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

Primary Purpose

Multiple Sclerosis, Primary Progressive Multiple Sclerosis, Secondary-progressive Multiple Sclerosis

Status
Not yet recruiting
Phase
Phase 2
Locations
Belgium
Study Type
Interventional
Intervention
Metformin Hydrochloride 850 mg Oral Tablet
Placebo
Sponsored by
University Hospital, Antwerp
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Sclerosis focused on measuring 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

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • AZ Sint-Jan Brugge
  • Antwerp University Hospital
  • University Hospital Ghent
  • National MS Center Melsbroek
  • Noorderhart

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Treatment group

Control group

Arm Description

The treatment group will receive Metformin Hydrochloride oral tablets 850mg tid or bid, during a maximum of 96 weeks.

The control group will receive a matching placebo, during a maximum of 96 weeks.

Outcomes

Primary Outcome Measures

Change in walking speed
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
Change in cognitive function as measured by Symbol Digit Modalities Test (SDMT) between baseline and 96 weeks of treatment
Change in hand function
Change in hand function as measured by Nine-Hole Peg Test (9HPT) between baseline and 96 weeks of treatment
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.
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
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
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
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

Full Information

First Posted
February 28, 2022
Last Updated
May 30, 2023
Sponsor
University Hospital, Antwerp
Collaborators
University Hospital, Ghent, Hasselt University, AZ Sint-Jan AV, Noorderhart Pelt, National MS Center Melsbroek
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1. Study Identification

Unique Protocol Identification Number
NCT05893225
Brief Title
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

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
July 15, 2023 (Anticipated)
Primary Completion Date
August 15, 2026 (Anticipated)
Study Completion Date
December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Antwerp
Collaborators
University Hospital, Ghent, Hasselt University, AZ Sint-Jan AV, Noorderhart Pelt, National MS Center Melsbroek

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment group
Arm Type
Active Comparator
Arm Description
The treatment group will receive Metformin Hydrochloride oral tablets 850mg tid or bid, during a maximum of 96 weeks.
Arm Title
Control group
Arm Type
Placebo Comparator
Arm Description
The control group will receive a matching placebo, during a maximum of 96 weeks.
Intervention Type
Drug
Intervention Name(s)
Metformin Hydrochloride 850 mg Oral Tablet
Intervention Description
Metformin Hydrochloride oral tablets 850 mg t.i.d. or b.i.d.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo matching Metformin Hydrochloride oral tablets t.i.d. or b.i.d.
Primary Outcome Measure Information:
Title
Change in walking speed
Description
Change in walking speed as measured by the Timed 25 Foot Walk (T25FW) between baseline and 96 weeks of treatment
Time Frame
From baseline to 96 weeks
Secondary Outcome Measure Information:
Title
Change in cognitive function
Description
Change in cognitive function as measured by Symbol Digit Modalities Test (SDMT) between baseline and 96 weeks of treatment
Time Frame
From baseline to 96 weeks
Title
Change in hand function
Description
Change in hand function as measured by Nine-Hole Peg Test (9HPT) between baseline and 96 weeks of treatment
Time Frame
From baseline to 96 weeks
Title
Change in EDSS
Description
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.
Time Frame
From baseline to 96 weeks
Title
Change in brain volume
Description
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
Time Frame
From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Title
Change in T2 lesion volume
Description
Change in T2 lesion volume from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Time Frame
From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Title
Change in T1 lesion volume
Description
Change in T1 lesion volume from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Time Frame
From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Title
Change in brain magnetic resonance imaging diffusion tensor imaging (MRI-DTI) metrics
Description
Change in brain MRI-DTI metrics from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Time Frame
From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Other Pre-specified Outcome Measures:
Title
Change in quality of life measured by EQ-5D-5L
Description
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.
Time Frame
From baseline to 96 weeks
Title
Change in quality of life measured by MSIS-29
Description
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).
Time Frame
From baseline to 96 weeks
Title
Change in the Composite endpoint
Description
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.
Time Frame
From baseline to 96 weeks
Title
Change in 2 minute walk test
Description
Change in 2 minute walk test between baseline and 96 weeks of treatment
Time Frame
From baseline to 96 weeks
Title
Change in number of susceptibility weighted imaging (SWI) lesions
Description
Change in number of SWI lesions from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Time Frame
From baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
Title
Change in caregiver strain index (CSI)
Description
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.
Time Frame
From baseline to 96 weeks
Title
Health resource questionnaire
Description
This questionnaire is adapted from Kobelt et al. and will be used to generate data for health economic analysis.
Time Frame
From baseline to 96 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Clinical Trials Department of Neurology
Phone
+3238213000
Email
studies.neurologie@uza.be
First Name & Middle Initial & Last Name or Official Title & Degree
Lauren Meers
Phone
+3238212162
Email
lauren.meers@uza.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barbara Willekens, MD, PhD
Organizational Affiliation
University Hospital, Antwerp
Official's Role
Principal Investigator
Facility Information:
Facility Name
AZ Sint-Jan Brugge
City
Brugge
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melissa Cambron, MD, PhD
Facility Name
Antwerp University Hospital
City
Edegem
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Barbara Willekens, MD, PhD
First Name & Middle Initial & Last Name & Degree
Tatjana Reynders, MD, PhD
First Name & Middle Initial & Last Name & Degree
Judith Derdelinckx, MD, PhD
First Name & Middle Initial & Last Name & Degree
Anna-Victoria De Keersmaecker, MD
First Name & Middle Initial & Last Name & Degree
Jeroen Kerstens, MD
Facility Name
University Hospital Ghent
City
Ghent
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Guy Laureys, MD, PhD
Facility Name
National MS Center Melsbroek
City
Melsbroek
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Miguel D'Haeseleer, MD, PhD
First Name & Middle Initial & Last Name & Degree
Marie D'Hooghe, MD, PhD
Facility Name
Noorderhart
City
Overpelt
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bart van Wijmeersch, MD, PhD
First Name & Middle Initial & Last Name & Degree
Veronica Popescu, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

Learn more about this trial

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

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