Simvastatin in Secondary Progressive Multiple Sclerosis (MS-OPT)

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

Multiple sclerosis (MS) is a neurological condition which is a common cause of disability in young people. It is thought to be an autoimmune condition, where the body's immune system begins to attack itself. The cause of MS is unknown but is thought to be a mix of genetic and environmental factors. There are treatments available for early stages of MS, but the later stage known as Secondary Progressive MS (SPMS) has no current treatment. Statins are a safe treatment traditionally used to reduce cholesterol levels. However, statins also have other effects which could reduce the progression of SPMS, such as effects on the immune system and circulation. A recent study (Chataway et al., 2014) showed that treatment with high-dose simvastatin, a type of statin, reduced the progression of SPMS but no effect on the immune system was seen. It is possible that simvastatin does not treat the immune system but improves how the blood and blood vessels in the brain work in this disease. The purpose of the clinical trial is to test how Simvastatin (80mg/day) may slow down disease progression in people living with SPMS compared to placebo (dummy pill). Participants will receive either Simvastatin or placebo and will be asked to take 2 tablets daily, for up to 17 weeks.

Approximately 60% of those affected with relapsing-remitting MS (RRMS) enter a SPMS stage after a median interval of 10 to 15 years, where disability accumulates gradually in the absence of relapses. A smaller proportion (15%), run a progressive course from onset (primary progressive (PP) MS). The progressive, "neurodegenerative" component of MS, rather than the clinical deficit resulting from incomplete recovery from each relapse in RRMS, is the dominant cause of long-term disability. Whilst over ten therapies are now licensed for RRMS, no treatment strategies, with the exception of a recent study by the investigators, have succeeded in slowing the progression of this later debilitating stage. Optic neuritis, inflammation of the optic nerve, is a common event associated with MS resulting in 27% of subjects with residual visual impairment. The impact of damage arising from an inflammatory lesion in the optic nerve can be visualised using optical coherence tomography (OCT) as a reduction in both ganglion cell layer and retinal nerve fibre layer thickness. However it is increasingly being appreciated that a number of other inflammatory and neurodegenerative changes occur in the retina of MS patients. These retinal changes, reflecting both the disease and its level of activity, have highlighted its potential as a surrogate outcome measure to study preservation of neuronal and/or vascular structure/function after an inflammatory event or as the disease progresses. During the last two decades there have been significant advances in the understanding of MS leading to treatment for the RRMS phase. Despite this, there has been a failure to find an effective treatment for progression and this remains a major unmet need, as highlighted by the International Progressive MS Alliance. The many challenges of progressive studies including optimal design, sensitive outcomes, suitable length and subject numbers are gradually being overcome by the MS community, but as yet extending the anti-inflammatory approach that has been effective in RRMS has not borne fruit in SPMS. Indeed the failure of the recent PPMS trial using fingolimod makes the success of simvastatin in the SPMS study all the more exciting, especially as the extensive systemic immunological assessment in this latter study revealed no impact on immune status. The real success of this simvastatin phase II study may be that it initiates novel avenues of investigation driven by the wide-ranging and well-characterised effects statins have on the body as well as a prelude to a definitive phase III trial. This premise underpins the research strategy. Preclinical work has focused on the role played by the vascular barriers (the blood-brain and blood retinal barriers) in the inflammatory process and in particular how they support leukocyte traffic to the central nervous system (CNS). This research, along with that of others, led to the identification and characterisation of endothelial cell (EC) signalling processes that facilitate leukocyte diapedesis and activate pro-inflammatory responses. The investigators found that a key central regulator of the EC signalling pathway supporting leukocyte diapedesis was the small GTPase Rho, and this led to investigating whether small GTPases could be targeted pharmacologically to reduce aberrant leukocyte migration into the brain and retina. Since small GTPases require posttranslational lipid modification (prenylation) to become functional, the investigators tested whether inhibition of Rho prenylation with prenyl transferase inhibitors (PTIs) affects lymphocyte migration. Treatment of brain endothelial cell monolayers in vitro, or animals induced for experimental autoimmune encephalomyelitis (EAE, the animal model of MS), resulted in inhibition of lymphocyte migration and attenuation of the disease respectively. Since the isoprenoids used for post-translational prenylation of small GTPases are derived from the cholesterol synthesis pathway, the investigators next investigated whether HMGCoA reductase inhibitors (statins) were also able to significantly inhibit Rho activity and reduce the severity of brain and retinal inflammatory disease. This research revealed that statins effectively reduced Rho prenylation and attenuated disease in experimentally induced models of MS and posterior uveitis. Whilst the investigators were able to demonstrate that one of the effects of statin treatment was to modify endothelia cell function and inhibit transendothelial migration of leukocytes, it is clear from many other experimental studies that efficacy may also be due to effects on other cell types such as immune cells. Indeed, it is now widely recognised that statins have anti-inflammatory properties that operate independently of their cholesterol lowering effect. Accordingly, statins have been shown to inhibit MHC class II restricted Ag presentation, attenuate antigen-presenting cell maturation and down-regulate T cell activation and proliferation. Of those T cells that proliferate, statins induce a shift from a proinflammatory Th1 to a regulatory Th2 phenotype. In addition, statins block adhesion molecule expression and their interactions, inhibit the production of chemokines and their receptors, and reduce the secretion of matrix metalloproteinases. Activation of the transcription factor NFκB, an important activator of pro-inflammatory mediators, is also inhibited by statins, alongside a concomitant upregulation of endothelial cell protective genes. Finally, it has been shown that endothelial nitric oxide synthase (eNOS) activity is enhanced, whilst inducible NOS (iNOS) is inhibited. This remarkable pleiotropic capacity for modulating the immune system and inflammation has prompted the clinical testing of statins for the treatment of RRMS and other inflammatory diseases. In one such study in 30 patients with RRMS, simvastatin (80mg) taken over 6 months reduced the number of brain lesions by 40%, although no change in disability scores was observed over this short study period. Other studies, however, have failed to demonstrate any significant clinical improvement in RRMS following statin treatment alone or in combination with other disease modifying drugs. Nevertheless, it should be noted that none of the studies so far have been sufficiently powered, rendering definitive conclusions impossible. Whilst there is a clear-cut rationale for using statins for the treatment of RRMS, in SPMS there is less obvious justification, as disease progression in the absence of new plaque formation is thought to be due predominantly to neurodegeneration (or neuronal loss). This results from several mechanisms, including microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Whereas large scale inflammatory lesions rarely occur at this stage of the disease, inflammation is prominent in progressive MS, where it is found throughout the grey and white matter, and in the meninges, with its most severe form being represented by the ectopic follicles that contribute to grey matter damage. This suggested that given their Immunomodulatory / anti-inflammatory actions, statins might still provide some benefit in SPMS. Nonetheless, neuronal loss is regarded as the key pathological feature, which raised the question whether statins also possess neuroprotective properties. Several lines of evidence suggest this may be the case. Firstly, statins are increasingly seen as vasculoprotective with a capacity to improve vascular perfusion and maintain/enhance blood vessel function thus protecting against long-term chronic hypoxic damage. This is germane given the growing evidence that dysfunctional/reduced blood flow in MS may predispose the tissue to damage resulting in neuronal cell dysfunction and ultimately cell death. Such beneficial effects on microvascular perfusion may be mediated through statins enhancing eNOS activation and inhibiting endothelin-1. Secondly, there are reports that statins may also be neuroprotective through reducing free radical damage either by improving blood flow and reducing hypoxia-mediated reactive oxygen species (ROS) production, or through direct inhibition of cytotoxic pathways. In the latter case, statins may protect neuroparenchymal cells via inhibition of iNOS in activated microglia and astrocytes, resulting in attenuated cytotoxic damage to neurons and oligodendrocytes. Furthermore, statins may also exert a neuroprotective effect by preventing glutamate-mediated excitotoxicity. Together these data provided a compelling rationale for testing the potential therapeutic effect of statins in SPMS. In 2008, the investigators therefore embarked on a two-year double-blind, controlled trial of 140 patients, randomising them to either 80mg of simvastatin or placebo. The recently published results of this trial showed that brain atrophy was reduced by over 40% alongside a similar favourable effect on two major disability outcome measures. This is the first evidence of a drug having a beneficial effect on SPMS disease progression. Surprisingly, however, and contrary to expectations, the investigators did not identify any modulation of the immune system, raising the critical question of the mechanism of statin action. It is the hypothesis, therefore, that the neuroprotective effects of statins in SPMS are mediated by stimulating enhanced microvascular perfusion and/or by inhibition of oxidative damage/neurotoxicity. This study will test this hypothesis. There are no current treatments for SPMS. Given the investigators demonstrated that simvastatin was beneficial in a phase II trial but were unable to elucidate any mechanism, it is important to try and understand the mechanism of action to develop further therapies. The investigators will investigate the impact of high dose simvastatin (80mg/day) on cerebral and retinal blood perfusion and vascular structure/function, brain neuroaxonal density and glutamate excitotoxicity in SPMS. In addition, various systemic parameters will be evaluated to determine the effect of high dose statin treatment on immune function, oxidative damage and vascular barrier function. Simvastatin is being used outside of its posology and method of administration. The previous phase two trial found simvastatin was safe up to the maximum dose of 80 mg/day given as a single dose in the evening. Based on the recommendations of the SPC and previous studies, the proposed use of 80mg of Simvastatin will, therefore, be used for this study.

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. Oral Simvastatin will be taken 40mg daily (one tablet in the evening) for 4 weeks and then at week 4 up titrated to 80mg daily (two tablets in the evening.

Matched Placebo (one tablet in the evening) for 4 weeks and then at week 4 up titrated to two tablets daily in the evening.

compared between 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 subtlechangesinCBFoccur over time between placebo and simvastatin treated patients, including potential waning of the effects of the drug over time.

To explore whether statin treatment reduces glutamate levels. These will be measured applying an advanced MRI technique called spectroscopy which detects biochemical changes in the brain.

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.

To establish whether Arterial Spin Labelling (ASL) measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment. The cerebral arterial hemodynamic measure bolus arrival time will be measured, as the time from labeling of blood in feeding arteries to its first arrival in the capillary network of the voxel of interest. This will be supported by a questionnaire investigating factors that influence brain perfusion (related to lifestyle and health, mental state, personality and cognition and use of caffeine and recreational drugs) to improve the accuracy and to facilitate the interpretation of perfusion-derived parameters.

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.

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. Changes in score (including no changes) will be recorded to determine progression of disability.

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. Changes in scores will be recorded over the time-points described.

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. This is timed and recorded at the time-points described.

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.

Patient reported Multiple Sclerosis Walking Score version 2 (MSWSv2) 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. Changes in scores will be recorded over the time-points described.

The EuroQol Health Related Quality of Life (EQ5d5L) is a five-item questionnaire that assesses mobility, self-care, pain/discomfort, anxiety/depression and a person's usual activities. It incorporates an additional visual analogue scale (VAS) which enables a calculation of quality of life years (QALY) so health economic analyses can be performed. Each item of the EQ5D5L is responded to on a scale as follows: no problems, slight problems, moderate problems, severe problems and extreme problems. Changes in scores will be recorded over the time-points described.

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).

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 will be recorded over the time-points described.

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 will be recorded over the time-points described.

Oxygen saturation of retinal vessels will be measured using the Oxymap T1. The device measures oxygen saturation quickly and non-invasively by taking two simultaneous images of the retina using two different wavelengths to determine the amount of oxygen bound haemoglobin in the blood.

Density of retinal vessels will be measured using optical coherence tomography angiography (OCTA). OCTA 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.

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.

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.

To assess whether patients develop new lesions or pre-existing lesions enlarge over time as surrogate markers for the inflammatory process.

Inclusion Criteria: 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. EDSS 4.0 - 6.5 (inclusive). Male and Females aged 18 to 65 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 purpose of clarity, True abstinence is when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence, withdrawal, spermicides only or lactational amenorrhoea method for the duration of a trial, are not acceptable methods of contraception. Females of childbearing potential have a negative pregnancy test within 7 days prior to being registered/randomised. Participants are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal. Willing and able to comply with the trial protocol (e.g. can tolerate MRI and fulfils the requirements for MRI, e.g. not fitted with pacemakers or permanent hearing aids) ability to understand and complete questionnaires Willing and able to provide written informed consent Willing to ingest gelatine (placebo will contain this). Participants must therefore be informed sensitive to personal beliefs e.g. faith, diet. Exclusion criteria Unable to give informed consent. Primary progressive MS. Those that have experienced a relapse or have been treated with steroids (both i.v. and oral) for multiple sclerosis relapse within 3 months of the screening visit. These patients may undergo a further screening visit once the 3 month window has expired and may be included if no steroid treatment has been administered in the intervening period. Patients on steroids for another medical condition may enter as long as the steroid prescription is not for multiple sclerosis (relapse/ progression). Patient is already taking or is anticipated to be taking a statin or lomitapide for cholesterol control. Any medications that unfavourably interact with statins as per Spc recommendations e.g.: fibrates, nicotinic acid, cyclosporin, azole anti-fungal preparations, macrolideantibiotics, protease inhibitors, nefazodone, verapamil, amiodarone, large amounts of grapefruit juice or alcohol abuse within 6 months. The use of immunosuppressants (e.g. azathioprine, methotrexate, cyclosporin) or disease modifying treatments (avonex, rebif, betaferon, glatiramer, dimethyl fumerate, fingolimod) within the previous 6 months. The use of mitoxantrone if treated within the last 12 months. Patient has received treatment with alemtuzumab. Use of other experimental disease modifying treatment (including research in an investigational medicinal product) within 6 months of baseline visit Active Hepatic disease or known severe renal failure (creatinine clearance <30ml/min) Screening levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatine kinase (CK) are three times the upper limit of normal patients. If the patient reports any ophthalmic conditions such as glaucoma, ocular trauma or degenerative eye disease Patient unable to tolerate or unsuitable to have baseline MRI scan (e.g. metal implants, heart pacemaker) or MRI scan not of adequate quality for analysis (e.g. too much movement artefact). Females who are pregnant, planning pregnancy or breastfeeding. Allergies to IMP active substance or to any excipients of IMP and placebo or other conditions that contraindicate use of galactose (eg. Hereditary galactose intolerance, Lactase deficiency, glucose-galactose malabsorption).

No identifiable patient information will be supplied to other researchers external to the organisation.

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