Simvastatin in Secondary Progressive Multiple Sclerosis

NCT03896217 | Completed Phase 2 Results

• 1 other identifier: 16/0730 & 2017-003008-30
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Secondary Progressive Multiple Sclerosis

Keywords

Multiple sclerosis

Outcome Measures

Primary Outcomes (2)

• Effect on Cerebral Blood Flow in White Matter, Gray Matter, Deep White Matter, Deep Gray Matter, and Thalamus

  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.

  At week 16

• AOSLO Measurements of Blood Flow

  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.

  At week 16

Secondary Outcomes (16)

• MRI: ASL in White Matter, Gray Matter, Deep White Matter, Deep Gray Matter, and Thalamus

  At baseline

• AOSLO Blood Flow Dynamics

  Over 16 weeks

• MRI: Brain Atrophy

  At week 16

• MRI: Diffusion Tensor Imaging (DTI)

  At week 16

• MRI: Neurite Density and Orientation Dispersion Imaging

  At week 16

Other Outcomes (1)

• Exploratory Outcomes: Immune Parameters, and Biomarkers.

  At week 4

Study Arms (2)

Simvastatin

ACTIVE COMPARATOR

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.

Drug: Simvastatin

Placebo

PLACEBO COMPARATOR

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

Drug: Simvastatin

Interventions

Simvastatin DRUG

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

Also known as: ATC-Code: C10A A01

Placebo; Simvastatin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• EDSS 4.0 - 6.5 (inclusive).
• Male and Females aged 18 with no upper age limit
• 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.

You may not qualify if:

• Unable to give informed consent.
• 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. . 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
• 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.

Sponsors & Collaborators

• University College, London: lead
• National Multiple Sclerosis Society: collaborator

Study Sites (1)

Department of Neuroinflammation, UCL Institute of Neurology

London, WC1B 5EH, United Kingdom

Location

Related Publications (37)

• 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.

  PMID: 24655729 BACKGROUND

• 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.

  PMID: 25713617 BACKGROUND

• 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.

  PMID: 25311917 BACKGROUND

• 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.

  PMID: 25662342 BACKGROUND

• 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.

  PMID: 22917690 BACKGROUND

• 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.

  PMID: 26827074 BACKGROUND

• 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.

  PMID: 20946472 BACKGROUND

• 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.

  PMID: 11937568 BACKGROUND

• 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.

  PMID: 12626426 BACKGROUND

• 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.

  PMID: 15699169 BACKGROUND

• 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.

  PMID: 16639429 BACKGROUND

• 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.

  PMID: 16860400 BACKGROUND

• 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.

  PMID: 17197237 BACKGROUND

• 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.

  PMID: 15145635 BACKGROUND

• 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.

  PMID: 17492904 BACKGROUND

• 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.

  PMID: 18066611 BACKGROUND

• 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.

  PMID: 23176705 BACKGROUND

• 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.

  PMID: 24138695 BACKGROUND

• 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.

  PMID: 25772897 BACKGROUND

• 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.

  PMID: 16230320 BACKGROUND

• 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.

  PMID: 17438020 BACKGROUND

• 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.

  PMID: 12243846 BACKGROUND

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

  PMID: 12793855 BACKGROUND

• 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.

  PMID: 15289372 BACKGROUND

• 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.

  PMID: 22872079 BACKGROUND

• 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.

  PMID: 9671773 BACKGROUND

• 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.

  PMID: 22929438 BACKGROUND

• 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.

  PMID: 20157644 BACKGROUND

• 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.

  PMID: 18594554 BACKGROUND

• 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.

  PMID: 23509249 BACKGROUND

• 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.

  PMID: 24045400 BACKGROUND

• 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.

  PMID: 9537338 BACKGROUND

• 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.

  PMID: 15678081 BACKGROUND

• 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.

  PMID: 9389730 BACKGROUND

• 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.

  PMID: 19428962 BACKGROUND

• 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.

  PMID: 16720944 BACKGROUND

• 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.

  PMID: 21399906 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: Prof. Richard Nicholas
• Organization: UCL Institute of Neurology

richard.nicholas3@nhs.net

0208 383 0675

Study Officials

• Richard Nicholas, MD

  UCL

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2018
• First Posted: March 29, 2019
• Study Start: May 16, 2019
• Primary Completion: September 13, 2022
• Study Completion: June 15, 2023
• Last Updated: July 1, 2025
• Results First Posted: July 1, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)