Age-Related Macular Degeneration, Dry Macular Degeneration, Geographic Atrophy, Macular Degeneration, Age-Related
Conditions
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.
Interventions
DRUGMetformin
Sponsors
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
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fundus Autofluorescence Imaging to Measure the Rate of Change in Area of Geographic Atrophy | 0 months, 18 months | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Best Corrected Visual Acuity (BCVA) | 0 months, 18 months | 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) | 0 months, 18 months | 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 | 0 months, 6 months, 12 months, 18 months, 24 months | 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 | 0 months, 6 months, 12 months, 18 months, 24 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin 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.
Metformin | 32 |
| Metformin 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.
Metformin | 53 |
| Observe 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. | 34 |
| Observe 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. | 57 |
| Total | 176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible after reviewing baseline imaging | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Missing follow-up data | 0 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 7 |
Baseline characteristics
| Characteristic | Metformin | Observe | Total |
|---|---|---|---|
| Age, Continuous | 78.5 years STANDARD_DEVIATION 10.9 | 79.3 years STANDARD_DEVIATION 7.3 | 78.9 years STANDARD_DEVIATION 9.2 |
| Best corrected visual acuity | 58.5 number of letters read on ETDRS STANDARD_DEVIATION 18.5 | 57.0 number of letters read on ETDRS STANDARD_DEVIATION 19.4 | 57.7 number of letters read on ETDRS STANDARD_DEVIATION 18.9 |
| Foveal center point involvement | 45 eyes | 48 eyes | 93 eyes |
| Fundus autofluorescence (FAF) Pattern, None or Focal | 38 eyes | 34 eyes | 72 eyes |
| Geographic atrophy (GA) area | 6.2 mm^2 STANDARD_DEVIATION 4.4 | 8.7 mm^2 STANDARD_DEVIATION 6.1 | 7.5 mm^2 STANDARD_DEVIATION 5.5 |
| History of allergies | 9 Participants | 11 Participants | 20 Participants |
| History of cardiovascular diseases | 19 Participants | 22 Participants | 41 Participants |
| History of dermatological diseases | 2 Participants | 7 Participants | 9 Participants |
| History of ear, nose throat diseases | 7 Participants | 5 Participants | 12 Participants |
| History of endocrine diseases | 5 Participants | 6 Participants | 11 Participants |
| History of gastrointestinal diseases | 7 Participants | 11 Participants | 18 Participants |
| History of genitourinary diseases | 5 Participants | 9 Participants | 14 Participants |
| History of hematological diseases | 1 Participants | 4 Participants | 5 Participants |
| History of hepatobiliary diseases | 1 Participants | 3 Participants | 4 Participants |
| History of immunological diseases | 1 Participants | 3 Participants | 4 Participants |
| History of musculoskeletal diseases | 16 Participants | 12 Participants | 28 Participants |
| History of neoplasia | 4 Participants | 4 Participants | 8 Participants |
| History of neurological diseases | 5 Participants | 7 Participants | 12 Participants |
| History of other diseases | 1 Participants | 1 Participants | 2 Participants |
| History of psychological diseases | 5 Participants | 2 Participants | 7 Participants |
| History of respiratory diseases | 6 Participants | 10 Participants | 16 Participants |
| Low luminance visual acuity | 42.8 number of letters read on ETDRS STANDARD_DEVIATION 16.4 | 40.0 number of letters read on ETDRS STANDARD_DEVIATION 17.9 | 41.3 number of letters read on ETDRS STANDARD_DEVIATION 17.2 |
| Multifocal lesion | 34 eyes | 33 eyes | 67 eyes |
| Number of eligible eyes | 53 eyes | 57 eyes | 110 eyes |
| Presence of GA in both eyes | 27 Participants | 32 Participants | 59 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) White | 29 Participants | 30 Participants | 59 Participants |
| Region of Enrollment United States | 32 participants | 34 participants | 66 participants |
| Sex: Female, Male Female | 19 Participants | 19 Participants | 38 Participants |
| Sex: Female, Male Male | 13 Participants | 15 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 2 / 34 |
| other Total, other adverse events | 16 / 32 | 4 / 34 |
| serious Total, serious adverse events | 5 / 32 | 3 / 34 |
Outcome results
Primary
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).
Time frame: 0 months, 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Fundus Autofluorescence Imaging to Measure the Rate of Change in Area of Geographic Atrophy | 0.41 mm/year | Standard Deviation 0.05 |
| Observation | Fundus Autofluorescence Imaging to Measure the Rate of Change in Area of Geographic Atrophy | 0.35 mm/year | Standard Deviation 0.05 |
p-value: 0.39Linear mixed-effects regression
Secondary
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).
Time frame: 0 months, 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Best Corrected Visual Acuity (BCVA) | -3.2 letters correctly read | Standard Error 0.9 |
| Observation | Change in Best Corrected Visual Acuity (BCVA) | -3.2 letters correctly read | Standard Error 1.3 |
p-value: 0.97Linear mixed-effects
Secondary
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).
Time frame: 0 months, 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Low-luminance Visual Acuity (LLVA) | -2.1 letters correctly read | Standard Error 2 |
| Observation | Change in Low-luminance Visual Acuity (LLVA) | -6.3 letters correctly read | Standard Error 1.9 |
p-value: 0.12Linear mixed-effects
Secondary
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.
Time frame: 0 months, 6 months, 12 months, 18 months, 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin | Ocular Safety as Measured by the Presence of Novel Intraocular Inflammation Judged by the Investigator to be Due to the Study Drug Metformin | 0 Participants |
Secondary
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.
Time frame: 0 months, 6 months, 12 months, 18 months, 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin | Systemic Safety as Measured by Presence of Side Effects Listed on Metformin Drug Label as Severe | 0 Participants |