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

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.