Oral Metformin for Treatment of ABCA4 Retinopathy

• Register: ClinicalTrials.gov
• Last refreshed on: 24 March 2025
• Main ID: NCT04545736
• Date of registration: 10/09/2020
• Prospective Registration: Yes
• Primary sponsor: National Eye Institute (NEI)
• Public title: Oral Metformin for Treatment of ABCA4 Retinopathy
• Scientific title: Oral Metformin for Treatment of ABCA4 Retinopathy
• Date of first enrolment: November 23, 2020
• Target sample size: 56
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT04545736
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

United States

Contacts

• Name: Cathy Kangale-Whitney, R.N.

• Name: Brian P Brooks, M.D.
• Affiliation: National Eye Institute (NEI)

Key inclusion & exclusion criteria

- INCLUSION CRITERIA:

To be eligible, the following inclusion criteria must be met, where applicable.

1. Participant must be at least 12 years of age.

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

3. 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.

4. 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).

1. Potential participants with three natural history data points may be enrolled
to obtain their fourth natural history data point on protocol.

2. 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.

3. 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.

5. Participant must agree to adhere to Lifestyle Considerations throughout study
duration.

6. 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.

7. Any female participant of childbearing potential must:

- Have had a surgical sterilizationa OR

- Completely abstain from intercourse OR

- Practice at least one form of contraceptionb during 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 for the duration of the
study and at least one week after the female participant discontinues IP.

Any male participants must:

- Have had a surgical sterilization (a) OR

- Completely abstain from intercourse OR

- Practice at least one form of contraception (b) throughout 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 for the duration of the study
and at least 3 months after the male participant discontinues IP.

1. Acceptable forms of surgical sterilization include: vasectomy, hysterectomy, or
tubal ligation.

2. 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.

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 and male participants in this trial
to use these forms of contraception.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from
participation in this study:

1. Participant is actively receiving study IP in another investigational
study.

2. 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.

3. Any female participant of childbearing potential that is pregnant,
breast-feeding or planning to become pregnant during the study.

4. Participant has definitive pathogenic or likely pathogenic mutations in
RDS/peripherin (PRPH2), PROM1, and/or ELOVL4.

5. 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).

6. Participant is taking any medication that could adversely interact with
metformin (e.g., cimetidine, furosemide, nifedipine) and cannot switch to
an alternative medication.

7. 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).

8. Participant has a known hypersensitivity to metformin.

9. 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.

10. Participant has a history of chronic lactic acidosis, including diabetic
ketoacidosis, with or without coma.

11. Participant has type 1 diabetes mellitus.

12. 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.


Age minimum: 12 Years
Age maximum: 100 Years
Gender: All

Health Condition(s) or Problem(s) studied

ABCA4 Retinopathy

Retinal Degeneration

Retinal Dystrophy

Stargardt Disease

Intervention(s)

Drug: Metformin hydrochloride

Primary Outcome(s)

The difference in growth rate of square-root transformed area of EZ band loss (vAreaEZloss) [Time Frame: Pre-treatment, Baseline, Month 24]

Secondary Outcome(s)

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]

Number and severity of adverse events [Time Frame: ongoing throughout study]

Changes in best corrected visual acuity (BCVA) [Time Frame: Baseline, Month 24]

Proportion of participants with a 30% reduction in growth rate of vAreaEZloss [Time Frame: Pre-treatment, Baseline, Month 24]

Secondary ID(s)

20-EI-0163

200163

Source(s) of Monetary Support

Please refer to primary and secondary sponsors