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

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 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Sclerosis; Primary Progressive Multiple Sclerosis; Secondary-progressive Multiple Sclerosis
• Intervention / Treatment: Drug: Metformin Hydrochloride 850 mg Oral Tablet; Drug: Placebo

Detailed Description

Multiple Sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease leading to focal and diffuse damage of myelin sheath and axons in the central nervous system (CNS). Pathophysiologically, the adaptive and innate immune system are involved in the inflammatory process, while mitochondrial dysfunction, oxidative stress and failure of remyelination are important mechanisms leading to chronic neurodegeneration. Despite currently available disease modifying treatments (DMTs) that target the immune system, patients continue to accumulate disability. Unfortunately, no neuroprotective or remyelinating agents are available to treat progressive MS. Hence, drugs to tackle disease progression in MS represent a major unmet need. In this respect, metformin is a very interesting drug to investigate in MS patients as a neuroprotective and remyelinating therapy. Several preclinical studies in animal models of MS have shown that metformin has both anti-inflammatory, neuroprotective and remyelinating properties. A clinical study with metformin in a limited sample of MS patients did not demonstrate significant adverse events. The aim of this clinical trial is to provide evidence for the neuroprotective and remyelinating effects of metformin (I) in MS patients (P) via measurement of clinical and MRI outcome measures (O), via a multicentre randomized placebo-controlled (C) clinical trial.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment group; The treatment group will receive Metformin Hydrochloride oral tablets 850mg tid or bid, during a maximum of 96 weeks.	Drug: Metformin Hydrochloride 850 mg Oral Tablet; Metformin Hydrochloride oral tablets 850 mg t.i.d. or b.i.d.
Placebo Comparator: Control group; The control group will receive a matching placebo, during a maximum of 96 weeks.	Drug: Placebo; Placebo matching Metformin Hydrochloride oral tablets t.i.d. or b.i.d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in walking speed	Change in walking speed as measured by the Timed 25 Foot Walk (T25FW) between baseline and 96 weeks of treatment	From baseline to 96 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cognitive function	Change in cognitive function as measured by Symbol Digit Modalities Test (SDMT) between baseline and 96 weeks of treatment	From baseline to 96 weeks
Change in hand function	Change in hand function as measured by Nine-Hole Peg Test (9HPT) between baseline and 96 weeks of treatment	From baseline to 96 weeks
Change in EDSS	Change in Expanded Disability Status Scale. The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10.0 (death) and is determined based on functional system scores (FSS) that are assigned after a standardized clinical neurological examination.	From baseline to 96 weeks
Change in brain volume	Change in brain volume (whole brain volume and gray matter volume) from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Change in T2 lesion volume	Change in T2 lesion volume from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Change in T1 lesion volume	Change in T1 lesion volume from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Change in brain magnetic resonance imaging diffusion tensor imaging (MRI-DTI) metrics	Change in brain MRI-DTI metrics from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in quality of life measured by EQ-5D-5L	Change in quality of life as measured by EuroQol 5-dimension, 5-level (EQ-5D-5L) questionnaire between baseline and 96 weeks of treatment. The EQ-5D-5L is a self-assessed, health related, quality of life questionnaire. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This tool also has an overall health scale where the rater selects a number between 1-100 to describe the condition of their health, 100 being the best imaginable.	From baseline to 96 weeks
Change in quality of life measured by MSIS-29	Change in quality of life as measured by Multiple Sclerosis Impact Scale-29 between baseline and 96 weeks of treatment. The MSIS, is a 29-item patient-reported measure of the physical and psychological impacts of MS. Patients are asked to rate how much their functioning and well-being has been impacted over the past 14 days on a 4-point scale, from "Not at all" (1) to "Extremely" (4).	From baseline to 96 weeks
Change in the Composite endpoint	Change in the Composite endpoint as measured by Overall Disability Response Score (ODRS) between baseline and 96 weeks of treatment. The ODRS is based on changes in EDSS, T25FW and 9HPT. At each time point, in individual patients, the scores of the four components are summed, which leads to a total score ranging from +4 to -4. A positive ODRS score means that there is a disability improvement compared to baseline and a negative ODRS score means a disability worsening from baseline.	From baseline to 96 weeks
Change in 2 minute walk test	Change in 2 minute walk test between baseline and 96 weeks of treatment	From baseline to 96 weeks
Change in number of susceptibility weighted imaging (SWI) lesions	Change in number of SWI lesions from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Change in caregiver strain index (CSI)	Change in caregiver strain index from baseline to 96 weeks. It is a 13-question tool that measures strain related to care provision. There is at least one item for each of the following major domains: Employment, Financial, Physical, Social and Time.	From baseline to 96 weeks
Health resource questionnaire	This questionnaire is adapted from Kobelt et al. and will be used to generate data for health economic analysis.	From baseline to 96 weeks

Collaborators and Investigators

• Sponsor: University Hospital, Antwerp
• Collaborators: Hasselt University; University Hospital, Ghent; AZ Sint-Jan AV; National MS Center Melsbroek; Noorderhart Pelt
• Investigators: Principal Investigator: Barbara Willekens, MD, PhD, University Hospital, Antwerp

Publications and helpful links

General Publications

• De Keersmaecker AV, Van Doninck E, Popescu V, Willem L, Cambron M, Laureys G, D' Haeseleer M, Bjerke M, Roelant E, Lemmerling M, D'hooghe MB, Derdelinckx J, Reynders T, Willekens B. A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): study protocol for a multi-center randomized placebo controlled clinical trial. Front Immunol. 2024 Feb 21;15:1362629. doi: 10.3389/fimmu.2024.1362629. eCollection 2024.

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2023
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: February 28, 2022
• First Submitted That Met QC Criteria: May 30, 2023
• First Posted (Actual): June 7, 2023

Study Record Updates

• Last Update Posted (Actual): June 24, 2025
• Last Update Submitted That Met QC Criteria: June 18, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Pathologic Processes; Metformin; Neurodegeneration; Secondary Progressive Multiple Sclerosis; Primary Progressive Multiple Sclerosis; Sclerosis; Autoimmune Diseases of the Nervous System; Demyelinating Autoimmune Diseases, CNS; Brain Remyelination
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Chronic Disease; Disease Attributes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Chronic Progressive; Nerve Degeneration; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: MACSiMiSE-BRAIN; 2023-503190-38-00 (Other Identifier: Clinical Trials Information System (CTIS))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Protocol section 14.9 Access to the Study Data describes this in detail.
• IPD Sharing Time Frame: After peer-reviewed publication of study protocol and clinical trial results
• IPD Sharing Access Criteria: See protocol section 14.9 Access to the Study Data
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No