Clinical Trial Results:
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
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Summary
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EudraCT number |
2017-003008-30 |
Trial protocol |
GB |
Global end of trial date |
15 Jun 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Nov 2025
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First version publication date |
26 Nov 2025
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
16/0730
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03896217 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
250 Euston Road, London, United Kingdom, NW1 2PG
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Public contact |
Richard Nicholas, University College London , ctimps@ucl.ac.uk
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Scientific contact |
Richard Nicholas, University College London , ctimps@ucl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Dec 2024
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Sep 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Jun 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary objective: To establish whether simvastatin has an effect on cerebral blood flow in progressive MS over 20 weeks using arterial spin labelling MRI.
Secondary objectives:
• To establish whether ASL and AOSLO measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment.
• To explore whether statin could influence conventional and advanced MRI measures.
• To examine the clinical effect of simvastatin treatment as reported by the clinician and and patient reported
outcome measures.
• To investigate the effect statins on retinal parameters such as blood flow, oxygen saturation, structure of vascular plexuses, neuronal structure and retinal layer thicknesses.
Exploratory objectives:
• To investigate phenotypic immune markers in whole blood to determine effect simvastatin has on immune function.
• To measure the effect of statins on biomarkers of blood brain barrier dysfunction, vascular leakage and oxidative damage.
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Protection of trial subjects |
To protect participants and minimise pain or distress during the MS-OPT trial, a range of carefully designed safety and comfort measures were implemented. Eligibility screening was rigorous, including clinical, laboratory, and MRI safety assessments, to exclude individuals at higher risk of adverse effects from simvastatin. Participants with recent MS relapses, contraindicated medications, or significant liver, kidney, or cardiac issues were not enrolled. Throughout the trial, participants underwent regular monitoring, including blood tests for liver function and creatine kinase levels, allowing early detection of hepatotoxicity or myopathy.
Importantly, to reduce travel burden and physical strain — particularly given participants’ disability levels — study visits were split across two days and conducted at two different specialist centres: UCL Queen Square and Moorfields Eye Hospital. This approach ensured that no single visit became overly long or exhausting.
In addition, advanced imaging procedures such as MRI and retinal scans were only conducted with participants able to tolerate them, and clear exclusions (e.g. for metal implants or claustrophobia) were in place.
Retinal imaging involved pupil dilation using single-use sterile drops, with patients advised to bring sunglasses to ease post-visit discomfort. Venepuncture was carried out using standard precautions by trained staff to minimise discomfort and risk.
Participants were well-informed about possible side effects through detailed written information provided in the Participant Information Sheet, which was discussed thoroughly during the informed consent process. Participants were well-informed about possible side effects, encouraged to report symptoms promptly, and supported throughout the trial. These combined measures helped ensure a safe, ethical, and participant-centred study experience.
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Background therapy |
Simvastatin is a widely used HMG-CoA reductase inhibitor, traditionally prescribed to lower LDL cholesterol and reduce cardiovascular risk. Beyond lipid regulation, simvastatin shows pleiotropic effects — immunomodulatory, anti-inflammatory, and vasculoprotective — which support its potential use in multiple sclerosis (MS). In progressive MS (PMS), disease progression is driven more by microglial activation, mitochondrial dysfunction, oxidative damage, and vascular insufficiency than by acute inflammation. Simvastatin may counter these through enhancing endothelial nitric oxide synthase (eNOS), inhibiting iNOS, reducing pro-inflammatory cytokines, and modulating leukocyte-endothelial interactions. Preclinical studies have shown that statins can reduce leukocyte infiltration across the blood-brain and blood-retinal barriers by interfering with Rho prenylation and endothelial cell signalling. Furthermore, in animal models of MS, simvastatin has been shown to attenuate disease severity by reducing oxidative stress and preserving vascular function. Clinically, a previous Phase II double-blind, placebo-controlled trial conducted by the same investigator group demonstrated that high-dose simvastatin (80 mg daily) led to a significant 43% reduction in the rate of brain atrophy in individuals with SPMS, alongside favourable trends in disability progression. Interestingly, this study found no significant changes in immune markers, suggesting that the benefits of simvastatin may not be mediated through traditional immunosuppression but rather through neuroprotective and vasoprotective mechanisms. The MS-OPT trial was thus designed to explore these mechanisms. It assesses whether high-dose simvastatin improves cerebral and retinal perfusion, reduces oxidative damage, and protects neuroaxonal integrity in progressive MS. Advanced imaging and biomarker analyses will help clarify its mode of action and support its potential repositioning for this under-treated phase of MS. | ||
Evidence for comparator |
The comparator in the MS-OPT trial is a matched placebo, formulated to be visually identical to simvastatin capsules to maintain double-blinding. The placebo tablets consist of gelatin and microcrystalline cellulose and do not contain any pharmacologically active ingredients. Participants randomised to the placebo arm follow the same dosing schedule as those receiving simvastatin: one tablet daily for four weeks, followed by two tablets daily for the remaining 17-week treatment period. Importantly, at the time this trial was conducted, there were no specific disease-modifying treatments approved for secondary progressive multiple sclerosis (SPMS), making the use of a placebo both ethically and scientifically appropriate. The placebo control enables a clear assessment of simvastatin’s effects by accounting for the natural course of disease progression and eliminating bias due to participant or investigator expectations. All participants — whether receiving simvastatin or placebo — underwent identical safety monitoring, clinical assessments, and support procedures, ensuring ethical parity and high-quality data collection across both trial arms. | ||
Actual start date of recruitment |
19 Jun 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 40
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Worldwide total number of subjects |
40
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
37
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
The MS-OPT trial recruited 40 participants with SPMS or PPMS, aged 18 and over, with EDSS scores between 4.0 and 6.5 and evidence of steady progression. Recruitment took place at a single site split across UCL Queen Square and Moorfields Eye Hospital, with visits coordinated between both locations. | |||||||||||||||
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Pre-assignment
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Screening details |
Screening included medical history, physical exam, EDSS assessment, blood tests (including liver and kidney function, CK), ECG, and MRI safety checks. Participants also underwent review of prior MS progression and current medications to confirm eligibility and ensure no contraindications to simvastatin. | |||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||
Blinding implementation details |
The MS-OPT trial was double-blind, meaning neither participants nor investigators knew the treatment allocation. Simvastatin and placebo tablets were identical in appearance and packaging, prepared by a third-party manufacturer. Randomisation was managed using a secure minimisation algorithm, and all study procedures, including dosing and assessments, were conducted identically across both arms to maintain blinding integrity.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Simvastatin | |||||||||||||||
Arm description |
Participants randomised to the simvastatin arm received oral simvastatin starting at a dose of 40 mg once daily in the evening for the first four weeks. Following a satisfactory safety review, the dose was increased to 80 mg daily (administered as two 40 mg capsules) for the remaining 13 weeks of the 17-week treatment period. Simvastatin was over-encapsulated to match the placebo in appearance, maintaining the integrity of the double-blind design. Participants were advised to take the medication at a consistent time each evening, with or without food, and were monitored regularly for safety through blood tests and clinical assessments. Adherence was reinforced through medication diaries and pill counts. Dose adjustments or discontinuation were allowed if clinically indicated due to adverse effects or lab abnormalities. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Simvastatin
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Investigational medicinal product code |
ATC-Code: C10A A01
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
In the MS-OPT trial, simvastatin was administered orally at a high dose, following a structured titration schedule to enhance tolerability. Participants assigned to the active treatment arm received 40 mg once daily in the evening for the first four weeks. After a satisfactory safety assessment at Week 4, the dose was increased to 80 mg once daily for the remaining 13 weeks of the 17-week treatment period. Simvastatin and placebo tablets were over-encapsulated to ensure visual indistinguishability and preserve blinding. Participants were instructed to take the medication with water in the evening and maintain consistent timing throughout the study. Adherence was supported through the use of medication diaries and pill counts at each visit. Dose modifications or discontinuation were permitted at the discretion of the treating clinician if adverse effects occurred. All participants received clear guidance on how to take the medication and were monitored regularly for safety throughout th
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Arm title
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Placebo | |||||||||||||||
Arm description |
Participants in the placebo arm received capsules containing an inert substance (gelatin and microcrystalline cellulose), matched in appearance and dosing schedule to the active treatment. Like the simvastatin arm, dosing began with one capsule daily for the first four weeks, increasing to two capsules daily for the remaining 13 weeks. All procedures, including monitoring, assessments, and participant instructions, were identical to those in the simvastatin arm to preserve blinding and ensure consistent data collection. The use of placebo was considered ethically appropriate, as no approved disease-modifying treatments for secondary progressive MS were available at the time of the trial. This design allowed for a rigorous evaluation of simvastatin’s effects while ensuring participant safety and trial integrity. | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants randomised to the placebo arm received visually identical capsules containing inactive ingredients—gelatin and microcrystalline cellulose. The dosing schedule matched that of the simvastatin arm to maintain blinding and ensure consistency. Participants began with one placebo capsule (equivalent to 40 mg simvastatin in appearance) taken once daily in the evening for the first four weeks. Following this initial phase, and provided no safety concerns were identified, the dose was increased to two placebo capsules daily (equivalent in appearance to 80 mg simvastatin) for the remaining 13 weeks of the 17-week treatment period. Capsules were taken orally with water, preferably at the same time each evening. Participants were instructed to maintain adherence using a medication diary and to return unused capsules at follow-up visits for compliance checks. All procedures, including safety monitoring and clinical assessments, were identical to those in the simvastatin arm.
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Baseline characteristics reporting groups
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Reporting group title |
Simvastatin
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Reporting group description |
Participants randomised to the simvastatin arm received oral simvastatin starting at a dose of 40 mg once daily in the evening for the first four weeks. Following a satisfactory safety review, the dose was increased to 80 mg daily (administered as two 40 mg capsules) for the remaining 13 weeks of the 17-week treatment period. Simvastatin was over-encapsulated to match the placebo in appearance, maintaining the integrity of the double-blind design. Participants were advised to take the medication at a consistent time each evening, with or without food, and were monitored regularly for safety through blood tests and clinical assessments. Adherence was reinforced through medication diaries and pill counts. Dose adjustments or discontinuation were allowed if clinically indicated due to adverse effects or lab abnormalities. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants in the placebo arm received capsules containing an inert substance (gelatin and microcrystalline cellulose), matched in appearance and dosing schedule to the active treatment. Like the simvastatin arm, dosing began with one capsule daily for the first four weeks, increasing to two capsules daily for the remaining 13 weeks. All procedures, including monitoring, assessments, and participant instructions, were identical to those in the simvastatin arm to preserve blinding and ensure consistent data collection. The use of placebo was considered ethically appropriate, as no approved disease-modifying treatments for secondary progressive MS were available at the time of the trial. This design allowed for a rigorous evaluation of simvastatin’s effects while ensuring participant safety and trial integrity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Simvastatin
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Reporting group description |
Participants randomised to the simvastatin arm received oral simvastatin starting at a dose of 40 mg once daily in the evening for the first four weeks. Following a satisfactory safety review, the dose was increased to 80 mg daily (administered as two 40 mg capsules) for the remaining 13 weeks of the 17-week treatment period. Simvastatin was over-encapsulated to match the placebo in appearance, maintaining the integrity of the double-blind design. Participants were advised to take the medication at a consistent time each evening, with or without food, and were monitored regularly for safety through blood tests and clinical assessments. Adherence was reinforced through medication diaries and pill counts. Dose adjustments or discontinuation were allowed if clinically indicated due to adverse effects or lab abnormalities. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants in the placebo arm received capsules containing an inert substance (gelatin and microcrystalline cellulose), matched in appearance and dosing schedule to the active treatment. Like the simvastatin arm, dosing began with one capsule daily for the first four weeks, increasing to two capsules daily for the remaining 13 weeks. All procedures, including monitoring, assessments, and participant instructions, were identical to those in the simvastatin arm to preserve blinding and ensure consistent data collection. The use of placebo was considered ethically appropriate, as no approved disease-modifying treatments for secondary progressive MS were available at the time of the trial. This design allowed for a rigorous evaluation of simvastatin’s effects while ensuring participant safety and trial integrity. | ||
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End point title |
Effect on Cerebral Blood Flow in White Matter, Gray Matter, Deep White Matter, Deep Gray Matter, and Thalamus | |||||||||||||||||||||||||||
End point description |
To compare patients on simvastatin or placebo using multiple linear regressions. ASL is an MRI method that allows non-invasive measurement of CBF using inversion of arterial water spins as a tracer.The aim is to explore whether subtle changes in CBF occur over time between placebo and simvastatin treated patients, including potential waning of the effects of the drug over time.
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End point type |
Primary
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End point timeframe |
At week 16
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Statistical analysis title |
Effect of simvastatin on Cerebral Blood Flow | |||||||||||||||||||||||||||
Statistical analysis description |
To compare patients on simvastatin or placebo using multiple linear regressions. ASL is an MRI method that allows non-invasive measurement of CBF using inversion of arterial water spins as a tracer.The aim is to explore whether subtle changes in CBF occur over time between placebo and simvastatin treated patients, including potential waning of the effects of the drug over time.
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Comparison groups |
Simvastatin v Placebo
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Number of subjects included in analysis |
38
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||||||||
P-value |
> 0.05 [1] | |||||||||||||||||||||||||||
Method |
Regression, Linear | |||||||||||||||||||||||||||
Confidence interval |
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| Notes [1] - The difference in mean percentage change at visit 3 was 3.43 (p=0.627) for white matter CBF, 3.72 (p=0.499) for grey matter CBF, 1.70 (p=0.822) for deep white matter CBF, 4.56 (p=0.435) for deep grey matter CBF, and 5.57 (p=0.400) for thalamus. |
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End point title |
AOSLO Measurements of Blood Flow | ||||||||||||
End point description |
To establish if Adaptive Optics Scanning Laser Ophthalmoscope (AOSLO) measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment.
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End point type |
Primary
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End point timeframe |
At week 16
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Statistical analysis title |
AOSLO Measurements of Blood Flow | ||||||||||||
Statistical analysis description |
To establish if Adaptive Optics Scanning Laser Ophthalmoscope (AOSLO) measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment.
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Comparison groups |
Simvastatin v Placebo
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Number of subjects included in analysis |
34
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.66 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Confidence interval |
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End point title |
MRI: ASL in White Matter, Gray Matter, Deep White Matter, Deep Gray Matter, and Thalamus | |||||||||||||||||||||||||||
End point description |
To evaluate whether ASL is useful correlate for cerebral blood flow measurement on and off treatment.
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End point type |
Secondary
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End point timeframe |
At baseline
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
AOSLO Blood Flow Dynamics | ||||||||||||||||||
End point description |
AOSLO of retinal capillary microvessels was applied to calculate retinal perfusion and measure blood flow dynamics at the capillary level. We measured relative venous and artery blood pO2 levels near the optic nerve (central 3 disk diameters) to obtain vessel width and velocity.
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End point type |
Secondary
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End point timeframe |
Over 16 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
MRI: Brain Atrophy | ||||||||||||||||||||||||||||||||||||
End point description |
To explore whether statin reduce the rate of brain atrophy, including grey matter volumes, on MRI (excluding the effect of pseudo-atrophy, which is a temporary response to the drug rather than an actual loss of tissue). The MRI images will be analysed using softwares developed at UCL to quantify the amount of brain tissue loss over time.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
MRI: Diffusion Tensor Imaging (DTI) | ||||||||||||||||||
End point description |
Diffusion weighted imaging (DWI) is an MR imaging technique based upon the measurement of the random Brownian motion of water within a voxel of tissue. This technique has been used to analyse the microstructure of neuronal tissue in particular myelin and axonal integrity. Data are reported for white matter
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
MRI: Neurite Density and Orientation Dispersion Imaging | ||||||||||||||||||
End point description |
To assess changes in axonal parameters, such as fiber orientation dispersion and axonal densities occurring over time using NODDI, an advanced MRI technique that reflects the microstructural complexity of dendrites and axons in vivo. Data are reported for white matter.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
MRI: MTV | |||||||||||||||||||||||||||
End point description |
Macromolecular tissue volume (MTV) is a method of myelin mapping to determine the role of myelin loss or changes in progressive MS. With the macromolecular volume being made up of 50% myelin, we are able to use an in-house analysis pipeline to calculate the MTV - a surrogate marker of brain myelin volume. This metric, alongside diffusion weighted imaging will provide micro-structural detail into the cross-sectional and longitudinal changes occurring in the brain parenchyma of people with progressive MS.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
OCT-A: Retinal Nerve Fibre Layer | ||||||||||||
End point description |
Inner retinal thickness will be measured using optical coherence tomography (OCT). OCT is a method of retinal imaging which is non-invasive and involves the patient holding their head still and staring at a dim light while imaging takes place. Peripapillary retinal nerve fibre layer (pRNFL) thickness is a strong candidate as a biomarker of axonal degeneration in MS.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
OCT-A: Vessel Density | ||||||||||||
End point description |
OCT-A images will be processed to produce quantitative data of perfusion indices. Vessel density (VD) is defined as the "percentage area occupied by vessels in the segmented area.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical Outcome: EDSS | ||||||||||||
End point description |
To examine the clinical effect of simvastatin treatment as reported by the clinician. Clinician observed expanded disability status score (EDSS) 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. Scoring is based on an examination by a neurologist and encompasses pyramidal, cerebellar, brainstem, sensory, bowel/bladder function in addition to visual, cerebral and other functions. Mean change from baseline to visit 3 is reported.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical Outcomes: MSFC: 25 Foot Timed Walk | ||||||||||||
End point description |
To examine the clinical effect of simvastatin treatment as reported by the clinician . Multiple Sclerosis Function Composite (MSFC) includes the 25 foot timed foot walk (25TFW), which involves marking a 25-foot distance in an unobstructed hallway; an assistive device (if needed) may be used by the participant and recorded. Their speed is then timed up to a time limit of 3 mins in both directions. Mean change from baseline to visit 3 is reported.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Clinical Outcomes: MSFC: 9 Hole Peg Test | ||||||||||||||||||
End point description |
To examine the clinical effect of simvastatin treatment as reported by the clinician. Multiple Sclerosis Function Composite (MSFC) includes the 9 hole peg test (9HPT). The 9-HPT is a quantitative measure of upper extremity (arm and hand) function. Both the dominant and non-dominant hands are tested twice (two consecutive trials of the dominant hand, followed immediately by two consecutive trials of the non-dominant hand). It is important that the 9-HPT be administered on a solid table (not a rolling hospital bedside table) and that the 9-HPT apparatus be anchored (e.g., with Dycem). The pegs are selected one at a time, using one hand only, and put into the holes as quickly as possible in any order until all the holes are filled. Then, without pausing, the pegs are removed one at a time and returned to the container. Mean change from baseline to visit 3 is reported.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Clinical Outcomes: SDMT | ||||||||||||
End point description |
Symbol Digit Modalities Test (SDMT) is measure of cognitive impairment. The subject is asked to match single digits to symbols using a key as a guide that pairs the numbers to the symbols. They are presented with a page headed by a key that pairs the single digits 1-9 with nine symbols and they then write or orally report their responses in a scoring form. It can be administered in oral and written form and is timed and guided by a trained examiner ie. suitably qualified member of the research team. Changes in scores were recorded over the time-points described. Scores range from 0 to 110, with higher scores indicating better cognitive functioning. Mean change from baseline to visit 3 is reported.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical Outcomes: Frontal Executive Functioning: FAB | ||||||||||||
End point description |
Frontal Assessment Battery (FAB). The FAB is a brief tool that can be used at the bedside or in a clinic setting to assist in discriminating between dementias with a frontal dysexecutive phenotype and dementia of Alzheimer‟s Type (DAT). The FAB has validity in distinguishing Fronto-temporal type dementia from DAT in mildly demented patients (MMSE > 24). Total score is from a maximum of 18, higher scores indicating better performance. Changes in scores were recorded over the time-points described. The FAB evaluates executive functions through six subtests, including conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. Each subtest is scored from 0 to 3, yielding a total score range of 0 to 18. Higher scores indicate better executive functioning. The total score is calculated by summing the six subtest scores. Mean change from baseline to visit 3 is reported.
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End point type |
Secondary
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End point timeframe |
At week 20
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Patient-Reported Outcomes: MSIS-29v2 Questionnaires | ||||||||||||||||||
End point description |
To examine the clinical effect of simvastatin treatment as reported by patient reported outcome measures. Patient reported multiple sclerosis impact scale version 2 (MSIS-29v2) is a self-administered questionnaire covering 29 items that asks to what degree MS has impacted the person physically and mentally over the past two weeks. It consists of 29 items divided into two subscales: Physical Impact (20 items; score range: 20-100) and Psychological Impact (9 items; score range: 9-45). Each item is rated on a 5-point Likert scale. Higher scores reflect a greater negative impact of MS on the individual's quality of life. Mean change from baseline to visit 3 is reported.
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End point type |
Secondary
|
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||||||||
|
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End point title |
Patient-Reported Outcomes: MSWT-12V2 Questionnaires | ||||||||||||
End point description |
Patient reported Multiple Sclerosis Walking Test version 2 (MSWT-12V2) is a 12 item self-administered questionnaire that measures walking performance over the previous two weeks. Each items is summed to generate a total score which is then transformed to a scale ranging from 0 to 100. Higher scores indicate greater impact on walking. Mean change from baseline to visit 3 is reported.
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End point type |
Secondary
|
||||||||||||
End point timeframe |
At week 16
|
||||||||||||
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Health Economic Outcomes: EQ5D5L | ||||||||||||||||||||||||||||||
End point description |
The EuroQol Health-Related Quality of Life (EQ-5D-5L) is a standardized instrument for assessing health-related quality of life across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain is rated on a five-level scale, ranging from 1 (no problems) to 5 (extreme problems). The EQ-5D-5L also includes a visual analogue scale (VAS), on which individuals rate their overall health from 0 (worst imaginable health state) to 100 (best imaginable health state). Results are reported as the mean change in domain scores and VAS ratings from baseline to Visit 3.
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End point type |
Secondary
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End point timeframe |
At week 16
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Immune Parameters, and Biomarkers | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Blood samples from these patients will be taken at baseline and at weeks 4, 16 and 20 to investigate the effect of statins on vascular leakage and free radical damage. Biomarkers will be determined as follows: (i) For RNA/DNA oxidative damage serum levels of 8-hydroxyguanosine (8-OHG)/8-hydroxydeoxyguanosine (8-OHdG); (ii) Protein oxidative damage will be determined by assaying plasma proteins for nitrotyrosine and carbonyl content; and (iii) Detection of lipid oxidative damage by assaying for the advanced lipid peroxidation end products 4-hydroxynonenal (4-HNE or HNE), malondialdehyde (MDA), 8-iso-prostaglandin F2α and thiobarbituric acid reactive substances (TBARS) (Miller et al., 2012). Mean percentage of change from baseline to visit 2.
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End point type |
Secondary
|
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End point timeframe |
At week 4
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse event data were collected from June 2019 to 12 October 2022, covering each participant from baseline to one month post-final visit, with individual assessment periods of about 24 weeks depending on enrollment and visit schedule.
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Adverse event reporting additional description |
Adverse Event (AE): Any untoward medical occurrence in a trial participant given a medicinal product, not necessarily causally related to treatment.
Serious AE, SAR, or unexpected SAR: An AE or reaction that results in death, is life-threatening, or causes serious health consequences.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
Simvastatin
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Reporting group description |
Simvastatin is part of the pharmacotherapeutic group of HMG-CoA reductase inhibitors (ATC-Code: C10A A01). Simvastatin is licensed within the EU for hypercholesterolemia and cardiovascular prevention but for this trial its use will be outside its licensed indication. The starting dose at baseline was 40 mg of Simvastatin or placebo (one tablet) to be taken orally in the evening. This was up titrated at Visit 2 (week 4) to 80 mg (two tablets) if all safety parameters were met at Visit 2. Participants were allocated one bottle each containing 220 tablets for the duration of the study. There was therefore one drug dispensation at baseline, and the patient was reminded to up-titrate after one month at Visit 2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matched placebo taking a dummy pill (Placebo IMP: gelatine tablet with added cellulose microcrystalline). The starting dose at baseline for placebo was 1 tablet to be taken orally in the evening. This was up titrated at Visit 2 (week 4) to 2 tablets if all safety parameters were met at Visit 2. Participants were allocated one bottle each containing 220 tablets for the duration of the study. There was therefore one drug dispensation at baseline, and the patient was reminded to up-titrate after one month at Visit 2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
30 Jan 2018 |
Additional information and clarifications related to the study procedures have been incorporated into the protocol (Protocol Version 1.2, dated 12 Jan 2018). Accordingly, the following documents have been amended:
- Participant Information Leaflet (PIL) Version 1.1, dated 04 Jan 2018;
- Consent Form Version 1.1, dated 04 Jan 2018;
- Pregnancy Monitoring Form Version 1.1, dated 04 Jan 2018;
- Pregnancy Monitoring Consent Form Version 1.1, dated 04 Jan 2018;
- IMPD Versions 1.2, 1.3, and 1.4. |
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26 Aug 2018 |
An update to the protocol has been made in response to the REC Provisional Opinion and submitted to the MHRA. The following new documents have been included:
- Protocol Version 1.2, dated 12 Jan 2018;
- IMPD Version 1.4, dated 01 Feb 2018. |
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19 Dec 2018 |
An update to the protocol has been made to clarify the storage of the Investigational Medicinal Product (IMP) at the site and to remove the PASAT assessment (Protocol Version 1.4). The IMPD has been updated accordingly to Version 1.5. Validated study instruments have also been submitted for REC review and approval. |
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15 May 2019 |
This non-substantial amendment updated the protocol to Version 1.5 to provide clarification on the randomisation process at Visit 1. |
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29 Sep 2020 |
The protocol has been updated to Version 1.6 to include primary progressive multiple sclerosis (PPMS) patients. Associated documents, including the Participant Information Sheet (PIS) and Informed Consent Form (ICF), have been updated accordingly. The Reference Safety Information (RSI) has been revised, and two new documents — the Retinal Imaging Questionnaire and COVID-19 Participant Information Leaflet (PIL) — have been added. |
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26 Nov 2020 |
This non-substantial amendment updates the GP Letter template, Neurologist Letter template, Diary Card template, and 24-hour Contact Card to reflect the new trial title following the inclusion of primary progressive multiple sclerosis (PPMS) patients: "A double-blind, randomised, placebo-controlled, single-site study of high-dose simvastatin treatment for progressive multiple sclerosis: impact on vascular perfusion and oxidative damage". |
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24 Oct 2022 |
This amendment includes the removal of the Independent Data Monitoring Committee (IDMC), an amendment to the End of Trial definition, and an update to the imaging (MRI) protocol. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Recruitment and follow-up were affected by COVID-19, causing delays and out-of-window visits. The small sample size and single-site design may limit generalisability and consistency of results. | |||
