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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether metformin, a drug typically used for diabetes, is safe for individuals with progressive multiple sclerosis (MS), a condition where the immune system attacks the protective sheath covering nerve fibers. Researchers aim to compare the effects of metformin to a placebo (a pill with no active medicine) on MS. Individuals with primary or secondary progressive MS who haven't experienced a relapse or new brain lesions in the past year might be suitable candidates. Participants should continue their current MS treatment during the trial. As an Early Phase 1 trial, this research seeks to understand how metformin affects people with MS, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that metformin is likely to be safe for humans?

Research has shown that metformin is usually well-tolerated by patients. In studies involving people with multiple sclerosis (MS), metformin did not raise any major safety concerns. For instance, when used by patients with relapsing MS who were also obese, metformin helped reduce the number of brain lesions, which are damaged areas in the brain, without causing serious side effects.

Metformin is also a common drug for treating type 2 diabetes, and it has been used safely by many people for a long time. However, this study specifically examines its safety for progressive multiple sclerosis, which is a different condition.

Like any medication, some people might experience mild side effects such as an upset stomach or diarrhea, but these are usually manageable. Always discuss any concerns with a healthcare provider. ^{1 2 3 4}

Why do researchers think this study treatment might be promising for multiple sclerosis?

Unlike the standard treatments for progressive multiple sclerosis, which often focus on managing symptoms or modifying the disease course with drugs like ocrelizumab or siponimod, metformin offers a unique approach by possibly targeting cellular aging and metabolism. Metformin, commonly known for its use in diabetes, is thought to have neuroprotective effects that might help in slowing the progression of multiple sclerosis. Researchers are excited about metformin because it represents a potential new mechanism for altering disease progression, rather than just alleviating symptoms. By addressing underlying metabolic pathways, metformin could offer a novel strategy that complements existing therapies.

What evidence suggests that metformin might be an effective treatment for progressive multiple sclerosis?

Research shows that metformin, which participants in this trial may receive, might help treat progressive multiple sclerosis (PMS). Studies have found that it can reduce harmful substances and swelling in the body, aiding in PMS management. Metformin may also protect nerve cells by reducing damage and aiding repair. Early results suggest that metformin could slow the worsening of symptoms in PMS patients. However, more research is needed to fully understand its effectiveness for this condition. ^{1 2 5 6 7}

Who Is on the Research Team?

Kevin R Patel, MD

Principal Investigator

University of California, Los Angeles

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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Metformin Treatment in Progressive Multiple Sclerosis

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 ...