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Metformin for the Minimization of Geographic Atrophy Progression in Patients With AMD (METforMIN)

Primary Purpose

Age-Related Macular Degeneration, Macular Degeneration, Age-Related, Dry Macular Degeneration

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Metformin
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Age-Related Macular Degeneration

Eligibility Criteria

55 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Subject must be >/= 55 years of age
  • Subject must have evidence of advanced dry AMD, defined by the characteristic presence of drusen and/or pigmentary changes as well as geographic atrophy
  • Subject must have clear ocular media and adequate pupillary dilation
  • Subject must be able to swallow capsules
  • Study eye must have best corrected visual acuity (BCVA) of 20/20-20/400
  • Subject must be willing and able to pay for monthly prescription of Metformin HCl for 18 months in the event that their insurance carrier will not cover the cost of the drug

Exclusion Criteria:

  • Subjects with insufficient baseline size of geographic atrophy, less than 1.25 mm2 (0.5 Macular Photocoagulation Study Disc Areas). GA is defined as one or more well-defined and often circular patches of partial or complete depigmentation of the RPE, typically with exposure of underlying choroidal blood vessels. Even if much of the RPE appears to be preserved and large choroidal vessels are not visible, a round patch of RPE partial depigmentation may be classified as early GA. The GA in the study eye must be able to be photographed in its entirety, and it must not be contiguous with any areas of peripapillary atrophy, which can complicate area measurements.
  • Subjects who are already taking metformin for another purpose
  • Subjects with type 1 or 2 diabetes
  • Subjects with compromised kidney function:
  • Serum creatinine ≥1.5 mg/dL for males and ≥1.4 mg/dL for females
  • Subjects with moderate to severe heart failure (Class III or IV, New York Heart Association Functional Classifications)
  • Subjects with Child's class C cirrhosis
  • Evidence of retinal atrophy due to causes other than atrophic AMD.
  • Subjects who have had anti-VEGF injections or active choroidal neovascularization in the study eye during the last 12 months

  • Current evidence or history of ocular disorders in the study eye that in the opinion of the investigator confounds study outcome measures, including (but not limited to):

    1. Non-proliferative diabetic retinopathy involving 10 or more hemorrhages or microaneurysms, or active proliferative diabetic retinopathy
    2. Branch or central retinal vein or artery occlusion
    3. Macular hole
    4. Pathologic myopia
    5. Uveitis
    6. Pseudovitelliform maculopathy
    7. Intraoperative surgery within the last 90 days prior to study eye enrollment

Sites / Locations

  • University of California, Davis
  • Palo Alto Veteran Affairs Medical Center
  • Retinal Consultants Medical Group
  • San Francisco Veteran Affairs Medical Center
  • University of California San Francisco
  • California Retina Consultants
  • North Bay Vitreoretinal Consultants
  • Retina Health Center
  • Northwestern University
  • University of Illinois at Chicago
  • Oregon Health and Science University
  • Austin Retina Associates

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Metformin

Observe

Arm Description

This arm will be receiving the study drug, Metformin, for the duration of the 24 month study. They will begin this drug on a low dose of Metformin, increasing the dosage in a step-wise fashion to avoid unwanted gastrointestinal discomfort, a common side effect when patients begin taking Metformin. During the 24 month study, subjects assigned to this arm will have 4 follow-up exams after the initial enrollment exam, at 6 month intervals.

This arm will maintain standard of care for dry AMD, which is observation. During the 24 month study, subjects assigned to this arm will have 4 follow-up exams after the initial enrollment exam, at 6 month intervals.

Outcomes

Primary Outcome Measures

Fundus Autofluorescence Imaging to Measure the Rate of Change in Area of Geographic Atrophy
The primary efficacy endpoint was the annualized growth rate of the square root of geographic atrophy (GA) area in mm/year in the study eye as imaged by fundus autofluorescence (FAF) imaging. Change = (Month 18 GA Area - Baseline GA Area).

Secondary Outcome Measures

Change in Best Corrected Visual Acuity (BCVA)
BCVA is the best possible vision an eye can see with corrective lenses and is measured as then number of letters read on the ETDRS chart. Change = (Month 18 Score - Baseline Score).
Change in Low-luminance Visual Acuity (LLVA)
LLVA involves standard BCVA testing in low-light conditions, which is achieved by adding a neutral density filter in front of the eye being tested. LLVA is measured as the number of letters read on the ETDRS chart. This measure has been shown to correlate well with enlargement of GA. Change = (Month 18 Score - Baseline Score).
Ocular Safety as Measured by the Presence of Novel Intraocular Inflammation Judged by the Investigator to be Due to the Study Drug Metformin
Subjects assigned to the Metformin study arm will be assessed at each follow-up eye exam to confirm ocular safety of metformin. The Data Safety and Management Board for this study will also assess the safety of metformin at different time points throughout the study. They will formally meet to discuss study subject safety at 25% enrollment and 75% enrollment. The potential for ocular side effects due to metformin is thought to be very low, due to the large number of diabetic patients who take this drug and are followed closely for diabetic retinopathy or other ocular disease. This outcome measures the number of treatment arm patients who experienced adverse ocular events during 1 or more follow-up visits.
Systemic Safety as Measured by Presence of Side Effects Listed on Metformin Drug Label as "Severe"
These include: Infrequent side effects of metformin (severe): Trouble Breathing Rare side effects of metformin (severe): Increased Blood Acidity due to High Levels of Lactic Acid (Lactic acidosis) Low Blood Sugar Megaloblastic Anemia Reaction due to an Allergy Subjects assigned to the Metformin study arm will be assessed for these side-effects at each follow-up eye exam to confirm ocular safety of metformin. The Data Safety and Management Board for this study will also assess the safety of metformin at different time points throughout the study. They will formally meet to discuss study subject safety at 25% enrollment and 75% enrollment. This outcome measures the number of treatment arm patients who experienced side effects listed on Metformin drug label as "severe" during 1 or more follow-up visits.

Full Information

First Posted
February 9, 2016
Last Updated
May 16, 2023
Sponsor
University of California, San Francisco
Collaborators
San Francisco Veterans Affairs Medical Center, VA Palo Alto Health Care System, University of California, Davis, University of California, San Diego, Northwestern University, University of Illinois at Chicago, Retinal Consultants Medical Group, Retina Health Center, California Retina Consultants, Oregon Health and Science University
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1. Study Identification

Unique Protocol Identification Number
NCT02684578
Brief Title
Metformin for the Minimization of Geographic Atrophy Progression in Patients With AMD
Acronym
METforMIN
Official Title
METforMIN: Metformin Administration for the Minimization of Geographic Atrophy Progression in Patients With Age-related Macular Degeneration
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
April 2016 (undefined)
Primary Completion Date
April 2022 (Actual)
Study Completion Date
October 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco
Collaborators
San Francisco Veterans Affairs Medical Center, VA Palo Alto Health Care System, University of California, Davis, University of California, San Diego, Northwestern University, University of Illinois at Chicago, Retinal Consultants Medical Group, Retina Health Center, California Retina Consultants, Oregon Health and Science University

4. Oversight

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

5. Study Description

Brief Summary
The purpose of this study is to determine whether metformin, an FDA-approved drug for the treatment of type II diabetes, is a safe and effective treatment to decrease the progression of geographic atrophy in non-diabetic patients with Age-related Macular Degeneration (AMD).
Detailed Description
This is a phase II, single-blind, randomized, evaluation of the safety and efficacy of metformin use to decrease geographic atrophy (GA) progression in non-diabetic patients with dry Age-related Macular Degeneration (AMD). Approximately 186 study subjects throughout four separate study sites will be randomized in a 1:1 ratio to the treatment group and the observation group. The treatment group will be assigned to the study intervention (oral Metformin) for 18 months while the observation group will receive no intervention for 18 months, instead continuing with standard of care ophthalmic exams and close monitoring of their disease. There will be one additional follow up visit at 24 months. Throughout the 24 month study period, the progression of subjects' GA or drusen growth will be measured via ocular imaging taken at standard of care follow-up examinations, including fundus autofluorescence imaging, optical coherence tomography (OCT), and fundus photography.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Age-Related Macular Degeneration, Macular Degeneration, Age-Related, Dry Macular Degeneration, Geographic Atrophy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
66 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Metformin
Arm Type
Experimental
Arm Description
This arm will be receiving the study drug, Metformin, for the duration of the 24 month study. They will begin this drug on a low dose of Metformin, increasing the dosage in a step-wise fashion to avoid unwanted gastrointestinal discomfort, a common side effect when patients begin taking Metformin. During the 24 month study, subjects assigned to this arm will have 4 follow-up exams after the initial enrollment exam, at 6 month intervals.
Arm Title
Observe
Arm Type
No Intervention
Arm Description
This arm will maintain standard of care for dry AMD, which is observation. During the 24 month study, subjects assigned to this arm will have 4 follow-up exams after the initial enrollment exam, at 6 month intervals.
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage
Primary Outcome Measure Information:
Title
Fundus Autofluorescence Imaging to Measure the Rate of Change in Area of Geographic Atrophy
Description
The primary efficacy endpoint was the annualized growth rate of the square root of geographic atrophy (GA) area in mm/year in the study eye as imaged by fundus autofluorescence (FAF) imaging. Change = (Month 18 GA Area - Baseline GA Area).
Time Frame
0 months, 18 months
Secondary Outcome Measure Information:
Title
Change in Best Corrected Visual Acuity (BCVA)
Description
BCVA is the best possible vision an eye can see with corrective lenses and is measured as then number of letters read on the ETDRS chart. Change = (Month 18 Score - Baseline Score).
Time Frame
0 months, 18 months
Title
Change in Low-luminance Visual Acuity (LLVA)
Description
LLVA involves standard BCVA testing in low-light conditions, which is achieved by adding a neutral density filter in front of the eye being tested. LLVA is measured as the number of letters read on the ETDRS chart. This measure has been shown to correlate well with enlargement of GA. Change = (Month 18 Score - Baseline Score).
Time Frame
0 months, 18 months
Title
Ocular Safety as Measured by the Presence of Novel Intraocular Inflammation Judged by the Investigator to be Due to the Study Drug Metformin
Description
Subjects assigned to the Metformin study arm will be assessed at each follow-up eye exam to confirm ocular safety of metformin. The Data Safety and Management Board for this study will also assess the safety of metformin at different time points throughout the study. They will formally meet to discuss study subject safety at 25% enrollment and 75% enrollment. The potential for ocular side effects due to metformin is thought to be very low, due to the large number of diabetic patients who take this drug and are followed closely for diabetic retinopathy or other ocular disease. This outcome measures the number of treatment arm patients who experienced adverse ocular events during 1 or more follow-up visits.
Time Frame
0 months, 6 months, 12 months, 18 months, 24 months
Title
Systemic Safety as Measured by Presence of Side Effects Listed on Metformin Drug Label as "Severe"
Description
These include: Infrequent side effects of metformin (severe): Trouble Breathing Rare side effects of metformin (severe): Increased Blood Acidity due to High Levels of Lactic Acid (Lactic acidosis) Low Blood Sugar Megaloblastic Anemia Reaction due to an Allergy Subjects assigned to the Metformin study arm will be assessed for these side-effects at each follow-up eye exam to confirm ocular safety of metformin. The Data Safety and Management Board for this study will also assess the safety of metformin at different time points throughout the study. They will formally meet to discuss study subject safety at 25% enrollment and 75% enrollment. This outcome measures the number of treatment arm patients who experienced side effects listed on Metformin drug label as "severe" during 1 or more follow-up visits.
Time Frame
0 months, 6 months, 12 months, 18 months, 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subject must be >/= 55 years of age Subject must have evidence of advanced dry AMD, defined by the characteristic presence of drusen and/or pigmentary changes as well as geographic atrophy Subject must have clear ocular media and adequate pupillary dilation Subject must be able to swallow capsules Study eye must have best corrected visual acuity (BCVA) of 20/20-20/400 Subject must be willing and able to pay for monthly prescription of Metformin HCl for 18 months in the event that their insurance carrier will not cover the cost of the drug Exclusion Criteria: Subjects with insufficient baseline size of geographic atrophy, less than 1.25 mm2 (0.5 Macular Photocoagulation Study Disc Areas). GA is defined as one or more well-defined and often circular patches of partial or complete depigmentation of the RPE, typically with exposure of underlying choroidal blood vessels. Even if much of the RPE appears to be preserved and large choroidal vessels are not visible, a round patch of RPE partial depigmentation may be classified as early GA. The GA in the study eye must be able to be photographed in its entirety, and it must not be contiguous with any areas of peripapillary atrophy, which can complicate area measurements. Subjects who are already taking metformin for another purpose Subjects with type 1 or 2 diabetes Subjects with compromised kidney function: Serum creatinine ≥1.5 mg/dL for males and ≥1.4 mg/dL for females Subjects with moderate to severe heart failure (Class III or IV, New York Heart Association Functional Classifications) Subjects with Child's class C cirrhosis Evidence of retinal atrophy due to causes other than atrophic AMD. Subjects who have had anti-VEGF injections or active choroidal neovascularization in the study eye during the last 12 months Current evidence or history of ocular disorders in the study eye that in the opinion of the investigator confounds study outcome measures, including (but not limited to): Non-proliferative diabetic retinopathy involving 10 or more hemorrhages or microaneurysms, or active proliferative diabetic retinopathy Branch or central retinal vein or artery occlusion Macular hole Pathologic myopia Uveitis Pseudovitelliform maculopathy Intraoperative surgery within the last 90 days prior to study eye enrollment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jay M Stewart, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, Davis
City
Davis
State/Province
California
ZIP/Postal Code
95616
Country
United States
Facility Name
Palo Alto Veteran Affairs Medical Center
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Retinal Consultants Medical Group
City
Sacramento
State/Province
California
ZIP/Postal Code
95819
Country
United States
Facility Name
San Francisco Veteran Affairs Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94121
Country
United States
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
California Retina Consultants
City
Santa Maria
State/Province
California
ZIP/Postal Code
93454
Country
United States
Facility Name
North Bay Vitreoretinal Consultants
City
Santa Rosa
State/Province
California
ZIP/Postal Code
95403
Country
United States
Facility Name
Retina Health Center
City
Fort Myers
State/Province
Florida
ZIP/Postal Code
33907
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Austin Retina Associates
City
Austin
State/Province
Texas
ZIP/Postal Code
78705
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Metformin for the Minimization of Geographic Atrophy Progression in Patients With AMD

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