The purpose of the clinical trial is to test how Simvastatin (80mg/day) may decrease attacks and progression of disease in patients with multiple sclerosis under disease modifying therapy (DMTs)

Multiple sclerosis (MS), the most prevalent neurological disability, is an autoimmune-mediated disorder that affects the central nervous system (CNS) and often leads to severe physical or cognitive incapacitation as well as neurological problems in young adults . Multifocal zones of inflammation due to focal T-lymphocytic and macrophage infiltrations, and oligodendrocyte death are the primary causes of myelin sheath destruction (2) that result in the formation of CNS plaques composed of inflammatory cells and their products, demyelinated and transected axons, and astrogliosis in both white and gray matter. These lesions can cross-talk with the correct transmission of nerve impulses and lead to neuronal dysfunction such as autonomic and sensorimotor defects, visual disturbances, ataxia, fatigue, difficulties in thinking, and emotional problems .

Subtypes of MS are considered important not only for prognosis but also for treatment decisions and include:

• Relapsing remitting MS (RRMS)
• Primary progressive MS (PPMS)
• Secondary progressive MS (SPMS)
• Progressive relapsing MS (PRMS). RRMS is the most common subtype (approximately 87%) which characterized by unpredictable acute attacks followed by periods of remission . During RRMS, inflammatory attacks on myelin and nerve fibers occur. Activated immune cells cause lesions in the CNS which generate symptoms of visual impairments, tingling and numbness, episodic bouts of fatigue, intestinal and urinary system disorders, spasticity, and learning and memory impairment. Approximately 10-15% of MS patients are diagnosed with PPMS which largely affect the nerves of the spinal cord. PPMS patients tend to have fewer brain lesions. Induced symptoms include problems with walking, weakness, stiffness, and trouble with balance.

Nearly 65% of patients with RRMS will subsequently develop SPMS which is considered the second phase of this disease. Many individuals experience increased weakness, intestinal and urinary system disorders, fatigue, stiffness, mental disorders, and psychological impairment. Finally, PRMS is the least common type of MS that occurs in approximately 5% of patients and is associated with symptoms such as eye pain and double vision, along with sexual, intestinal and urinary system dysfunction, dizziness, and depression. Generally MS is detected between the ages of 20 and 40 years, but less than 1% can occur in childhood and approximately 2-10% after 50 years of age .

This pathologic condition affects women more than men (sex ratio 2.5:1) and the prevalence varies by geographic area, ranging from 120 per 100,000 individuals . The etiology of MS remains unclear, however it can be considered a multifactorial disease and include a genetic predisposition combined with environmental influences .

The initial treatment strategy for MS is largely based on disease-modifying drugs such as interferon-β and glatiramer acetate . The effects of these treatments are partially for symptomatic alleviation and do not stop the ongoing neurodegeneration.

Simvastatin Simvastatin belongs to a group of medicines called statins. Its action is inhibiting 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase. HMG-CoA reductase, the rate-limiting enzyme of the HMG-CoA reductase pathway, the metabolic pathway responsible for the endogenous production of cholesterol. Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration Furthermore, simvastatin has pleiotropic effects associated with onset and progression of autoimmune and inflammatory diseases, cancer, neurodegenerative disorders, strokes, bacterial infections, and human immunodeficiency virus. Understanding these issues will improve the prognosis of patients who are administered statins and potentially expand our ability to treat a wide variety of diseases .

Simvastatin was found to decrease the incidence of hemodynamically significant rejection episodes in cardiac transplant patients. This effect was not significantly correlated to reduction in cholesterol levels in these patients. Subsequent studies have revealed many immunological pathways sensitive to modulation by statins:

1. Simvastatin inhibit interferon-γ-inducible class II transactivator (CIITA) to decrease the induction/up regulation of MHC class II molecules on professional & non- professional antigen presenting cells.
2. Statins bind to β2 integrin and thereby block T-cell co-stimulation by means of lymphocyte function-associated antigen-1 (LFA-1).
3. In monocytes and macrophages, statins decrease chemotaxis, lipopolysaccharide (LPS) mediated release of tumour necrosis factor-α (TNF-α), activation of NO synthase8 and LPS-stimulated secretion of matrix metalloproteinase-9 (12).

Common simvastatin side effects may include:

• Headache;
• Constipation, nausea, stomach pain; or
• Cold symptoms such as stuffy nose, sneezing, sore throat.

Inclusion Criteria:

• 1. Patients must have a confirmed diagnosis of multiple sclerosis according to revised Mc Donald criteria 2017 and have relapsing remitting multiple scelerosis type.

  2. EDSS up to 4. 3. Males and Females aged 18 to 65 4. pregnancy test within 7 days prior to being registered/randomized. Participants are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.

  5. Willing and able to comply with the trial protocol (e.g. can tolerate MRI and fullfills the requirements for MRI, e.g. not fitted with pacemakers or permanent hearing aids), with ability to understand and complete questionnaires 6. Willing and able to provide written informed consent

Exclusion Criteria:

• 1. Unable to give informed consent. 2. Patient with other types of multiple scelerosis (Secondary-Progressive MS (SPMS), Primary progressive MS, Progressive-Relapsing MS (PRMS) ) 3. Any medications that unfavourably interact with statins e.g.: fibrates, nicotinic acid, cyclosporin, azole anti-fungal preparations, macrolideantibiotics, protease inhibitors, nefazodone, verapamil, amiodarone, large amounts of grapefruit juice or alcohol abuse within 6 months.

  4. Active Hepatic disease or known severe renal failure (creatinine clearance <30ml/min) 5. Screening levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatine kinase (CK) are three times the upper limit of normal patients.

  6. Patient unable to tolerate or unsuitable to have baseline MRI scan (e.g. metal implants, heart pacemaker) or MRI scan not of adequate quality for analysis (e.g. too much movement artefact).

  7. Females who are pregnant, planning pregnancy or breastfeeding. 8. Allergy to simvastatin