Clinical trial NCT03387670: Multiple Sclerosis-Simvastatin Trial 2
Official title: A Phase 3 Randomised, Double Blind, Clinical Trial Investigating the Effectiveness of Repurposed Simvastatin Compared to Placebo, in Secondary Progressive Multiple Sclerosis, in Slowing the Progression of Disability
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Secondary Progressive Multiple Sclerosis (SPMS)
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: University of Edinburgh
name: Queen Mary University of London
name: London School of Hygiene and Tropical Medicine
name: University of Leeds
name: The Leeds Teaching Hospitals NHS Trust
name: Imperial College Healthcare NHS Trust
First posted: 2018-01-02
Enrollment: 964
Sex: ALL
Minimum age (years): 25
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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 \&lt;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.

Primary outcomes:
measure: Time to confirmed disability progression between simvastatin and placebo arm based on change in EDSS scores compared to baseline.
timeFrame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36, 42, 48, 54
Secondary outcomes:
measure: Response rate on the patient reported outcome form Multiple Sclerosis Walking Scale-12 version 2 (MSWS-12v2)
timeFrame: Annually - baseline, month 12, 24 and 36
measure: Response rate on the patient reported outcome form Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2)
timeFrame: Annually - baseline, month 12, 24 and 36
measure: Cost effectiveness of intervention
timeFrame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36
measure: Evaluating change in degree of disability based on the modified Rankin scale (mRS)
timeFrame: Annually - baseline, month 12, 24 and 36
measure: Change in visual function based on the Sloan Low Contrast Visual Acuity (SLCVA)
timeFrame: Annually - baseline, month 12, 24 and 36
measure: Difference in patient reported quality of life based on the EuroQoL Health Related Quality of Life - 5 Dimensions - 5 Levels (EQ-5D 5L) scores
timeFrame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36
measure: Change in a modified Multiple Sclerosis Functional Composite scores
timeFrame: Annually - baseline, month 12, 24 and 36
measure: Change in cognitive performance as measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)
timeFrame: Baseline and month 36
measure: Change in cognitive impairment based on Symbol Digit Modalities Test (SDMT) scores
timeFrame: Annually - baseline, month 12, 24 and 36
measure: Change in fatigue as measured by the Chalder Fatigue Scale
timeFrame: Annually - baseline, month 12, 24 and 36
measure: Change in rates of service utilisation as measured by the Client Service Receipt Inventory (CSRI) questionnaire
timeFrame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36
measure: Change in time taken to complete 25-Foot Timed Walk (T25FW)
timeFrame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36, 42, 48, 54
measure: Difference in the number and severity of multiple sclerosis related relapse events between treatment groups
timeFrame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36, 42, 48, 54
measure: Evaluating the time to disability progression based on a secondary composite progression outcome measure
timeFrame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36, 42, 48, 54
measure: Change in time taken to complete 9 hole peg test (9HPT)
timeFrame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36, 42, 48, 54
Other outcomes:
Locations:
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Bradford
country: United Kingdom
facility: St Luke s Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Coventry
country: United Kingdom
facility: University Hospital Coventry and Warwickshire
city: Edinburgh
country: United Kingdom
facility: The Anne Rowling Regenerative Neurology Clinic
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Glasgow
country: United Kingdom
facility: The Queen Elizabeth University Hospital
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
city: Liverpool
country: United Kingdom
facility: The Walton Centre NHS Foundation Trust
city: London
country: United Kingdom
facility: Queen's Hospital, Barking, Havering and Redbridge University Hospitals
city: London
country: United Kingdom
facility: Queen Elizabeth Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: Manchester
country: United Kingdom
facility: Salford Royal Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Poole
country: United Kingdom
facility: Poole Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: University Hospital of North Staffordshire
city: Swansea
country: United Kingdom
facility: Morriston & Neath Port Talbot Hospitals (Abertawe Bro Morgannwg University Local Health Board)
city: Torquay
country: United Kingdom
facility: Torbay Hospital
Study officials:
affiliation: University College, London
name: Jeremy Chataway
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.