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| ID | Type | Description | Link |
|---|---|---|---|
| 2023-503190-38-00 | Other Identifier | Clinical Trials Information System (CTIS) |
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| Name | Class |
|---|---|
| University Hospital, Ghent | OTHER |
| Hasselt University | OTHER |
| AZ Sint-Jan AV | OTHER |
| Noorderhart Pelt |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment group | Active Comparator | The treatment group will receive Metformin Hydrochloride oral tablets 850mg tid or bid, during a maximum of 96 weeks. |
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| Control group | Placebo Comparator | The control group will receive a matching placebo, during a maximum of 96 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin Hydrochloride 850 mg Oral Tablet | Drug | Metformin Hydrochloride oral tablets 850 mg t.i.d. or b.i.d. |
|
| 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 |
| 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 |
| 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. |
Inclusion Criteria:
A diagnosis of non-active progressive Multiple Sclerosis (PPMS and SPMS), as evidenced by:
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:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Barbara Willekens, MD, PhD | University Hospital, Antwerp | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AZ Sint-Jan Brugge | Bruges | Belgium | ||||
| Antwerp University Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38680485 | Background | 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. |
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Protocol section 14.9 Access to the Study Data describes this in detail.
After peer-reviewed publication of study protocol and clinical trial results
See protocol section 14.9 Access to the Study Data
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| OTHER |
| National MS Center Melsbroek | OTHER |
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| Placebo | Drug | Placebo matching Metformin Hydrochloride oral tablets t.i.d. or b.i.d. |
|
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 |
| 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 |
| Edegem |
| Belgium |
| University Hospital Ghent | Ghent | Belgium |
| National MS Center Melsbroek | Melsbroek | Belgium |
| Noorderhart | Overpelt | Belgium |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D020528 | Multiple Sclerosis, Chronic Progressive |
| D012598 | Sclerosis |
| D010335 | Pathologic Processes |
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009410 | Nerve Degeneration |
| ID | Term |
|---|---|
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D056784 | Leukoencephalopathies |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| D013607 | Tablets |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
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