Multiple Sclerosis-Simvastatin Trial 2

NCT03387670 | Completed Phase 3 DMC

• 2 other identifiers: 17/01582017-003328-56
• Study Type: interventional
• Target: 964
• Locations: 1 country
• Sites: 31

Brief Summary

Multiple Sclerosis (MS) is a progressive neurological disorder of the brain and spinal cord. It affects approximately 120,000 people in the United Kingdom and 2.5 million people globally. Most people with MS experience two stages of the disease: Early MS - Relapsing-Remitting MS (RRMS), which is partially reversible, and Late MS - Secondary Progressive MS (SPMS), which affects the majority of patients, usually after 10 to 15 years after diagnosis. SPMS results from progressive neuronal degeneration that causes accumulating and irreversible disability affecting walking, balance, manual function, vision, cognition, pain control, bladder and bowel function. The pathological process driving the accrual of disability in SPMS is not known at present. Immunomodulatory anti-inflammatory disease modifying therapies (DMTs) are increasingly effective in reducing relapse frequency in RRMS, however, they have been unsuccessful in slowing disease progression in SPMS. This is the overwhelming conclusion from an analysis of 18 phase 3 trials (n=8500), of which 70% of the population had SPMS, all performed in the last 25 years. In an earlier study (Multiple Sclerosis-Simvastatin 1; MS-STAT1), 140 people with SPMS were randomly assigned to receive either placebo or simvastatin for a period of two years. The investigators found that the rate of brain atrophy (loss of neurons - 'brain shrinkage'), as measured by magnetic resonance imaging (MRI), was reduced in patients receiving simvastatin compared to those taking placebo. Several other long term studies have also reported that there might be a relationship between the rate of brain atrophy and the degree of impairment. The study is designed to test the effectiveness of repurposed simvastatin (80mg) in a phase 3 double blind, randomised, placebo controlled trial (1:1) in patients with secondary progressive MS (SPMS), to determine if the rate of disability progression can be slowed over a 3 to 4.5 year period. The results generated from this trial may help to improve the treatment options of people with MS. In addition, taking part in this trial will mean regular review by an experienced neurologist regardless of the drug that patients are randomly allocated to receive.

Conditions

Secondary Progressive Multiple Sclerosis (SPMS)

Outcome Measures

Primary Outcomes (1)

• Time to confirmed disability progression between simvastatin and placebo arm based on change in EDSS scores compared to baseline.

  The initial disability progression event is finalised as positive if disability is sustained and confirmed ≥6\* months later. Progression of disability defined as an increase of at least 1 point if EDSS baseline score \<6, or an increase of 0.5 point if baseline EDSS score is ≥6.

  6 monthly - baseline, month 6, 12, 18, 24, 30, 36, 42, 48, 54

Secondary Outcomes (15)

• Response rate on the patient reported outcome form Multiple Sclerosis Walking Scale-12 version 2 (MSWS-12v2)

  Annually - baseline, month 12, 24 and 36

• Response rate on the patient reported outcome form Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2)

  Annually - baseline, month 12, 24 and 36

• Cost effectiveness of intervention

  6 monthly - baseline, month 6, 12, 18, 24, 30, 36

• Evaluating change in degree of disability based on the modified Rankin scale (mRS)

  Annually - baseline, month 12, 24 and 36

• Change in visual function based on the Sloan Low Contrast Visual Acuity (SLCVA)

  Annually - baseline, month 12, 24 and 36

Study Arms (2)

Simvastatin

ACTIVE COMPARATOR

Drug: Simvastatin

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Simvastatin DRUG

* One (1 = 40mg) simvastatin tablet once daily at night for 1 month * Two (2 = 80mg) simvastatin tablets once daily at night, for the next 35 to 53 months

Simvastatin

Placebo DRUG

* One (1) placebo tablet once daily at night for 1 month * Two (2) placebo tablets once daily at night, for the next 35 to 53 months

Placebo

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a confirmed diagnosis of multiple sclerosis (MS) that have entered the secondary progressive stage. 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 1 point if EDSS score \<6, or an increase of 0.5 point if EDSS score ≥6, or clinical documentation of increasing disability;
• EDSS 4.0 - 6.5 (inclusive);
• Aged 25 to 65 years old;
• Patients must be able and willing to comply with the terms of this protocol;
• Written informed consent provided.

You may not qualify if:

• Relapse within 3 months of baseline visit. Patients will be eligible where 3 months from the final day of the relapse, has elapsed by the date of the baseline visit;
• Patients that have been treated with steroids (intravenous and/or oral) due to MS relapse/progression within 3 months from the final day of relapse to the baseline 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; (Note: Patients on steroids for another medical condition may be included in the trial provided the steroid prescription is not for MS relapse/progression)
• Significant organ co-morbidity e.g. cardiac failure, renal failure, malignancy;
• Screening levels of alanine aminotransferase (ALT) / aspartate aminotransferase (AST) or creatine kinase (CK) ≥3 x upper limit of normal (ULN);
• Current use of a statin; or any use within the last 6 months;
• Medications that interact unfavourably with simvastatin as outlined in the current summary of product characteristics (SmPC); including but not limited to CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, erythromycin, clrithromycin, telithromycin, telaprevir, nefazodone, fibrates (including fenofibrates), nicotinic acid (or products containing niacin), azole anti-fungal preparations, macrolide antibiotics, protease inhibitors, verapamil, amiodarone, amlodipine, gemfibrozil, ciclosporin, danazol, diltiazem, rifampicin, fusidic acid, elbasvir, grazoprevir,ticagrelor, daptomycin, grapefruit juice or alcohol abuse;
• Primary progressive MS;
• Diabetes mellitus type 1;
• Uncontrolled hypothyroidism;
• Female participants that are pregnant or breast feeding. Women of child bearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period, and up to 4 weeks after the last dose of study drug;
• Use of immunosuppressants (e.g. azathioprine, methotrexate, ciclosporine) or disease modifying treatments (avonex, rebif, betaferon, glatiramer) within the previous 6 months;
• Use of mitoxantrone, natalizumab, alemtuzumab, daclizumab or other monoclonal antibody treatment, if treated within the last 12 months;
• Use of fingolimod, dimethyl fumarate, teriflunomide, cladribine within the last 12 months;
• Use of other experimental disease modifying treatment within the last 6 months;
• Commencement of fampridine ≤6 months from day of randomisation;

Sponsors & Collaborators

• University College, London: lead
• University of Edinburgh: collaborator
• Queen Mary University of London: collaborator
• London School of Hygiene and Tropical Medicine: collaborator
• University of Leeds: collaborator
• The Leeds Teaching Hospitals NHS Trust: collaborator
• Imperial College Healthcare NHS Trust: collaborator

Study Sites (31)

Belfast City Hospital

Belfast, BT9 7AB, United Kingdom

Location

St Luke s Hospital

Bradford, BD5 ONA, United Kingdom

Location

Royal Sussex County Hospital

Brighton, BN2 5BE, United Kingdom

Location

Southmead Hospital

Bristol, BS10 5NB, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Kent and Canterbury Hospital

Canterbury, CT1 3NG, United Kingdom

Location

University Hospital of Wales

Cardiff, CF14 4XW, United Kingdom

Location

University Hospital Coventry and Warwickshire

Coventry, CV2 2DX, United Kingdom

Location

The Anne Rowling Regenerative Neurology Clinic

Edinburgh, EH16 4SB, United Kingdom

Location

Royal Devon and Exeter Hospital

Exeter, EX2 5DW, United Kingdom

Location

The Queen Elizabeth University Hospital

Glasgow, G51 4TF, United Kingdom

Location

Hull Royal Infirmary

Hull, HU3 2JZ, United Kingdom

Location

Leeds General Infirmary

Leeds, LS1 3EX, United Kingdom

Location

The Walton Centre NHS Foundation Trust

Liverpool, L9 7LJ, United Kingdom

Location

Queen's Hospital, Barking, Havering and Redbridge University Hospitals

London, RM7 0AG, United Kingdom

Location

Queen Elizabeth Hospital

London, SE18 4QH, United Kingdom

Location

Charing Cross Hospital

London, W6 8RF, United Kingdom

Location

University College London Hospital

London, WC1N 3BG, United Kingdom

Location

Salford Royal Hospital

Manchester, M6 8HD, United Kingdom

Location

Royal Victoria Infirmary

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Norfolk and Norwich University Hospital

Norwich, NR4 7UY, United Kingdom

Location

Queen's Medical Centre

Nottingham, NG7 2UH, United Kingdom

Location

John Radcliffe Hospital

Oxford, OX3 9DU, United Kingdom

Location

Derriford Hospital

Plymouth, PL6 8BH, United Kingdom

Location

Poole Hospital

Poole, BH15 2JB, United Kingdom

Location

Royal Preston Hospital

Preston, PR2 9HT, United Kingdom

Location

Royal Hallamshire Hospital

Sheffield, S10 2JF, United Kingdom

Location

Southampton General Hospital

Southampton, SO16 6YD, United Kingdom

Location

University Hospital of North Staffordshire

Stoke-on-Trent, ST4 6QG, United Kingdom

Location

Morriston & Neath Port Talbot Hospitals (Abertawe Bro Morgannwg University Local Health Board)

Swansea, United Kingdom

Location

Torbay Hospital

Torquay, TQ2 7AA, United Kingdom

Location

Related Publications (6)

• Chataway J, Williams T, Blackstone J, John N, Braisher M, De Angelis F, Bianchi A, Calvi A, Doshi A, Apap Mangion S, Wade C, Bordea E, Merry R, Barton G, Lyle D, Jarman E, Mahad D, Shehu A, Arun T, McDonnell G, Geraldes R, Craner M, Hillier C, Ganesalingam J, Fisniku L, Hobart J, Spilker C, Robertson NP, Kalra S, Pluchino S, Harikrishnan S, Mattoscio M, Harrower T, Young C, Lee M, Chhetri SK, Ahmed F, Rog D, Silber E, Gallagher P, Duddy M, Straukiene A, Nicholas R, Rice C, Tebbs S, Hawton A, Hunter R, Giovannoni G, Ciccarelli O, Beveridge J, Nixon S, Thompson AJ, Greenwood J, Pearson OR, Evangelou N, Sharrack B, Galea I, Gray E, Pavitt S, Chandran S, Ford HL, Frost C, Nicholas JM; MS-STAT2 Investigators. Effect of repurposed simvastatin on disability progression in secondary progressive multiple sclerosis (MS-STAT2): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2025 Oct 11;406(10512):1611-1624. doi: 10.1016/S0140-6736(25)01039-6. Epub 2025 Oct 1.

  PMID: 41045938 DERIVED

• Blackstone J, Williams T, Nicholas JM, Bordea E, De Angelis F, Bianchi A, Calvi A, Doshi A, John N, Apap Mangion S, Wade C, Merry R, Barton G, Lyle D, Jarman E, Mahad D, Shehu A, Arun T, McDonnell G, Geraldes R, Craner M, Hillier C, Ganesalingam J, Fisniku L, Hobart J, Spilker C, Robertson N, Kalra S, Pluchino S, Harikrishnan S, Mattoscio M, Harrower T, Young C, Lee M, Chhetri S, Ahmed F, Rog D, Silber E, Gallagher P, Duddy M, Straukiene A, Nicholas R, Rice C, Nixon SJ, Beveridge J, Hawton A, Tebbs S, Braisher M, Giovannoni G, Ciccarelli O, Greenwood J, Thompson AJ, Hunter R, Pavitt S, Pearson O, Evangelou N, Sharrack B, Galea I, Chandran S, Ford HL, Frost C, Chataway J. Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK. BMJ Open. 2024 Sep 16;14(9):e086414. doi: 10.1136/bmjopen-2024-086414.

  PMID: 39284697 DERIVED

• Williams T, John N, Calvi A, Bianchi A, De Angelis F, Doshi A, Wright S, Shatila M, Yiannakas MC, Chowdhury F, Stutters J, Ricciardi A, Prados F, MacManus D, Braisher M, Blackstone J, Ciccarelli O, Gandini Wheeler-Kingshott CAM, Barkhof F, Chataway J; UCL MS-STAT2 investigators. Cardiovascular risk factors in secondary progressive multiple sclerosis: A cross-sectional analysis from the MS-STAT2 randomized controlled trial. Eur J Neurol. 2023 Sep;30(9):2769-2780. doi: 10.1111/ene.15924. Epub 2023 Jun 23.

  PMID: 37318885 DERIVED

• Williams T, Tur C, Eshaghi A, Doshi A, Chan D, Binks S, Wellington H, Heslegrave A, Zetterberg H, Chataway J. Serum neurofilament light and MRI predictors of cognitive decline in patients with secondary progressive multiple sclerosis: Analysis from the MS-STAT randomised controlled trial. Mult Scler. 2022 Oct;28(12):1913-1926. doi: 10.1177/13524585221114441. Epub 2022 Aug 9.

  PMID: 35946107 DERIVED

• Williams T, Alexander S, Blackstone J, De Angelis F, John N, Doshi A, Beveridge J, Braisher M, Gray E, Chataway J; MS-SMART and MS-STAT2 Investigators. Optimising recruitment in clinical trials for progressive multiple sclerosis: observational analysis from the MS-SMART and MS-STAT2 randomised controlled trials. Trials. 2022 Aug 9;23(1):644. doi: 10.1186/s13063-022-06588-z.

  PMID: 35945550 DERIVED

• Williams TE, Holdsworth KP, Nicholas JM, Eshaghi A, Katsanouli T, Wellington H, Heslegrave A, Zetterberg H, Frost C, Chataway J. Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial. Neurol Neuroimmunol Neuroinflamm. 2022 Jan 14;9(2):e1130. doi: 10.1212/NXI.0000000000001130. Print 2022 Mar.

  PMID: 35031587 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Multiple Sclerosis; 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

Study Officials

• Jeremy Chataway

  University College, London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 28, 2017
• First Posted: January 2, 2018
• Study Start: March 28, 2018
• Primary Completion: July 26, 2024
• Study Completion: August 25, 2024
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (31)