Metformin Add-on Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination And Neurodegeneration

Prior treatment

• Use of an experimental therapy in the past 6 months
• 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)

Other illness

• Acute conditions where there is a risk of alteration of renal function, such as: dehydration, severe infection, shock occurring between screening and randomization.

Lab values

• 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
• 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

Other

• A medical or neurological problem other than MS that is a cause of progressive or fluctuating gait dysfunction
• Unable to complete T25FW
• Unable to undergo MRI
• Pregnant or breast-feeding or planning pregnancy
• Expected change in ongoing DMT or start of DMT if untreated
• Current use of metformin or known intolerance for metformin
• Known sensitivity to the active substance or to any of the excipients listed in section 6.1 of the Summary of Product Characteristics.
• All forms of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis), diabetic precoma.
• Chronic use of NSAID

• A diagnosis of non-active progressive Multiple Sclerosis (PPMS and SPMS), as evidenced by:
  • the absence of relapses and new T2 lesions on brain MRI in the past year or longer (No Evidence of Disease Activity-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.
• Age 18-70 years inclusive
• EDSS 2.0-6.5 inclusive
• Able to give informed consent (signed, written) and to adhere to study procedures
• Dutch/Flemish speaking (patient reported outcomes and questionnaires available in Dutch/Flemish)
• Stable use of Disease Modifying Treatment (DMT) or no treatment in the past year or longer
• Use of adequate contraceptive measures in women of childbearing potential (WOCBP)