MACSiMiSE-BRAIN_v1.0

Treatment tested

• Metformin

Placebo or sham

• Placebo
• The placebo will be manufactured based on the Metformin Hydrochloride 850 mg (Metformin STADA® 850 mg) specifications to match the characteristics (appearance, size) of the IMP, without containing the active ingredient (see IMPD).
• The placebo will be manufactured based on the metformin hydrochloride 850 mg (metformin ALIUD® 850 mg) specifications to match the characteristics (appearance, size) of the imp, without containing the active ingredient (see impd).

Other measures (19)

Inclusion Criteria: 1. A diagnosis of non-active progressive Multiple Sclerosis (PPMS and SPMS), as evidenced by: 1. the absence of relapses and new T2 lesions on brain MRI in the past year or longer (No Evidence of Disease Activity-2) 2. progression of disability independent of relapses in the past 1-2 years or longer If progression is defined as one of the following, over the past 1-2 years or less, the patient can be included without additional review: * minimum increase in the EDSS of 1.0, or 0.5 from a baseline level of 2.0-5.0, and 5.5-6.0, respectively * ≥20% in the T25FW * ≥20% 9HPT * reduction of ≥4 points or a 10% worsening in the Symbol Digit Modality Test without concomitant depression or fatigue. If the investigator is in the opinion that the patient is clearly progressing, but not enough data are available to demonstrate this, a narrative needs to be provided, which will be judged by at least 2 members of the Trial Steering Committee, from a center that is not submitting the case for review. 2. Age 18-70 years inclusive 3. EDSS 2.0-6.5 inclusive 4. Able to give informed consent (signed, written) and to adhere to study procedures 5. Dutch/Flemish speaking (patient reported outcomes and questionnaires available in Dutch/Flemish) 6. Stable use of Disease Modifying Treatment (DMT) or no treatment in the past year or longer 7. Use of adequate contraceptive measures in women of childbearing potential (WOCBP) Exclusion Criteria: 1. A medical or neurological problem other than MS that is a cause of progressive or fluctuating gait dysfunction 2. Diagnosis of diabetes mellitus or fasting glucose level of 126mg/dl or more; random glucose level of 200mg/dl or more; HbA1C of 6.5% or more at screening 3. Unable to complete T25FW 4. Unable to undergo MRI 5. Current major disease or disorder other than MS (e.g., active malignancy, significant renal insufficiency eGFR (estimated Glomerular Filtration Rate) \<60 mL/min/1.73 m2, end-stage cardiopulmonary disease, alcoholism, liver insufficiency with AST (aspartate aminotransferase) >3 times Upper Limit of Normal (ULN), chronic active infection etc.) that may interfere with study procedures and/or intake of study drug 6. Pregnant or breast-feeding or planning pregnancy 7. Use of an experimental therapy in the past 6 months 8. Ongoing immune reconstitution therapy schedule (cladribine second course ended at least 12 months before inclusion, alemtuzumab second/last course at least 12 months before inclusion, Autologous Hematopoietic Stem Cell Transplantation at least 12 months before inclusion) 9. Expected change in ongoing DMT or start of DMT if untreated 10. Current use of metformin or known intolerance for metformin 11. Known sensitivity to the active substance or to any of the excipients listed in section 6.1 of the Summary of Product Characteristics. 12. All forms of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis), diabetic precoma. 13. Acute conditions where there is a risk of alteration of renal function, such as: dehydration, severe infection, shock occurring between screening and randomization. 14. Chronic use of NSAID

This clinical trial aims to demonstrate that metformin can prevent clinical disability in patients with progressive MS by stopping or slowing down neurodegeneration by enhancing endogenous remyelination. Patients will continue their DMT treatment: metformin or placebo will be used as add-on study treatment.