Oral Metformin for Treatment of ABCA4 Retinopathy

  • End date
    Aug 31, 2026
  • participants needed
  • sponsor
    National Eye Institute (NEI)
Updated on 23 July 2022



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.


To see if metformin is safe and possibly helps to slow the rate of ABCA4 retinopathy.


People age 12 and older who have ABCA4 retinopathy and have problems with their vision.


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....


Study Description:

ABCA4 retinopathy is an autosomal recessive progressive retinal dystrophy that leads to retinal pigment epithelium (RPE) and photoreceptor degeneration, with consequent central visual loss. A treatment that either reduces the rate of lipofuscin accumulation or improves the clearance of lipofuscin in the RPE could potentially slow the degeneration associated with this disease. Metformin hydrochloride is a well-characterized, commonly-prescribed oral anti-diabetic medication that acts by suppressing liver gluconeogenesis and increasing peripheral insulin sensitivity. An additional effect of metformin is to increase macroautophagy via the Mammalian target of rapamycin complex (1mTORC1)/ AMP-activated Kinase (AMPK) pathway; stimulation of this pathway would be predicted to enable the RPE to more efficiently handle lipofuscin. This suggests an association between metformin use and slowing of retinal degeneration. The objective of this study is to investigate the safety and potential efficacy of oral metformin in slowing the rate of change in photoreceptor degeneration in ABCA4 retinopathy.


The objective of this study is to investigate the safety and potential efficacy of oral metformin in slowing the rate of change in photoreceptor degeneration in ABCA4 retinopathy.


Primary Endpoint: The difference in growth rate of square-root transformed area of EZ band loss (square-root AreaEZloss) between the pre-treatment phase and 24 month metformin treatment phase.

Secondary Endpoints: Proportion of participants with a 30% reduction in growth rate of square-root AreaEZloss during the treatment phase compared to the pre-treatment phase, changes from baseline to Month 24 in BCVA total letters read, perimetry, and color fundus photography measurements and the change in rate of area of atrophy enlargement between the pre-treatment and 24 month metformin treatment phase.

Study Population:

The targeted enrollment is 34 metformin-treated participants evaluated for the primary endpoint. Up to 38 participants will be recruited in order to reach this target. NEI participants will primarily be recruited from the population of participants with Stargardt disease currently enrolled in the NEI ABCA4 Natural History study, 12-EI-0203, although participants from outside this study will be considered if they have sufficient supporting data that meet the inclusion criteria (e.g. Point 4: Inclusion Criteria). Patients outside the original 12-EI-0203 cohort who have been followed for at least 2 years and have met the eligibility criteria will be considered at the discretion of the Principal Investigator (PI) or Lead Associate Investigator.


Phase I/II

Description of Sites/Facilities Enrolling Participants:

Participants will be seen at the NIH Clinical Center (CC) and University of Michigan Kellogg Eye Center.

Description of Study Intervention:

This is a multi-center center, Phase I/II, prospective, open-label study to evaluate metformin as a potential treatment to decrease the rate of photoreceptor degeneration in ABCA4 retinopathy. After establishing a baseline, participants will receive a starting oral dose of 500 mg metformin daily, increasing to the maximum tolerated dose, up to 2000 mg/day, over four weeks. Participants will receive investigational product (IP) for a total of 24 months (treatment phase). Participants will be followed for safety for another 12 months after receiving the final dose of IP with visits every six months.

Study Duration:

60 months

Participant Duration:

36 months

Condition ABCA4 Retinopathy, Stargardt Disease, Retinal Dystrophy, Retinal Degeneration
Treatment Metformin Hydrochloride
Clinical Study IdentifierNCT04545736
SponsorNational Eye Institute (NEI)
Last Modified on23 July 2022


Yes No Not Sure

Inclusion Criteria

To be eligible, the following inclusion criteria must be met, where
Participant must be at least 12 years of age
Participant (or legal guardian) must understand and sign the protocol's informed consent document
Participant must have at least one definite mutation in ABCA4 and a typical clinical presentation of Stargardt disease
Participant must have at least two years of natural history data with a rate of growth of square-root(Area(EZloss)) > 0.025 mm/year based on calculation from at least four data points
The four data points must be at least six months apart and the most recent
data point must be at least 4.5 months and no more than 16 months prior to the
baseline visit
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
Female participant of childbearing potential and male participants or their partners must have (or have a partner who has) had a surgical sterilization (vasectomy, hysterectomy, or tubal ligation), be completely abstinent from intercourse or must agree to practice at least one acceptable method of contraception throughout the course of the study and for at least one week after IP discontinuation for female participants or for at least 3 months after IP discontinuation for male participants or their partnets. Acceptable methods of contraception include
Metformin, like insulin, is considered a class B drug by the FDA (animal reproductive
studies have failed to demonstrate a risk to the fetus and there are no adequate and
well-controlled studies in pregnant women) and is frequently prescribed for gestational
diabetes. One meta-analysis showed outcomes with metformin were slightly superior to
insulin. Nonetheless, out of an abundance of caution, we will ask female, but not male
participants in this trial to use these forms of contraception
hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring)
intrauterine device
barrier methods (diaphragm, condom) with spermicide

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation
in this study
Participant has a condition that would preclude participation in the study (e.g
unstable medical status including blood pressure and glycemic control) by interfering
with the participant's ability to engage in the required protocol evaluation and
testing and/or comply with study visits
Any female participant of childbearing potential that is pregnant, breast-feeding or
planning to become pregnant during the study
Participant's retinal degeneration has advanced beyond a point where reliable
measurement of the integrity of the IS-OS on OCT is not possible
Participant has a history of chronic renal impairment as measured in the acute care
Participant is actively receiving study IP in another investigational study
panel (estimated glomerular filtration rate (eGFR)<45ml/min/1.73m^2) or severe
hepatic, pulmonary, or cardiovascular disease (hypoxic state)
Participant is taking any medication that could adversely interact with metformin
Participant has definitive mutations in RDS/peripherin (PRPH2), PROM1, and/or ELOV4
(e.g., cimetidine, furosemide, nifedipine) and cannot switch to an alternative
Participant is currently taking metformin
Participant has a known hypersensitivity to metformin
Participant has a history of chronic lactic acidosis, including diabetic ketoacidosis
with or without coma
Participant has type 1 diabetes mellitus
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