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

Phase 2

Recruiting

• Conditions: Primary Progressive Multiple Sclerosis; Secondary-progressive Multiple Sclerosis; Multiple Sclerosis
• Interventions: Drug: Metformin Hydrochloride 850 mg Oral Tablet; Drug: Placebo

• Registration Number: NCT05893225
• Lead Sponsor: University Hospital, Antwerp

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.

Study Timeline

• Study First Submitted: 2022-02-28
• Status Verified: 2023-05
• Study First Submitted QC: 2023-05-30
• Study First Posted: 2023-06-07
• Study Start: 2023-11-23
• Last Update Submitted: 2024-05-08
• Last Update Posted: 2024-05-10
• Primary Completion: 2026-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment group	Metformin Hydrochloride 850 mg Oral Tablet	The treatment group will receive Metformin Hydrochloride oral tablets 850mg tid or bid, during a maximum of 96 weeks.
Control group	Placebo	The control group will receive a matching placebo, during a maximum of 96 weeks.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Change in T2 lesion volume	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	Change in T2 lesion volume from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Change in hand function	From baseline to 96 weeks	Change in hand function as measured by Nine-Hole Peg Test (9HPT) between baseline and 96 weeks of treatment
Change in brain volume	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	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
Change in EDSS	From baseline to 96 weeks	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.
Change in cognitive function	From baseline to 96 weeks	Change in cognitive function as measured by Symbol Digit Modalities Test (SDMT) between baseline and 96 weeks of treatment
Change in brain magnetic resonance imaging diffusion tensor imaging (MRI-DTI) metrics	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	Change in brain MRI-DTI metrics from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Change in T1 lesion volume	From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks	Change in T1 lesion volume from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks

Trial Locations

Locations (5)

Antwerp University Hospital; 🇧🇪 Edegem, Belgium

Noorderhart; 🇧🇪 Overpelt, Belgium

University Hospital Ghent; 🇧🇪 Ghent, Belgium

AZ Sint-Jan Brugge; 🇧🇪 Brugge, Belgium

National MS Center Melsbroek; 🇧🇪 Melsbroek, Belgium