A double-blind, randomised, placebo-controlled single-site study of high dose simvastatin treatment for secondary progressive multiple sclerosis: impact on vascular perfusion and oxidative damage

INTERVENTION: Trade Name: Simvastatin 40 mg film‐coated tablets Product Name: Simvastatin 40 mg film‐coated tablets Product Code: Not applicable Pharmaceutical Form: Tablet INN or Proposed INN: Simvastatin Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 40‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Multiple Sclerosis (Secondary Progressive) ; MedDRA version: 20.0 Level: HLT Classification code 10052785 Term: Multiple sclerosis acute and progressive System Organ Class: 100000004852 Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: Primary: Cerebral arterial hemodynamics ; ; To establish whether simvastatin has an effect on cerebral blood flow (CBF) in SPMS measured at baseline, 16 and 20 weeks using arterial spin labelling (ASL) MRI.; ; We expect ASL to be able to detect subtle changes in CBF at baseline, 16 and 20 weeks comparing placebo to simvastatin treated patients.; Primary end point(s): To establish whether simvastatin has an effect on cerebral blood flow in SPMS up to 22 weeks using arterial spin labelling MRI.; Secondary Objective: • To establish whether ASL measurements of blood flow are useful correlates for CBF measurement on and off treatment. This will be supported by a questionnaire investigating factors that influence brain perfusion.; • To explore whether statin treatment reduces glutamate levels in the brain as measured by MRI. In MS, high glutamate levels have been shown to have a neurotoxic effect.; • To explore whether statin reduce the rate of brain atrophy on MRI (excluding the effect of pseudo‐atrophy, which is a temporary response to the drug rather than an actual loss of tissue).; • To examine the effects of simvastatin treatment on clinical measures, including ; Expanded disability status score (EDSS) which is a method of quantifying disability in MS and records changes in disability over time. The EDSS scale ranges from 0 (no disability) to 10 (death due to MS) in 0.5 unit increments that represent higher levels of disability. ; Multiple Sclerosis Functional Composite (MSFC) comprises quantitative Timepoint(s) of evaluation of this end point: Up to Week 17 weeks on treatment SECONDARY OUTCOME: Secondary end point(s): • To establish whether ASL and AOSLO measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment. This will be supported by a questionnaire investigating factors that influence brain perfusion.; • To explore whether statin treatment reduces glutamate levels as measured by MRI; • To examine for evidence of pseudo‐atrophy on MRI ; • To examine the clinical effect of simvastatin treatment as reported by the clinician (EDSS, MSFC inc. 9HPT, 25FTW and PASAT) and patient reported outcome measures (MSIS‐29v2, and MSWSv2).; • Frontal executive functioning will be assessed using the Frontal Assessment Battery (FAB).; • To collect health economic data (EQ5D5L) to inform future phase III trials ; • Investigate the effect statins may have on retinal parameters such as blood flow, oxygen saturation, structure of vascular plexuses, neuronal structure and retinal layer thicknesses.; Timepoint(s) of evaluation of this end point: It is expected that data analyses will commence when the last participant leaves the study. Recruitment is expected to take up to 1 year from January 2018 and data analyses will continue until June 2019. INCLUSION CRITERIA: The following inclusion criteria must be met (answer yes) when assessing patient’s eligibility onto the trial: 1. Patients must have a confirmed diagnosis of multiple sclerosis according to revised Mc Donald criteria and have entered the secondary progressive stage. (Polman et al., 2011, Lublin, 2014). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Progression can be evident from either an increase of at least one point on the EDSS or clinical documentation of increasing disability. 2. EDSS 4.0 – 6.5 (inclusive). 3. Male and Females aged 18 to 65 4. Females of childbearing potential and males with partners who are of childbearing age must be willing to use an effective method of contraception (Double barrier method of birth control or True abstinence) from the time consent is signed until 6 weeks after treatment discontinuation and inform the trial team if pregnancy occurs. For the