEW: A systematic review of all trials in Progressive MS (18 phase 3 trials,n=8500, 70% SPMS, updated to 16/1/16) overwhelming concludes all intervention have failed to slow disease progression in SPMS POPULATION: PwSPMS (progressing); ages of 25-65; fulfil the revised McDonald criteria for MS; no recent relapse activity within the last 3months (M). Expanded Disability Status Scale(EDSS) 4.0-6.5. Patients will be ineligible if they had PPMS or used immunosuppressants/modulators within the previous 6-12M(depending on agent). Fampridine not started/stopped within the last 6M. No other major organ co-morbidity. Not currently on statins/-ve vascular risk profile predicting future use of statins (QRISK2-2015 <10%) INTERVENTION: Repurposed,oral Simvastatin 80mg/day COMPARATOR: Matched placebo PRIMARY OUTCOME: Confirmed (6M) disability progression using the EDSS (increase from baseline EDSS of 1.0 or more if baseline <6.0;0.5 or more if baseline 6.0 or more) and final confirmation at Month (M) 36 or last available study visit SECONDARY OUTCOME: Multiple Sclerosis Functional Composite Score (MSFC [PASAT substituted for SDMT]); Sloan Low Contrast Visual Acuity (SLCVA).PROMS:MS Impact Scale-29 v2 (MSIS-29v2),MS Walking Scale v2 (MSWSv2),ABILHAND Questionnaire.Relapse rate HEALTH ECONOMICS: A cost-utility evaluation to assess the incremental cost/quality adjusted life year (QALY) from the NHS perspective. QALYs will be estimated, 6 monthly, using the EQ-5D-5L. Secondary analysis from a broader societal perspective will be performed. SAMPLE SIZE: 40% placebo rate of confirmed EDSS progression, 472 patients/arm (944 in total) will provide 90% power (at the 5% level) to determine a 30% reduction in the time to progression (hazard ratio 0.7) which is highly clinically meaningful. This gives 80% power to detect a 30% relative reduction if placebo progression rate is 30%, rather than 40%. To allow for 20% dropout (as commonly seen), 590 patients/arm will be planned (1180 in total). PROJECT TIMETABLES AND RECRUITMENT RATE:Duration 78M: Trial Setup 9M; Screening/Recruitment 24M; Follow-up 36M(+6M confirmation);Data cleaning 3M; Analysis & report 6M. Patient timeline: Trials screening(M-1), followed by trial randomisation within 30 days(M0).Follow-up visits at M1,3(by Tel),6,12,18,24,30 and 36.Confirmation of progression will take place at the next visit, at least 6 months. Using MS-STAT1 and MS-SMART site recruitment data we have modelled to generate a robust site-tailored recruitment strategy involving 24 sites in 2 tiers at differential monthly randomisation rates of 0.5-10/site. EXPERTISE IN TEAM: The multidisciplinary MS-STAT2 team has expertise and track-record to deliver the trial; timely research outputs & high impact publications; NHS diffusion; with a track-record of working together.

Lay abstract: AIM: To test if the rate of disability progression can be slowed in people with secondary progressive multiple sclerosis (PwSPMS) using simvastatin, a medicine used widely to reduce cholesterol levels. BACKGROUND:MS typically has two disease stages:Stage 1-Relapsing-remitting MS(RRMS),an increasingly treatable early inflammatory stage.Onset is usually at 20-30 years of age with progressive deterioration over 10-15yrs leading to Stage 2-SPMS currently untreatable and characterised by increasing levels of permanent disability, decreasing quality of life/ability to work, with large NHS, personal and societal costs estimated at £3-4 billion/year in the UK. In 2014, the MS-STAT1 clinical trial of 140 PwSPMS followed for 2 yrs showed promising results in those taking simvastatin (dose-80mg/day) compared to placebo (a dummy drug). There was less brain shrinkage(atrophy) seen on brain scans(MRI) in patients taking simvastatin compared to placebo. This was very encouraging as brain shrinkage is normally linked to increased disability. Indeed the trial results were widely reported around the world,(eg,BBC news). MS-STAT1 also showed a positive effect on disability using two other tests. Simvastatin offers a well-tolerated, and cheap medicine (8p/day or £30/year). DESIGN OF TRIAL:We have planned the MS-STAT2 trial based on MS-STAT1 but as a larger clinical trial (phase 3) to test if simvastatin can make this disability difference.It will use exactly the same patient characteristics (eligibility criteria) as MS-STAT1. Patients with progressing SPMS will be randomised to take either simvastatin dose-80mg/day or placebo;the medicine capsules will look identical and patients will not be told which treatment they receive (blinded) to reduce influencing results (bias).Patients will then be followed for 3 years to investigate whether there is confirmed slowing of disability progression or not.A wide-range of other clinical and patient outcomes will be collected to ensure the research delivers maximum patient benefits.Patient safety checking will be done all through the trial. We calculate that we will need about 1200 patients in the trial to prove that simvastatin can slow disability progression.Patients will be recruited from Neurology outpatient departments following referral from GP or hospital doctor (neurologist), and by self-referral via trial website (in another MS trial 2,500 patients self-referred). PATIENT & PUBLIC INVOLVEMENT:The MS-STAT2 research team works in partnership with people with MS and with members of the UK MS Society PPI Forum) to achieve a trial of value to people with MS. They recognised their community’s desperation for a treatment where none exist, “MS-STAT2 provides hope”. They have co-designed MS-STAT2 ensuring its research was shaped to maximise patient benefits, ensure safety checking of the high dose simvastatin and the trial schedule was not tiring, e.g. bloods can be taken at home avoiding clinic visits. The PPI contributors will continue to work with the PIs to build a positive trial community response & communication to aid recruitment and encourage people to keep taking their medicines even if they suspect they may be taking placebo DISSEMINATION: we will tell key stakeholders: patients, clinicians, scientists & policy makers about the MS-STAT2 trial using scientific conference presentations and publications but also including lay summary report, digital media & using the MS Society press & social media channel

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL