ABCA4 RetinopathyPhase 1/2NCT04545736
Oral Metformin for Treatment of ABCA4 Retinopathy
A Phase 1/2 study testing Metformin hydrochloride in people with ABCA4 Retinopathy and Stargardt Disease, run by National Eye Institute (NEI) at 2 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 12 to 100 years
- Conditions the study is for
- ABCA4 Retinopathy, Stargardt Disease, Retinal Dystrophy
- What is being tested?
- Metformin hydrochloride
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 55 participants
- Where
- 2 sitesUnited States
- Study dates
- 23 Nov 2020to 2 Feb 2029
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 100 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- To be eligible, the following inclusion criteria must be met, where applicable.
- 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 pathogenic or likely pathogenic mutation in ABCA4 and a typical clinical presentation of Stargardt disease and phenotypic presentation of ABCA4 retinopathy in both eyes.
- Participant must have at least two years of natural history data from at least four data points (a) The separation between any two consecutive data points must be at least six months (b) The most recent data point must be at least 4.5 months and no more than 16 months prior to the baseline visit (c)
- Potential participants with three natural history data points may be enrolled to obtain their fourth natural history data point on protocol.
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- The separation between any two consecutive data points may fall short of 6 months by no more than 45 days; however, the total separation among the data points must allow for at least two years of natural history data.
- Potential participants with four or more natural history data points completed off protocol, all of which having occurred more than 16 months prior to the baseline visit, may be enrolled to complete an additional natural history data point on protocol within the required timeframe from 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.
- Any female participant of childbearing potential must:
- Have had a surgical sterilization OR
- Completely abstain from intercourse OR
- Practice at least one form of contraception while actively taking IP on the study and at least one week after IP discontinuation OR
- Have a partner who had a surgical sterilization OR
- Have a partner who practices one form of contraception while the female participant is actively taking IP and at least one week after the female participant discontinues IP.
- Any male participants must:
- Have had a surgical sterilization OR
- Completely abstain from intercourse OR
- Practice at least one form of contraception while actively taking IP on the study and at least for 3 months after IP discontinuation OR
- Have a partner who had a surgical sterilization OR
- Have a partner who practices one form of contraception while the male participant actively takes IP and at least 3 months after the male participant discontinues IP.
- Acceptable forms of surgical sterilization include: vasectomy, hysterectomy, or tubal ligation.
- Acceptable methods of contraception include: hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, or barrier methods (diaphragm, condom) with spermicide.
Who cannot join
- An individual who meets any of the following criteria will be excluded from participation in this study:
- Participant is actively receiving study IP in another investigational 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 or breast-feeding at the time of enrollment or planning to become pregnant during the study.
- Participant has definitive pathogenic or likely pathogenic mutations in RDS/peripherin (PRPH2), PROM1, and/or ELOVL4.
- Participant has a history of chronic renal impairment as measured in the acute care panel estimated glomerular filtration rate (eGFR)<45 ml/min/1.73 m2) or severe hepatic, pulmonary, or cardiovascular disease (hypoxic state).
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- Participant is taking any medication that could adversely interact with metformin (e.g., cimetidine, furosemide, nifedipine) and cannot switch to an alternative medication.
- Participant is currently taking metformin or participant has taken metformin during the period of natural history data collection that will be used for this study for a cumulative total of more than one month (> 31 days).
- Participant has a known hypersensitivity to metformin.
- Participant has not stopped taking a glucagon-like peptide 1 (GLP-1) agonist at least two weeks prior to enrollment or is currently taking a GLP-1 agonist.
- Participant has a history of chronic lactic acidosis, including diabetic ketoacidosis, with or without coma.
- Participant has type 1 diabetes mellitus.
- Scarring due to choroidal neovascularization (CNV) is present in either eye.
- QUALIFYING EYE ELIGIBILITY CRITERIA:
- In order to participate in the study, the participant must have at least one qualifying eye that meets all of the inclusion and none of the exclusion criteria listed below.
- Qualifying Eye Inclusion Criteria:
- 1. A growth rate of square root AreaEZloss > 0.025 mm/year based on calculation from natural history data.
- Qualifying Eye Exclusion Criteria:
- 1. Retinal degeneration has advanced beyond a point where reliable measurement of the integrity of the IS-OS on OCT is possible.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Michigan
Ann Arbor, Michigan, 48109-0624
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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.
Read more
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....
Read the detailed description
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 1 (mTORC1)/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.
Objectives:
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.
Endpoints:
Primary Endpoint: The difference in growth rate of square-root transformed area of EZ band loss (square-root AreaEZloss), from OCT, 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 Best-Corrected Visual Acuity (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.
- Being tested
- Metformin hydrochloride
- Keywords
- Stargardt Disease, Retinal Dystrophy, Retinal Degeneration
- Medical subject headings
- Stargardt Disease, Retinal Dystrophies, Retinal Degeneration
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin hydrochlorideDrug
Metformin is commercially produced in immediate and extended release. Participants will receive an immediate release formulation of metformin of 500mg daily at study entry. This dose will be titrated up weekly in 500mg increments to reach a goal of 2000mg daily maximum. Once participants >=17 years of age reach 2000mg metformin immediate release they will switch to an extended-release formulation (1000mg twice a day by mouth). Participants >= 17 years of age that cannot tolerate 2000mg will be permitted to reduce their daily dose to a minimum of 1000mg/day. Because metformin extended release is not FDA-approved for children under the age of 17, participants under 17 will remain on the immediate release formulation. For these participants who remain on standard formulation, the maximum tolerated dose between 1000mg and 2000mg/day will be given.
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Oral administration of metformin Receives: Drug: Metformin hydrochloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
The difference in growth rate of square-root transformed area of EZ band loss (vAreaEZloss)
The difference in growth rate of vAreaEZloss, from OCT, between the pre-treatment phase and treatment phase.
Measured: Pre-treatment, Baseline, Month 24
Secondary outcomes (5)
Proportion of participants with a 30% reduction in growth rate of vAreaEZloss
Proportion of participants with 30% reduction in growth rate of vAreaEZloss, from OCT, during the treatment phase compared to the pre-treatment phase.
Measured: Pre-treatment, Baseline, Month 24
Number and severity of adverse events
The number and severity of systemic and ocular toxicities, adverse events and infections by severity, type and assessed relatedness to the IP throughout the study period.
Measured: ongoing throughout study
Changes in best corrected visual acuity (BCVA)
The change in BCVA total letters read from baseline to Month 24.
Measured: Baseline, Month 24
Change in rate of area of atrophy enlargement
The difference in rate of region of atrophy measurements from FAF between the pre-treatment phase and treatment phase.
Measured: Pre-treatment, Baseline, Month 24
Change in perimetry and color fundus photography measurements
The change in perimetry and color fundus photography from baseline to Month 24.
Measured: Baseline, Month 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Sep 2020
- Study start23 Nov 2020
- Primary completion2 Feb 2028 (estimated)
- Study completion2 Feb 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for ABCA4 RetinopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 55 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Eye Institute (NEI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Brian P Brooks, M.D., Principal investigator, National Eye Institute (NEI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04545736
- Sponsor's protocol ID
- 200163
- Other IDs
- 20-EI-0163
- Status last verified
- 16 Oct 2026
- First submitted
- 10 Sep 2020
- Last updated
- 22 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 22 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oral Metformin for Treatment of ABCA4 Retinopathy
- ClinicalTrials.gov ID
- NCT04545736
- Acronym / sponsor ID
- 200163
- Keywords
- Stargardt Disease, Retinal Dystrophy, Retinal Degeneration
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 55 participants (actual)
- Lead sponsor
- National Eye Institute (NEI)US National Institutes of Health
- Study start
- 23 Nov 2020 (actual)
- Primary completion
- 2 Feb 2028 (estimated)
- Study completion
- 2 Feb 2029 (estimated)
- First posted
- 11 Sep 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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....
Detailed description
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 1 (mTORC1)/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.
Objectives:
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.
Endpoints:
Primary Endpoint: The difference in growth rate of square-root transformed area of EZ band loss (square-root AreaEZloss), from OCT, 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 Best-Corrected Visual Acuity (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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: Metformin hydrochlorideOral administration of metformin |
Who may qualify
- Ages
- 12 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (24 listed)
- To be eligible, the following inclusion criteria must be met, where applicable.
- 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 pathogenic or likely pathogenic mutation in ABCA4 and a typical clinical presentation of Stargardt disease and phenotypic presentation of ABCA4 retinopathy in both eyes.
- Participant must have at least two years of natural history data from at least four data points (a) The separation between any two consecutive data points must be at least six months (b) The most recent data point must be at least 4.5 months and no more than 16 months prior to the baseline visit (c)
Key exclusion criteria (19 listed)
- An individual who meets any of the following criteria will be excluded from participation in this study:
- In order to participate in the study, the participant must have at least one qualifying eye that meets all of the inclusion and none of the exclusion criteria listed below.
- 1. A growth rate of square root AreaEZloss > 0.025 mm/year based on calculation from natural history data.
- 1. Retinal degeneration has advanced beyond a point where reliable measurement of the integrity of the IS-OS on OCT is possible.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Metformin hydrochlorideMetformin is commercially produced in immediate and extended release. Participants will receive an immediate release formulation of metformin of 500mg daily at study entry. This dose will be titrated up weekly in 500mg increments to reach a goal of 2000mg daily maximum. Once participants >=17 years of age reach 2000mg metformin immediate release they will switch to an extended-release formulation (1000mg twice a day by mouth). Participants >= 17 years of age that cannot tolerate 2000mg will be permitted to reduce their daily dose to a minimum of 1000mg/day. Because metformin extended release is not FDA-approved for children under the age of 17, participants under 17 will remain on the immediate release formulation. For these participants who remain on standard formulation, the maximum tolerated dose between 1000mg and 2000mg/day will be given. | Drug | Metformin |
Primary outcome
The difference in growth rate of square-root transformed area of EZ band loss (vAreaEZloss)
Time frame: Pre-treatment, Baseline, Month 24
The difference in growth rate of vAreaEZloss, from OCT, between the pre-treatment phase and treatment phase.
5 secondary outcomes
Proportion of participants with a 30% reduction in growth rate of vAreaEZloss
Time frame: Pre-treatment, Baseline, Month 24
Number and severity of adverse events
Time frame: ongoing throughout study
Changes in best corrected visual acuity (BCVA)
Time frame: Baseline, Month 24
Change in rate of area of atrophy enlargement
Time frame: Pre-treatment, Baseline, Month 24
Change in perimetry and color fundus photography measurements
Time frame: Baseline, Month 24
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Oct 2026.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
Related trials for ABCA4 Retinopathy
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Phase 1 Study of C.001 in Retinal Degeneration
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Active, not recruitingObservational study
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A Study About the Safety of a Single ASP2020 Eye Injection and if it Helps People With Vision Loss From Stargardt-type Eye Conditions
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brian P Brooks, M.D. principal investigator
National Eye Institute (NEI)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Metformin hydrochloride in people with ABCA4 Retinopathy and Stargardt Disease, run by National Eye Institute (NEI) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 22 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The difference in growth rate of square-root transformed area of EZ band loss (vAreaEZloss) (time frame: Pre-treatment, Baseline, Month 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2026.