Multiple Sclerosis-Simvastatin Trial 2

NCT ID: NCT03387670

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 964 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-28
• Study Completion Date: 2024-08-25

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)

Study Design

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

Study Groups

Simvastatin

Group Type: ACTIVE_COMPARATOR

Simvastatin

Intervention Type: 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

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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

Interventions

Simvastatin

• 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

Intervention Type: DRUG

Placebo

• 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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. 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;

2. EDSS 4.0 - 6.5 (inclusive);

3. Aged 25 to 65 years old;

4. Patients must be able and willing to comply with the terms of this protocol;

5. Written informed consent provided.

Exclusion Criteria

1. 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;

2. 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)

3. Significant organ co-morbidity e.g. cardiac failure, renal failure, malignancy;

4. Screening levels of alanine aminotransferase (ALT) / aspartate aminotransferase (AST) or creatine kinase (CK) ≥3 x upper limit of normal (ULN);

5. Current use of a statin; or any use within the last 6 months;

6. 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;

7. Primary progressive MS;

8. Diabetes mellitus type 1;

9. Uncontrolled hypothyroidism;

10. 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;

11. Use of immunosuppressants (e.g. azathioprine, methotrexate, ciclosporine) or disease modifying treatments (avonex, rebif, betaferon, glatiramer) within the previous 6 months;

12. Use of mitoxantrone, natalizumab, alemtuzumab, daclizumab or other monoclonal antibody treatment, if treated within the last 12 months;

13. Use of fingolimod, dimethyl fumarate, teriflunomide, cladribine within the last 12 months;

14. Use of other experimental disease modifying treatment within the last 6 months;

15. Commencement of fampridine ≤6 months from day of randomisation;

16. Concurrent participation in another clinical trial of an investigational medicinal product or medical device;

17. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Edinburgh

OTHER

Sponsor Role: collaborator

Queen Mary University of London

OTHER

Sponsor Role: collaborator

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role: collaborator

University of Leeds

OTHER

Sponsor Role: collaborator

The Leeds Teaching Hospitals NHS Trust

OTHER

Sponsor Role: collaborator

Imperial College Healthcare NHS Trust

OTHER

Sponsor Role: collaborator

University College, London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jeremy Chataway

Role: PRINCIPAL_INVESTIGATOR

University College, London

Locations

Belfast City Hospital

Belfast, , United Kingdom

St Luke s Hospital

Bradford, , United Kingdom

Royal Sussex County Hospital

Brighton, , United Kingdom

Southmead Hospital

Bristol, , United Kingdom

Addenbrooke's Hospital

Cambridge, , United Kingdom

Kent and Canterbury Hospital

Canterbury, , United Kingdom

University Hospital of Wales

Cardiff, , United Kingdom

University Hospital Coventry and Warwickshire

Coventry, , United Kingdom

The Anne Rowling Regenerative Neurology Clinic

Edinburgh, , United Kingdom

Royal Devon and Exeter Hospital

Exeter, , United Kingdom

The Queen Elizabeth University Hospital

Glasgow, , United Kingdom

Hull Royal Infirmary

Hull, , United Kingdom

Leeds General Infirmary

Leeds, , United Kingdom

The Walton Centre NHS Foundation Trust

Liverpool, , United Kingdom

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

London, , United Kingdom

Queen Elizabeth Hospital

London, , United Kingdom

Charing Cross Hospital

London, , United Kingdom

University College London Hospital

London, , United Kingdom

Salford Royal Hospital

Manchester, , United Kingdom

Royal Victoria Infirmary

Newcastle upon Tyne, , United Kingdom

Norfolk and Norwich University Hospital

Norwich, , United Kingdom

Queen's Medical Centre

Nottingham, , United Kingdom

John Radcliffe Hospital

Oxford, , United Kingdom

Derriford Hospital

Plymouth, , United Kingdom

Poole Hospital

Poole, , United Kingdom

Royal Preston Hospital

Preston, , United Kingdom

Royal Hallamshire Hospital

Sheffield, , United Kingdom

Southampton General Hospital

Southampton, , United Kingdom

University Hospital of North Staffordshire

Stoke-on-Trent, , United Kingdom

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

Swansea, , United Kingdom

Torbay Hospital

Torquay, , United Kingdom

Countries

United Kingdom

References

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 1:S0140-6736(25)01039-6. doi: 10.1016/S0140-6736(25)01039-6. Online ahead of print.

Reference Type: DERIVED

PMID: 41045938 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 39284697 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37318885 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35946107 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35945550 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35031587 (View on PubMed)

Other Identifiers

2017-003328-56

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

17/0158

Identifier Type: -

Identifier Source: org_study_id