Simvastatin in Secondary Progressive Multiple Sclerosis
Condition: Secondary Progressive Multiple Sclerosis
MeSH terms: Neoplasm Metastasis; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Simvastatin
Intervention type(s): Drug
Intervention description(s): Simvastatin 40mg for first 4 weeks and 80mg (if tolerated) thereafter up to 17 weeks
Other intervention name(s): ATC-Code: C10A A01
Intervention MeSH terms: Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Multiple sclerosis