Oral Metformin for Treatment of ABCA4 Retinopathy

• ClinicalTrials.gov Identifier: NCT04545736
• Recruitment Status: Recruiting
• First Posted: September 11, 2020
• Last Update Posted: January 15, 2021
• Sponsor: National Eye Institute (NEI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )

Tracking Information

• First Submitted Date: September 10, 2020
• First Posted Date: September 11, 2020
• Last Update Posted Date: January 15, 2021
• Estimated Study Start Date: January 20, 2021
• Estimated Primary Completion Date: August 31, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 10, 2020)

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

The difference in growth rate of square-root AreaEZloss, from OCT, between the pre-treatment phase and treatment phase.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 10, 2020)

• Proportion of participants with a 30% reduction in growth rate of square-root AreaEZloss [ Time Frame: Pre-treatment, Baseline, Month 24 ]
  Proportion of participants with 30% reduction in growth rate of square-root AreaEZloss, from OCT, during the treatment phase compared to the pre-treatment phase.
• Changes in best corrected visual acuity (BCVA) [ Time Frame: Baseline, Month 24 ]
  The change in BCVA total letters read from baseline to Month 24.
• Change in perimetry and color fundus photography measurements [ Time Frame: Baseline, Month 24 ]
  The change in perimetry and color fundus photography from baseline to Month 24.
• Change in rate of area of atrophy enlargement [ Time Frame: Pre-treatment, Baseline, Month 24 ]
  The difference in rate of region of atrophy measurements from FAF between the pre-treatment phase and treatment phase.
• Number and severity of adverse events [ Time Frame: ongoing throughout study ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Oral Metformin for Treatment of ABCA4 Retinopathy
• Official Title: Oral Metformin for Treatment of ABCA4 Retinopathy

Brief 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.

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. etformin hydrochloride is a well-characterized, commonly-prescribed oral anti-diabetic medication that acts by suppressing liver gluconeogenesis and increasing peripheral insulin ensitivity. An additional effect of metformin is to increase macroautophagy via the mTORC1/AMPK pathway; stimulation of this pathway would be predicted to enable the RPE to more efficiently handle ipofuscin. 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) 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 Population:

The targeted enrollment is 40 metformin-treated participants evaluated for the primary endpoint. Up to 44 participants will be recruited in order to reach this target. 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. Patients outside the original 12-EI-0203 cohort who have been followed for at least two years and have met the eligibility criteria will be considered at the discretion of the Principal Investigator (PI) or Lead Associate Investigator.

Phase: Phase I/II

Description of Sites/Facilities Enrolling Participants:

Participants will be seen at the NIH Clinical Center (CC). In the event that a second site is used in order to obtain sufficient power, we would enter into a collaboration only with sites if they 1) had a similarly-followed cohort of patients and 2) had identical testing equipment/conditions for our primary outcome variable and major secondary outcome variables.

Description of Study Intervention:

This is a single 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

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• ABCA4 Retinopathy
• Stargardt Disease
• Retinal Dystrophy
• Retinal Degeneration

Intervention

Drug: Metformin hydrochloride

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 Arms

Experimental: Metformin

Oral administration of metformin

Intervention: Drug: Metformin hydrochloride

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 10, 2020): 44
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 31, 2026
• Estimated Primary Completion Date: August 31, 2026 (Final data collection date for primary outcome measure)

Eligibility 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 mutation in ABCA4 and a typical clinical presentation of Stargardt disease.

4. 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 six months and no more than 16 months prior to 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 (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 two acceptable methods of contraception throughout the course of the study and for at least one week after IP discontinuation. Acceptable methods of contraception include:

   • hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring),
   • intrauterine device,
   • 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, but not male, participants in this trial to use these forms of contraception.

*This will most likely be obtained through the existing NEI protocol 12-EI-0203, but participants outside this study will be considered if they meet the requisite criteria.

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's retinal degeneration has advanced beyond a point where reliable measurement of the integrity of the inner and outer segment junction (IS-OS) on OCT is not possible.
5. Participant has definitive mutations in RDS/peripherin, PROM1, and/or ELOV4
6. Participant has a history of chronic renal impairment as measured in the acute care panel (estimated glomerular filtration rate (eGFR)<45ml/min/1.73m^2) or severe hepatic, pulmonary, or cardiovascular disease (hypoxic state).
7. Participant is taking any medication that could adversely interact with metformin (e.g., cimetidine, furosemide, nifedipine) and cannot switch to an alternative medication.
8. Participant is currently taking metformin.
9. Participant has a known hypersensitivity to metformin.
10. Participant has a history of chronic lactic acidosis, including diabetic ketoacidosis, with or without coma.
11. Participant has type 1 diabetes mellitus.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Allison T Bamji, R.N.; (301) 451-3437; bamjia@nei.nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04545736
• Other Study ID Numbers: 200163; 20-EI-0163
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )
• Study Sponsor: National Eye Institute (NEI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Brian P Brooks, M.D.; National Eye Institute (NEI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: November 25, 2020