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 ID: 35831
Short Title: MS-STAT2
Organisation: University Hospital Southampton NHS Foundation Trust
Location: Southampton General Hospital
Condition: Multiple sclerosis
Main Specialty: Neurological disorders
Expected End Date: 30/11/2019
Postcode: SO16 6YD
Contact Name: R&D department
Contact Email: R&Doffice@uhs.nhs.uk
Active: Yes

Inclusion Criteria

1. Patients with a confirmed diagnosis of multiple sclerosis (MS) that have entered the secondary progressive stage at randomisation. 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 Expanded Disability Status Scale (EDSS), or clinical documentation of increasing disability 2. EDSS 4.0 - 6.5 (inclusive) 3. Aged 25 to 65 years old 4. Male or Female 5. Patients must be able and willing to comply with the terms of this protocol. 6. Written informed consent provided

Exclusion Criteria

1. Relapse within 3 months of baseline visit 2. Patients that have been treated with steroids (intravenous and/or oral) due to MS relapse/progression within 3 months of 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 creatinine kinase (CK) > = 3x 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, clarithromycin, 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, 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, fumarate, teriflunomide within the last 12 months. 14. Use of other experimental disease modifying treatment within the last 6 months 15. Commencement of Fampridine < = 6 month from day of randomisation 16. Concurrent participation in another clinical trial of an investigational medicinal product or medical device

Study summary:

Multiple Sclerosis (MS) is a progressive neurological disorder of the brain and spinal cord. It affects approximately 120,000 people in the UK 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. There is no current disease modifying treatment (DMT) for SPMS. In an earlier study (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 year period.

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