Using metformin to help prevent disability in progressive multiple sclerosis

MACSiMiSE-BRAIN: Metformin add-on Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination and Neurodegeneration: a Phase II Placebo-controlled Randomized Clinical Trial

This study is testing if adding metformin to the usual treatments can help people with progressive multiple sclerosis feel better and prevent disability.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: University Hospital, Antwerp (Academic / other)
• Drugs / interventions: alemtuzumab
• Locations: 5 sites (Brugge and 4 other locations)
• Trial ID: NCT05893225 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the effects of metformin as an add-on treatment for patients with progressive forms of Multiple Sclerosis (MS). The study aims to determine if metformin can enhance remyelination and reduce neurodegeneration, potentially preventing clinical disability. Participants will continue their existing disease-modifying treatments while receiving either metformin or a placebo. The trial will measure clinical outcomes and MRI results to assess the drug's effectiveness in this patient population.

Who should consider this trial

Good fit: Ideal candidates are individuals diagnosed with non-active progressive Multiple Sclerosis, specifically Primary Progressive or Secondary Progressive forms.

Not a fit: Patients with active forms of MS or those experiencing relapses may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly slow down the progression of disability in patients with progressive MS.

How similar studies have performed: While previous studies have shown promise for metformin in animal models, this clinical trial represents a novel approach in human patients with progressive MS.

Eligibility criteria

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

Where this trial is running

Brugge and 4 other locations

• AZ Sint-Jan Brugge — Brugge, Belgium (Recruiting)
• Antwerp University Hospital — Edegem, Belgium (Recruiting)
• University Hospital Ghent — Ghent, Belgium (Recruiting)
• National MS Center Melsbroek — Melsbroek, Belgium (Recruiting)
• Noorderhart — Overpelt, Belgium (Recruiting)

Study contacts

• Principal investigator: Barbara Willekens, MD, PhD — University Hospital, Antwerp
• Study coordinator: Clinical Trials Department of Neurology

Conditions Multiple Sclerosis; Primary Progressive Multiple Sclerosis; Secondary-progressive Multiple Sclerosis; Secondary Progressive Multiple Sclerosis; Sclerosis; Metformin; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS