Oral Metformin for Stargardt Disease

Recruiting at 1 trial location

Overseen By Cathy Kangale-Whitney, R.N.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Eye Institute (NEI)

Must not be taking: Cimetidine, Furosemide, Nifedipine, GLP-1 agonists

Disqualifiers: Pregnancy, Chronic renal impairment, Type 1 diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 7

Duration: 24 months

56 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: ABCA4 retinopathy is a genetic disease in which the ABCA4 protein is absent or faulty. It can cause waste material to collect in the eye and may cause cells to die. The cell death can lead to vision loss. Researchers want to see if an oral drug called metformin can help. Objective: To see if metformin is safe and possibly helps to slow the rate of ABCA4 retinopathy. Eligibility: People age 12 and older who have ABCA4 retinopathy and have problems with their vision. Design: Participants will be screened under a separate protocol. Participants will have a medical and family history. They will complete a questionnaire about their vision and daily activities. They will have a physical exam. They may have blood drawn through a needle in the arm. Participants will have an eye exam. Their pupils may be dilated with eye drops. Their retina may be photographed. Participants will have a visual field test. They will sit in front of a large dome and press a button when they see a light within the dome. Participants will have an electroretinogram. It examines the function of the retina. They will sit in the dark for 30 minutes. Then their eyes will be numbed with eye drops. They will wear contact lenses that can sense signals from the retinas. They will watch flashing lights. Participants will have optical coherence tomography. This non-invasive procedure makes pictures of the retina. Participants will have fundus autofluorescence. A bright blue light will be shone into their eye. Participants will take metformin by mouth for 24 months. Participants will have study visits every 6 months. Participation will last for at least 36 months....

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

The trial requires that you stop taking certain medications that could interact negatively with metformin, such as cimetidine, furosemide, and nifedipine. Additionally, you must stop taking any glucagon-like peptide 1 (GLP-1) agonists at least two weeks before enrolling. If you are currently taking metformin, you cannot have taken it for more than one month during the natural history data collection period.

Is metformin generally safe for humans?

Metformin, often used to treat type 2 diabetes, is generally considered safe for humans and has been associated with protective effects against eye complications in diabetic patients. ^{1 2 3 4 5}

How does the drug Metformin hydrochloride differ from other treatments for Stargardt Disease?

Metformin hydrochloride is unique for Stargardt Disease as it is an oral medication traditionally used to treat diabetes, whereas other potential treatments like gene therapy, stem cell therapy, and visual cycle modulators are more experimental and not yet approved. This approach is novel because it repurposes a well-known diabetes drug for a condition with no standard treatments. ^{2 3 6 7 8}

Research Team

Brian P Brooks, M.D.

Principal Investigator

National Eye Institute (NEI)

Eligibility Criteria

This trial is for people aged 12 and older with ABCA4 retinopathy, a genetic eye condition leading to vision loss. Participants must have documented changes in their condition over two years and agree to lifestyle guidelines and contraception if of childbearing potential.

Inclusion Criteria

Participant must agree to adhere to Lifestyle Considerations throughout study duration

Any female participant of childbearing potential must have a negative urine pregnancy test at screening and be willing to undergo urine pregnancy tests throughout the study

Participant (or legal guardian) must understand and sign the protocol's informed consent document

Exclusion Criteria

Participant has a condition that would preclude participation in the study

I have scarring in my eye from abnormal blood vessel growth.

I have specific genetic mutations linked to my condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Baseline assessments including medical history, eye exams, and various retinal tests

Baseline

1 visit (in-person)

Treatment

Participants take metformin by mouth for 24 months

24 months

Study visits every 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Metformin hydrochloride

Trial Overview The study tests whether metformin hydrochloride, an oral medication commonly used for diabetes, can slow down the progression of ABCA4 retinopathy when taken over a period of 24 months.

Participant Groups

Group I: Metformin Experimental Treatment 1 Intervention

Oral administration of metformin

Who Is Running the Clinical Trial?

National Eye Institute (NEI)

Lead Sponsor

Trials

572

Recruited

1,320,000+

Findings from Research

In a study of 234 patients with type 2 diabetes, those treated with metformin experienced significantly fewer ocular complications, such as glaucoma and diabetic retinopathy, compared to those using other oral antihyperglycemic agents.

After adjusting for various factors, metformin treatment was associated with a 86% reduction in the odds of developing glaucoma and a 67% reduction in the odds of diabetic retinopathy, suggesting a protective effect of metformin on eye health in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin use associated with protective effects for ocular complications in patients with type 2 diabetes - observational study. Maleškić, S., Kusturica, J., Gušić, E., et al.[2022]

In a study involving 23 subjects with Stargardt disease, emixustat demonstrated a dose-dependent effect on rod b-wave recovery rates, with the 10 mg dose showing near-complete suppression, indicating its potential efficacy in targeting RPE65.

The safety profile of emixustat was consistent with previous studies, primarily involving ocular adverse events, which suggests it may be a viable treatment option for Stargardt disease as it moves into a longer phase 3 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised study evaluating the pharmacodynamics of emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease. Kubota, R., Birch, DG., Gregory, JK., et al.[2022]

Investigational therapies for Stargardt macular dystrophy (STGD1), including gene therapy and complement inhibitors, show promise in animal models but lack proven efficacy in human trials, highlighting the need for further research.

Visual cycle modulators (VCMs) like fenretinide and emixustat have not successfully improved vision in trials for age-related macular degeneration (AMD) and STGD1, indicating that while they are biologically plausible, their effectiveness remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stargardt macular dystrophy and evolving therapies. Hussain, RM., Ciulla, TA., Berrocal, AM., et al.[2019]

There are currently eight ongoing clinical trials for Stargardt disease, focusing on various treatment strategies including gene therapy, neuroprotection, and stem cell therapy.

These trials aim to address the disease through different mechanisms, such as inhibiting toxic vitamin A dimers and restoring the function of the ABCA4 gene, which raises hope for effective treatments in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Tests Testing New Therapies for Stargardt Disease]. Kousal, B., Ďuďáková, Ľ., Hlavatá, L., et al.[2019]

In a study of 217 patients with Stargardt disease, it was found that about 50% of eyes without definitely decreased autofluorescence (DDAF) at the first visit developed this lesion within 5 years, indicating that DDAF incidence could be a useful measure for evaluating treatment effectiveness.

The median time to develop DDAF lesions was 4.9 years, while for questionably decreased autofluorescence (QDAF) lesions it was 6.3 years, highlighting the progression of retinal damage in patients and the importance of monitoring these changes over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5. Strauss, RW., Muñoz, B., Ho, A., et al.[2022]

In a study involving healthy adults receiving intravenous infusions of 4-methylpyrazole (4-MP) or placebo, there were no significant differences in dark adaptation responses, indicating that 4-MP does not effectively inhibit the human visual cycle.

The results suggest that 4-MP is not a viable treatment option for Stargardt disease at this time, but further research in mouse models may still be valuable to explore its effects on lipofuscin production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of 4-methylpyrazole as a potential therapeutic dark adaptation inhibitor. Jurgensmeier, C., Bhosale, P., Bernstein, PS.[2018]

In a study involving 34 eyes of patients with Stargardt Disease, 61.8% showed improvement in vision after treatment with autologous bone marrow-derived stem cells, with an average improvement of nearly 18%.

The treatment was safe, with no adverse events reported, and 94.1% of patients either improved or maintained their vision stability over a one-year follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stem Cell Ophthalmology Treatment Study (SCOTS): Bone Marrow-Derived Stem Cells in the Treatment of Stargardt Disease. Weiss, JN., Levy, S.[2021]

A study of eight patients with genetically-confirmed Stargardt disease (STGD1) revealed a retinal phenotype on SD-OCT that resembles hydroxychloroquine (HCQ) retinopathy, despite none of the patients having a history of HCQ use.

The findings suggest a phenotypic overlap between STGD1 and HCQ retinopathy, highlighting the importance of genetic screening to avoid misdiagnosis in patients presenting with similar retinal changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recessive Stargardt disease phenocopying hydroxychloroquine retinopathy. Nõupuu, K., Lee, W., Zernant, J., et al.[2019]

References

1. Bosnia and Herzegovina pubmed.ncbi.nlm.nih.gov

Metformin use associated with protective effects for ocular complications in patients with type 2 diabetes - observational study. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Randomised study evaluating the pharmacodynamics of emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Stargardt macular dystrophy and evolving therapies. [2019]

4. Czech Republic pubmed.ncbi.nlm.nih.gov

[Clinical Tests Testing New Therapies for Stargardt Disease]. [2019]

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

Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Evaluation of 4-methylpyrazole as a potential therapeutic dark adaptation inhibitor. [2018]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Stem Cell Ophthalmology Treatment Study (SCOTS): Bone Marrow-Derived Stem Cells in the Treatment of Stargardt Disease. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

Recessive Stargardt disease phenocopying hydroxychloroquine retinopathy. [2019]