Multiple Sclerosis-Simvastatin Trial 2

University College, London964 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: ALLMin age: 25 YearsMax age: 65 Years

Medical Language ↔ Plain English

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.

Locations (31)

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

Outcomes

Primary Outcomes

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.

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

Secondary Outcomes

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

MSWS-12v2 is a12 item patient report measure on the impact of MS on the individual's walking ability over the previous 2 weeks. Each item will be summed to generate a total score and transformed to a scale with a range of 0 to 100 with high scores indicating greater impact on walking.