Multiple Sclerosis-Simvastatin Trial 2
Multiple Sclerosis-Simvastatin Trial 2
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. There is no current disease modifying treatment (DMT) for SPMS.

 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 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.
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;

 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) ≥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, 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 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.