Clinical trial NCT05893225: Metformin Add-on Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination And Neurodegeneration
Official title: MACSiMiSE-BRAIN: Metformin add-on Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination and Neurodegeneration: a Phase II Placebo-controlled Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Multiple Sclerosis
Primary Progressive Multiple Sclerosis
Secondary-progressive Multiple Sclerosis
Keywords: Multiple Sclerosis
Primary Progressive Multiple Sclerosis
Secondary Progressive Multiple Sclerosis
Sclerosis
Metformin
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Brain Remyelination
Neurodegeneration
Lead sponsor: University Hospital, Antwerp
Sponsor class: OTHER
Collaborators: name: University Hospital, Ghent
name: Hasselt University
name: AZ Sint-Jan AV
name: Noorderhart Pelt
name: National MS Center Melsbroek
First posted: 2023-06-07
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

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

Primary outcomes:
measure: Change in walking speed
timeFrame: From baseline to 96 weeks
Secondary outcomes:
measure: Change in cognitive function
timeFrame: From baseline to 96 weeks
measure: Change in hand function
timeFrame: From baseline to 96 weeks
measure: Change in EDSS
timeFrame: From baseline to 96 weeks
measure: Change in brain volume
timeFrame: From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
measure: Change in T2 lesion volume
timeFrame: From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
measure: Change in T1 lesion volume
timeFrame: From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
measure: Change in brain magnetic resonance imaging diffusion tensor imaging (MRI-DTI) metrics
timeFrame: From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Other outcomes:
measure: Change in quality of life measured by EQ-5D-5L
timeFrame: From baseline to 96 weeks
measure: Change in quality of life measured by MSIS-29
timeFrame: From baseline to 96 weeks
measure: Change in the Composite endpoint
timeFrame: From baseline to 96 weeks
measure: Change in 2 minute walk test
timeFrame: From baseline to 96 weeks
measure: Change in number of susceptibility weighted imaging (SWI) lesions
timeFrame: From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
measure: Change in caregiver strain index (CSI)
timeFrame: From baseline to 96 weeks
measure: Health resource questionnaire
timeFrame: From baseline to 96 weeks
Locations:
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Ghent
country: Belgium
facility: University Hospital Ghent
city: Melsbroek
country: Belgium
facility: National MS Center Melsbroek
city: Overpelt
country: Belgium
facility: Noorderhart
Study officials:
affiliation: University Hospital, Antwerp
name: Barbara Willekens, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.