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

Sponsor

University Hospital, Antwerp (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05893225

Collaborator

University Hospital, Ghent (Other), Hasselt University (Other), AZ Sint-Jan AV (Other), Noorderhart Pelt (Other), National MS Center Melsbroek (Other)

120

Enrollment

Locations

Arms

41.6

Anticipated Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis Primary Progressive Multiple Sclerosis Secondary-progressive Multiple Sclerosis	Drug: Metformin Hydrochloride 850 mg Oral Tablet Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Jul 15, 2023

Anticipated Primary Completion Date :

Aug 15, 2026

Anticipated Study Completion Date :

Dec 31, 2026

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

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

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 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 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 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 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 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
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

Other Outcome Measures

Change in quality of life measured by EQ-5D-5L [From baseline to 96 weeks]
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.
Change in quality of life measured by MSIS-29 [From baseline to 96 weeks]
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).
Change in the Composite endpoint [From baseline to 96 weeks]
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.
Change in 2 minute walk test [From baseline to 96 weeks]
Change in 2 minute walk test between baseline and 96 weeks of treatment
Change in number of susceptibility weighted imaging (SWI) lesions [From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks]
Change in number of SWI lesions from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Change in caregiver strain index (CSI) [From baseline to 96 weeks]
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.
Health resource questionnaire [From baseline to 96 weeks]
This questionnaire is adapted from Kobelt et al. and will be used to generate data for health economic analysis.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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)

Exclusion Criteria:

A medical or neurological problem other than MS that is a cause of progressive or fluctuating gait dysfunction
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
Unable to complete T25FW
Unable to undergo MRI
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
Pregnant or breast-feeding or planning pregnancy
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)
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.
Acute conditions where there is a risk of alteration of renal function, such as: dehydration, severe infection, shock occurring between screening and randomization.
Chronic use of NSAID

Contacts and Locations

Locations

	Site	City	Country
1	AZ Sint-Jan Brugge	Brugge	Belgium
2	Antwerp University Hospital	Edegem	Belgium
3	University Hospital Ghent	Ghent	Belgium
4	National MS Center Melsbroek	Melsbroek	Belgium
5	Noorderhart	Overpelt	Belgium