Metformin for Progressive Multiple Sclerosis

Overseen By Kevin R Patel, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of California, Los Angeles

Must not be taking: Glucocorticoids, Metformin, others

Disqualifiers: Renal dysfunction, Hepatic dysfunction, others

Compensation: Varies

Number of Visits: 4

Duration: 12 months

44 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing metformin, a diabetes medication, to see if it can help adults aged 30-65 with progressive multiple sclerosis. The goal is to find out if metformin can reduce inflammation and protect nerve cells, potentially slowing down the disease.

Do I have to stop taking my current medications for the trial?

The trial requires that you continue your current MS disease-modifying treatment throughout the study. However, if you are taking medications that interact with metformin, you may need to stop those. The protocol does not specify other medication changes.

What evidence supports the effectiveness of the drug metformin for treating progressive multiple sclerosis?

Research in mice shows that metformin can reduce inflammation and improve outcomes in a model of multiple sclerosis when given before symptoms start. Additionally, metformin has been shown to help reduce disease severity when used with another drug in a similar condition. ^{1 2 3 4 5}

How does the drug Metformin differ from other treatments for progressive multiple sclerosis?

Metformin is unique in the treatment of progressive multiple sclerosis because it is traditionally used for managing type 2 diabetes, and its use in MS is being explored for its potential effects on cellular metabolism and inflammation, which are different from the typical immunomodulatory drugs like interferons and glatiramer acetate. ^{2 6 7 8 9}

Research Team

Kevin R Patel, MD

Principal Investigator

University of California, Los Angeles

Eligibility Criteria

This trial is for people aged 30-65 with Progressive Multiple Sclerosis who have been stable on their current MS treatment for at least three months. They must not have had a clinical relapse or new lesions in the past year and should not be using metformin for other conditions, nor have kidney or liver issues, B12 deficiency, heart failure, alcohol abuse, metabolic acidosis, or plans to become pregnant.

Inclusion Criteria

I am between 30 and 65 years old.

I have signed the informed consent form.

My condition is diagnosed as progressive multiple sclerosis according to the 2017 criteria.

Exclusion Criteria

B12 deficiency

Alcohol abuse

I plan to change my current treatment for my condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Titration

Participants are titrated from 500 mg to 2,000 mg of metformin over a 30-day period

4 weeks

1 visit (in-person)

Treatment

Participants receive metformin or placebo for the duration of the trial

12 months

3 visits (in-person) at baseline, 6 months, and 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Metformin
• Placebo

Trial Overview The study is testing the safety of metformin (up to four 500 mg tablets daily) compared to a placebo in treating progressive multiple sclerosis. Participants will continue their usual MS treatments during the trial and either add metformin or a look-alike pill without active medication.

Participant Groups

Group I: Metformin Treatment Experimental Treatment 1 Intervention

Metformin 500 mg tablets up to 2,000 mg (4 tablets) a day divided into two doses. Patients will start on 500 mg Qday and a titration to maximum dose will be attempted during the first 30 day period of the study.

Group II: Placebo Treatment Placebo Group 1 Intervention

Placebo tablets identical to metformin 500 mg tablets divided into two doses. Patients will be started on 1 tablet a day and a titration to maximum dose (4 tablets) will be attempted during the first 30 day period of the study.

Metformin is already approved in United States, Canada, Japan, China, Switzerland, European Union for the following indications:

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Approved in European Union as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Findings from Research

In a mouse model of multiple sclerosis, metformin treatment given before the onset of symptoms significantly improved functional outcomes and reduced inflammation and dysmyelination.

However, administering metformin after symptoms appeared did not yield the same beneficial effects, indicating that timing of treatment is crucial for its efficacy in managing MS-related symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin treatment reduces inflammation, dysmyelination and disease severity in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. Gilbert, EAB., Livingston, J., Flores, EG., et al.[2023]

In a study involving 248 patients with relapsing-remitting multiple sclerosis, glatiramer acetate therapy did not show any significant effect on cognitive function over 24 months, despite improvements in neuropsychologic test scores for both treatment and placebo groups.

The study suggests that while glatiramer therapy may not impact cognitive decline, it also did not lead to measurable cognitive deterioration, highlighting the need for further research on emerging MS treatments and their effects on cognitive impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Weinstein, A., Schwid, SR., Schiffer, RB., et al.[2022]

In a 3-year trial involving 943 patients with primary progressive multiple sclerosis, glatiramer acetate (GA) did not show a significant effect on slowing disability accumulation compared to placebo, as indicated by a hazard ratio of 0.87 (p = 0.1753).

However, post hoc analysis revealed that GA may have beneficial effects in male patients, showing a significant delay in clinical progression compared to placebo, with a hazard ratio of 0.71 (p = 0.0193).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Wolinsky, JS., Narayana, PA., O'Connor, P., et al.[2022]

In a study involving 80 patients with relapsing-remitting multiple sclerosis, adding metformin to interferon beta 1a treatment showed a significant reduction in malondialdehyde (MDA), a marker of oxidative stress, suggesting a potential benefit in managing oxidative stress in MS patients.

However, there were no statistically significant improvements in immunological markers, MRI results, or clinical outcomes (measured by the Expanded Disability Status Scale) between the metformin and control groups after 6 months, indicating that while metformin may affect oxidative stress, it does not enhance overall treatment efficacy in RRMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of metformin use on the outcomes of relapse-remitting multiple sclerosis patients receiving interferon beta 1a: an exploratory prospective phase II open-label randomized controlled trial. Abdelgaied, MY., Rashad, MH., El-Tayebi, HM., et al.[2023]

The combination of metformin and lovastatin showed an additive therapeutic effect in reducing symptoms of experimental autoimmune encephalomyelitis (EAE), a model for Multiple Sclerosis, indicating that using these two FDA-approved drugs together may be more effective than using them individually.

This combination therapy not only reduced demyelination and axonal loss in the spinal cords of treated animals but also shifted the immune response from a harmful Th1 to a more protective Th2 profile, suggesting a potential strategy to limit the progression of Multiple Sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combinatorial Effect of Metformin and Lovastatin Impedes T-cell Autoimmunity and Neurodegeneration in Experimental Autoimmune Encephalomyelitis. Paintlia, AS., Mohan, S., Singh, I.[2021]

Glatiramer acetate (GA) has been an approved treatment for relapsing-remitting multiple sclerosis (MS) since 1996 and is one of the first-line therapies for this condition.

Recent studies suggest that GA works as an immunomodulatory agent by influencing immune responses, which is based on its development from the animal model of MS known as experimental autoimmune encephalomyelitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glatiramer acetate treatment of multiple sclerosis: an immunological perspective. Racke, MK., Lovett-Racke, AE.[2015]

Long-term treatment (4-8 years) with immunomodulating drugs like IFN beta-1b, IFN beta-1a, and glatiramer acetate showed a significant reduction in annual relapse rates for patients with relapsing-remitting multiple sclerosis (RR MS), with rates dropping to between 0.20 and 0.57.

While these treatments improved relapse rates and increased the number of progression-free patients, they did not significantly slow disease progression in secondary progressive multiple sclerosis (SP MS) according to some trials, indicating a need for further research on effective long-term management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Selected issues of immunomodulating treatment in multiple sclerosis]. Cendrowski, W.[2015]

Glatiramer acetate (GA) has been shown to significantly reduce relapse rates and neurological disability in patients with relapsing-remitting multiple sclerosis (MS), with effects maintained over a 10-year period based on the longest prospective study in MS therapeutics.

GA not only has a strong safety profile but also exhibits neuroprotective properties, making it a first-line treatment option for relapsing-remitting MS and a promising candidate for combination therapies in MS and other neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glatiramer acetate therapy for multiple sclerosis: a review. Perumal, J., Filippi, M., Ford, C., et al.[2019]

Immunotherapeutic treatments, particularly interferon-beta and glatiramer acetate, are effective for relapsing forms of multiple sclerosis (RRMS), especially when initiated early, as supported by Class I data from large clinical trials involving various patient populations.

Higher doses or more frequent administration of interferon-beta may lead to better clinical outcomes and reduced progression of brain lesions, but this comes with increased costs and potential side effects, including the development of antibodies that could reduce treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease-modifying Therapies for Multiple Sclerosis. Corboy, JR., Goodin, DS., Frohman, EM.[2020]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Metformin treatment reduces inflammation, dysmyelination and disease severity in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Neuropsychologic status in multiple sclerosis after treatment with glatiramer. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

The impact of metformin use on the outcomes of relapse-remitting multiple sclerosis patients receiving interferon beta 1a: an exploratory prospective phase II open-label randomized controlled trial. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Combinatorial Effect of Metformin and Lovastatin Impedes T-cell Autoimmunity and Neurodegeneration in Experimental Autoimmune Encephalomyelitis. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Glatiramer acetate treatment of multiple sclerosis: an immunological perspective. [2015]

7. Poland pubmed.ncbi.nlm.nih.gov

[Selected issues of immunomodulating treatment in multiple sclerosis]. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Glatiramer acetate therapy for multiple sclerosis: a review. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Disease-modifying Therapies for Multiple Sclerosis. [2020]