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Oral Metformin for Treatment of ABCA4 Retinopathy

Primary Purpose

ABCA4 Retinopathy, Stargardt Disease, Retinal Dystrophy

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Metformin hydrochloride
Sponsored by
National Eye Institute (NEI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ABCA4 Retinopathy focused on measuring Stargardt Disease, Retinal Dystrophy, Retinal Degeneration

Eligibility Criteria

12 Years - 100 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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 4.5 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. 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:

    • 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.

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 IS-OS on OCT is not possible.
  5. Participant has definitive mutations in RDS/peripherin (PRPH2), 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.

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting
  • University of MichiganRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Metformin

Arm Description

Oral administration of metformin

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
Changes in best corrected visual acuity (BCVA)
The change in BCVA total letters read from baseline to 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.
Change in perimetry and color fundus photography measurements
The change in perimetry and color fundus photography from baseline to Month 24.

Full Information

First Posted
September 10, 2020
Last Updated
August 23, 2023
Sponsor
National Eye Institute (NEI)
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1. Study Identification

Unique Protocol Identification Number
NCT04545736
Brief Title
Oral Metformin for Treatment of ABCA4 Retinopathy
Official Title
Oral Metformin for Treatment of ABCA4 Retinopathy
Study Type
Interventional

2. Study Status

Record Verification Date
August 22, 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 23, 2020 (Actual)
Primary Completion Date
August 31, 2027 (Anticipated)
Study Completion Date
August 31, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Eye Institute (NEI)

4. Oversight

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

5. Study Description

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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ABCA4 Retinopathy, Stargardt Disease, Retinal Dystrophy, Retinal Degeneration
Keywords
Stargardt Disease, Retinal Dystrophy, Retinal Degeneration

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Metformin
Arm Type
Experimental
Arm Description
Oral administration of metformin
Intervention Type
Drug
Intervention Name(s)
Metformin hydrochloride
Intervention Description
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.
Primary Outcome Measure Information:
Title
The difference in growth rate of square-root transformed area of EZ band loss (vAreaEZloss)
Description
The difference in growth rate of vAreaEZloss, from OCT, between the pre-treatment phase and treatment phase.
Time Frame
Pre-treatment, Baseline, Month 24
Secondary Outcome Measure Information:
Title
Proportion of participants with a 30% reduction in growth rate of vAreaEZloss
Description
Proportion of participants with 30% reduction in growth rate of vAreaEZloss, from OCT, during the treatment phase compared to the pre-treatment phase.
Time Frame
Pre-treatment, Baseline, Month 24
Title
Number and severity of adverse events
Description
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.
Time Frame
ongoing throughout study
Title
Changes in best corrected visual acuity (BCVA)
Description
The change in BCVA total letters read from baseline to Month 24.
Time Frame
Baseline, Month 24
Title
Change in rate of area of atrophy enlargement
Description
The difference in rate of region of atrophy measurements from FAF between the pre-treatment phase and treatment phase.
Time Frame
Pre-treatment, Baseline, Month 24
Title
Change in perimetry and color fundus photography measurements
Description
The change in perimetry and color fundus photography from baseline to Month 24.
Time Frame
Baseline, Month 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: 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. 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. 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 partners. 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 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: 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, breast-feeding or planning to become pregnant during the study. Participant has definitive 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). 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. 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. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Cathy Kangale-Whitney, R.N.
Phone
(301) 402-4174
Email
cathy.kangale-whitney@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Brian P Brooks, M.D.
Phone
(301) 496-3577
Email
brooksb@mail.nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brian P Brooks, M.D.
Organizational Affiliation
National Eye Institute (NEI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY8664111010
Email
prpl@cc.nih.gov
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0624
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Abby Sharp
Phone
734-232-9594
Email
abmckee@med.umich.edu

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2020-EI-0163.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

Oral Metformin for Treatment of ABCA4 Retinopathy

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