Simvastatin in Secondary Progressive Multiple Sclerosis

NCT ID: NCT03896217

Last Updated: 2025-07-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-16
• Study Completion Date: 2023-06-15

Brief 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.

Conditions

Secondary Progressive Multiple Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Simvastatin

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.

Group Type: ACTIVE_COMPARATOR

Simvastatin

Intervention Type: DRUG

Simvastatin 40mg for first 4 weeks and 80mg (if tolerated) thereafter up to 17 weeks

Placebo

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

Group Type: PLACEBO_COMPARATOR

Simvastatin

Intervention Type: DRUG

Simvastatin 40mg for first 4 weeks and 80mg (if tolerated) thereafter up to 17 weeks

Interventions

Simvastatin

Simvastatin 40mg for first 4 weeks and 80mg (if tolerated) thereafter up to 17 weeks

Intervention Type: DRUG

Other Intervention Names

ATC-Code: C10A A01

Eligibility Criteria

Inclusion Criteria

1. Patients must have a confirmed diagnosis of multiple sclerosis according to revised Mc Donald criteria and have entered the secondary progressive stage or a diagnosis of Primary Progressive MS.(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 with no upper age limit

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 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.

5. 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.

6. 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.

7. Willing and able to provide written informed consent.

8. Willing to ingest gelatine (placebo will contain this). Participants must therefore be informed sensitive to personal beliefs e.g. faith, diet.

Exclusion Criteria

1. Unable to give informed consent.

2. 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).

3. Patient is already taking or is anticipated to be taking a statin or lomitapide for cholesterol control.

4. 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.

5. 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.

6. The use of mitoxantrone if treated within the last 12 months.

7. Patient has received treatment with alemtuzumab.

8. Use of other experimental disease modifying treatment (including research in an investigational medicinal product) within 6 months of baseline visit.

9. Active Hepatic disease or known severe renal failure (creatinine clearance <30ml/min).

10. Screening levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatine kinase (CK) are three times the upper limit of normal patients.

11. If the patient reports any ophthalmic conditions such as glaucoma, ocular trauma or degenerative eye disease. . Cataracts are acceptable as long as they have not been advised to have surgery. No restrictions on post surgical care, unless the patient reports sight restricting capsule opacity. Short title: Simvastatin in Progressive MS Sponsor code: 16/0730 UCL protocol Version 1.7, dated 18/10/2022 Page 40 of 86

12. 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).

13. Females who are pregnant, planning pregnancy or breastfeeding.

14. 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Multiple Sclerosis Society

OTHER

Sponsor Role: collaborator

University College, London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Richard Nicholas, MD

Role: PRINCIPAL_INVESTIGATOR

UCL

Locations

Department of Neuroinflammation, UCL Institute of Neurology

London, , United Kingdom

Countries

United Kingdom

References

Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014 Jun 28;383(9936):2213-21. doi: 10.1016/S0140-6736(13)62242-4. Epub 2014 Mar 19.

Reference Type: BACKGROUND

PMID: 24655729 (View on PubMed)

Grecescu M. Optical coherence tomography versus visual evoked potentials in detecting subclinical visual impairment in multiple sclerosis. J Med Life. 2014 Oct-Dec;7(4):538-41.

Reference Type: BACKGROUND

PMID: 25713617 (View on PubMed)

Huang-Link YM, Al-Hawasi A, Lindehammar H. Acute optic neuritis: retinal ganglion cell loss precedes retinal nerve fiber thinning. Neurol Sci. 2015 Apr;36(4):617-20. doi: 10.1007/s10072-014-1982-3. Epub 2014 Oct 14.

Reference Type: BACKGROUND

PMID: 25311917 (View on PubMed)

Bennett JL, de Seze J, Lana-Peixoto M, Palace J, Waldman A, Schippling S, Tenembaum S, Banwell B, Greenberg B, Levy M, Fujihara K, Chan KH, Kim HJ, Asgari N, Sato DK, Saiz A, Wuerfel J, Zimmermann H, Green A, Villoslada P, Paul F; GJCF-ICC&BR. Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography. Mult Scler. 2015 May;21(6):678-88. doi: 10.1177/1352458514567216. Epub 2015 Feb 6.

Reference Type: BACKGROUND

PMID: 25662342 (View on PubMed)

Fox RJ, Thompson A, Baker D, Baneke P, Brown D, Browne P, Chandraratna D, Ciccarelli O, Coetzee T, Comi G, Feinstein A, Kapoor R, Lee K, Salvetti M, Sharrock K, Toosy A, Zaratin P, Zuidwijk K. Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS. Mult Scler. 2012 Nov;18(11):1534-40. doi: 10.1177/1352458512458169. Epub 2012 Aug 23.

Reference Type: BACKGROUND

PMID: 22917690 (View on PubMed)

Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung HP, Montalban X, Uitdehaag BMJ, Merschhemke M, Li B, Putzki N, Liu FC, Haring DA, Kappos L; INFORMS study investigators. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016 Mar 12;387(10023):1075-1084. doi: 10.1016/S0140-6736(15)01314-8. Epub 2016 Jan 28.

Reference Type: BACKGROUND

PMID: 26827074 (View on PubMed)

Greenwood J, Heasman SJ, Alvarez JI, Prat A, Lyck R, Engelhardt B. Review: leucocyte-endothelial cell crosstalk at the blood-brain barrier: a prerequisite for successful immune cell entry to the brain. Neuropathol Appl Neurobiol. 2011 Feb;37(1):24-39. doi: 10.1111/j.1365-2990.2010.01140.x.

Reference Type: BACKGROUND

PMID: 20946472 (View on PubMed)

Walters CE, Pryce G, Hankey DJR, Sebti SM, Hamilton AD, Baker D, Greenwood J, Adamson P. Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J Immunol. 2002 Apr 15;168(8):4087-4094. doi: 10.4049/jimmunol.168.8.4087.

Reference Type: BACKGROUND

PMID: 11937568 (View on PubMed)

Greenwood J, Walters CE, Pryce G, Kanuga N, Beraud E, Baker D, Adamson P. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 2003 May;17(8):905-7. doi: 10.1096/fj.02-1014fje. Epub 2003 Mar 5.

Reference Type: BACKGROUND

PMID: 12626426 (View on PubMed)

Harry R, Gegg M, Hankey D, Zambarakji H, Pryce G, Baker D, Calder V, Adamson P, Greenwood J. Suppression of autoimmune retinal disease by lovastatin does not require Th2 cytokine induction. J Immunol. 2005 Feb 15;174(4):2327-2335. doi: 10.4049/jimmunol.174.4.2327.

Reference Type: BACKGROUND

PMID: 15699169 (View on PubMed)

Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006 May;6(5):358-70. doi: 10.1038/nri1839.

Reference Type: BACKGROUND

PMID: 16639429 (View on PubMed)

Weber MS, Youssef S, Dunn SE, Prod'homme T, Neuhaus O, Stuve O, Greenwood J, Steinman L, Zamvil SS. Statins in the treatment of central nervous system autoimmune disease. J Neuroimmunol. 2006 Sep;178(1-2):140-8. doi: 10.1016/j.jneuroim.2006.06.006. Epub 2006 Jul 24.

Reference Type: BACKGROUND

PMID: 16860400 (View on PubMed)

Greenwood J, Mason JC. Statins and the vascular endothelial inflammatory response. Trends Immunol. 2007 Feb;28(2):88-98. doi: 10.1016/j.it.2006.12.003. Epub 2007 Jan 2.

Reference Type: BACKGROUND

PMID: 17197237 (View on PubMed)

Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004 May 15;363(9421):1607-8. doi: 10.1016/S0140-6736(04)16205-3.

Reference Type: BACKGROUND

PMID: 15145635 (View on PubMed)

Neuhaus O, Hartung HP. Evaluation of atorvastatin and simvastatin for treatment of multiple sclerosis. Expert Rev Neurother. 2007 May;7(5):547-56. doi: 10.1586/14737175.7.5.547.

Reference Type: BACKGROUND

PMID: 17492904 (View on PubMed)

Paraskevas KI. Statin treatment for rheumatoid arthritis: a promising novel indication. Clin Rheumatol. 2008 Mar;27(3):281-7. doi: 10.1007/s10067-007-0806-8. Epub 2007 Dec 8.

Reference Type: BACKGROUND

PMID: 18066611 (View on PubMed)

Yuan C, Zhou L, Cheng J, Zhang J, Teng Y, Huang M, Adcock IM, Barnes PJ, Yao X. Statins as potential therapeutic drug for asthma? Respir Res. 2012 Nov 24;13(1):108. doi: 10.1186/1465-9921-13-108.

Reference Type: BACKGROUND

PMID: 23176705 (View on PubMed)

Young RP, Hopkins RJ. Update on the potential role of statins in chronic obstructive pulmonary disease and its co-morbidities. Expert Rev Respir Med. 2013 Oct;7(5):533-44. doi: 10.1586/17476348.2013.838018.

Reference Type: BACKGROUND

PMID: 24138695 (View on PubMed)

Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015 Feb;14(2):183-93. doi: 10.1016/S1474-4422(14)70256-X.

Reference Type: BACKGROUND

PMID: 25772897 (View on PubMed)

Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005 Nov;128(Pt 11):2705-12. doi: 10.1093/brain/awh641. Epub 2005 Oct 17.

Reference Type: BACKGROUND

PMID: 16230320 (View on PubMed)

Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007 Apr;130(Pt 4):1089-104. doi: 10.1093/brain/awm038.

Reference Type: BACKGROUND

PMID: 17438020 (View on PubMed)

Liao JK. Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol. 2002 Nov;86(1):5-18. doi: 10.1016/s0167-5273(02)00195-x.

Reference Type: BACKGROUND

PMID: 12243846 (View on PubMed)

Mason JC. Statins and their role in vascular protection. Clin Sci (Lond). 2003 Sep;105(3):251-66. doi: 10.1042/CS20030148.

Reference Type: BACKGROUND

PMID: 12793855 (View on PubMed)

Haendeler J, Hoffmann J, Zeiher AM, Dimmeler S. Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cells: a novel vasculoprotective function of statins. Circulation. 2004 Aug 17;110(7):856-61. doi: 10.1161/01.CIR.0000138743.09012.93. Epub 2004 Aug 2.

Reference Type: BACKGROUND

PMID: 15289372 (View on PubMed)

Antonopoulos AS, Margaritis M, Shirodaria C, Antoniades C. Translating the effects of statins: from redox regulation to suppression of vascular wall inflammation. Thromb Haemost. 2012 Nov;108(5):840-8. doi: 10.1160/TH12-05-0337. Epub 2012 Aug 7.

Reference Type: BACKGROUND

PMID: 22872079 (View on PubMed)

Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8880-5. doi: 10.1073/pnas.95.15.8880.

Reference Type: BACKGROUND

PMID: 9671773 (View on PubMed)

Giannopoulos S, Katsanos AH, Tsivgoulis G, Marshall RS. Statins and cerebral hemodynamics. J Cereb Blood Flow Metab. 2012 Nov;32(11):1973-6. doi: 10.1038/jcbfm.2012.122. Epub 2012 Aug 29.

Reference Type: BACKGROUND

PMID: 22929438 (View on PubMed)

Xu G, Fitzgerald ME, Wen Z, Fain SB, Alsop DC, Carroll T, Ries ML, Rowley HA, Sager MA, Asthana S, Johnson SC, Carlsson CM. Atorvastatin therapy is associated with greater and faster cerebral hemodynamic response. Brain Imaging Behav. 2008 Jun 1;2(2):94. doi: 10.1007/s11682-007-9019-7.

Reference Type: BACKGROUND

PMID: 20157644 (View on PubMed)

De Keyser J, Steen C, Mostert JP, Koch MW. Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance. J Cereb Blood Flow Metab. 2008 Oct;28(10):1645-51. doi: 10.1038/jcbfm.2008.72. Epub 2008 Jul 2.

Reference Type: BACKGROUND

PMID: 18594554 (View on PubMed)

D'haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C, Demey J, De Keyser J. Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5654-8. doi: 10.1073/pnas.1222560110. Epub 2013 Mar 18.

Reference Type: BACKGROUND

PMID: 23509249 (View on PubMed)

Paling D, Thade Petersen E, Tozer DJ, Altmann DR, Wheeler-Kingshott CA, Kapoor R, Miller DH, Golay X. Cerebral arterial bolus arrival time is prolonged in multiple sclerosis and associated with disability. J Cereb Blood Flow Metab. 2014 Jan;34(1):34-42. doi: 10.1038/jcbfm.2013.161. Epub 2013 Sep 18.

Reference Type: BACKGROUND

PMID: 24045400 (View on PubMed)

Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998 Mar 31;97(12):1129-35. doi: 10.1161/01.cir.97.12.1129.

Reference Type: BACKGROUND

PMID: 9537338 (View on PubMed)

Mraiche F, Cena J, Das D, Vollrath B. Effects of statins on vascular function of endothelin-1. Br J Pharmacol. 2005 Mar;144(5):715-26. doi: 10.1038/sj.bjp.0706114.

Reference Type: BACKGROUND

PMID: 15678081 (View on PubMed)

Pahan K, Sheikh FG, Namboodiri AM, Singh I. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest. 1997 Dec 1;100(11):2671-9. doi: 10.1172/JCI119812.

Reference Type: BACKGROUND

PMID: 9389730 (View on PubMed)

van der Most PJ, Dolga AM, Nijholt IM, Luiten PG, Eisel UL. Statins: mechanisms of neuroprotection. Prog Neurobiol. 2009 May;88(1):64-75. doi: 10.1016/j.pneurobio.2009.02.002. Epub 2009 Feb 21.

Reference Type: BACKGROUND

PMID: 19428962 (View on PubMed)

Schmeer C, Kretz A, Isenmann S. Statin-mediated protective effects in the central nervous system: general mechanisms and putative role of stress proteins. Restor Neurol Neurosci. 2006;24(2):79-95.

Reference Type: BACKGROUND

PMID: 16720944 (View on PubMed)

Miller E, Mrowicka M, Saluk-Juszczak J, Ireneusz M. The level of isoprostanes as a non-invasive marker for in vivo lipid peroxidation in secondary progressive multiple sclerosis. Neurochem Res. 2011 Jun;36(6):1012-6. doi: 10.1007/s11064-011-0442-1. Epub 2011 Mar 12.

Reference Type: BACKGROUND

PMID: 21399906 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

16/0730 & 2017-003008-30

Identifier Type: -

Identifier Source: org_study_id