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| Name | Class |
|---|---|
| San Francisco Veterans Affairs Medical Center | FED |
| VA Palo Alto Health Care System | FED |
| University of California, Davis | OTHER |
| University of California, San Diego |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin | Experimental | 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. |
|
| Observe | No Intervention | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 0 months, 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 0 months, 18 months |
| Change in Low-luminance Visual Acuity (LLVA) |
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Inclusion Criteria:
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):
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| Name | Affiliation | Role |
|---|---|---|
| Jay M Stewart, MD | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, Davis | Davis | California | 95616 | United States | ||
| Palo Alto Veteran Affairs Medical Center |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 6, 2019 |
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| OTHER |
| Northwestern University | OTHER |
| University of Illinois at Chicago | OTHER |
| Retinal Consultants Medical Group | OTHER |
| Retina Health Center | INDUSTRY |
| California Retina Consultants | OTHER |
| Oregon Health and Science University | OTHER |
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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). |
| 0 months, 18 months |
| 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. | 0 months, 6 months, 12 months, 18 months, 24 months |
| Systemic Safety as Measured by Presence of Side Effects Listed on Metformin Drug Label as "Severe" | These include: Infrequent side effects of metformin (severe):
Rare side effects of metformin (severe):
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. | 0 months, 6 months, 12 months, 18 months, 24 months |
| Palo Alto |
| California |
| 94304 |
| United States |
| Retinal Consultants Medical Group | Sacramento | California | 95819 | United States |
| San Francisco Veteran Affairs Medical Center | San Francisco | California | 94121 | United States |
| University of California San Francisco | San Francisco | California | 94143 | United States |
| California Retina Consultants | Santa Maria | California | 93454 | United States |
| North Bay Vitreoretinal Consultants | Santa Rosa | California | 95403 | United States |
| Retina Health Center | Fort Myers | Florida | 33907 | United States |
| Northwestern University | Chicago | Illinois | 60611 | United States |
| University of Illinois at Chicago | Chicago | Illinois | 60612 | United States |
| Oregon Health and Science University | Portland | Oregon | 97239 | United States |
| Austin Retina Associates | Austin | Texas | 78705 | United States |
| FG001 | Observation | 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. |
| COMPLETED |
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| NOT COMPLETED |
|
|
| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| eyes |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years | Participants |
| ||||||||||||||
| Sex: Female, Male | Count of Participants | Participants | Participants |
| |||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants | Participants |
| |||||||||||||||
| Region of Enrollment | Number | participants | Participants |
| |||||||||||||||
| Presence of GA in both eyes | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of cardiovascular diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of respiratory diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of hepatobiliary diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of gastrointestinal diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of genitourinary diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of endocrine diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of hematological diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of musculoskeletal diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of neoplasia | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of neurological diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of psychological diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of immunological diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of dermatological diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of allergies | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of ear, nose throat diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| History of other diseases | Count of Participants | Participants | Participants |
| |||||||||||||||
| Number of eligible eyes | Number | eyes | Participants |
| |||||||||||||||
| Best corrected visual acuity | Best corrected visual acuity (BCVA) is the best possible vision that an eye can achieve with corrective lenses (e.g., glasses or contact lenses). For this study, BCVA was measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity charts. | Mean | Standard Deviation | number of letters read on ETDRS | Participants |
| |||||||||||||
| Low luminance visual acuity | Low luminance visual acuity (LLVA) involves standard BCVA testing under low-light conditions, which is achieved by adding a neutral density filter in front of the eye. For this study, LLVA was measured using the ETDRS visual acuity charts. | Mean | Standard Deviation | number of letters read on ETDRS | Participants |
| |||||||||||||
| Geographic atrophy (GA) area | Geographic atrophy (GA) is the advanced stage of non-neovascular age-related macular degeneration (AMD). Total area of the GA lesions on fundus autofluorescence (FAF) imaging was measured using Heidelberg Eye Explorer software. | Mean | Standard Deviation | mm^2 | eyes |
| |||||||||||||
| Multifocal lesion | Number | eyes | eyes |
| |||||||||||||||
| Foveal center point involvement | Number | eyes | eyes |
| |||||||||||||||
| Fundus autofluorescence (FAF) Pattern, "None" or "Focal" | FAF pattern refers to the morphology of the GA lesion border as seen on FAF imaging. "None" indicates no or very limited increase in autofluorescence at and beyond the border of GA. "Focal" indicates GA with one or more small spots of increased autofluorescence directly adjacent to its margin. One of 3 pairs of trained, masked graders independently and manually graded FAF patterns. | Number | eyes | eyes |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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). | Posted | Mean | Standard Deviation | mm/year | 0 months, 18 months | eyes | eyes |
|
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). | Posted | Mean | Standard Error | letters correctly read | 0 months, 18 months |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). | Posted | Mean | Standard Error | letters correctly read | 0 months, 18 months |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Posted | Count of Participants | Participants | 0 months, 6 months, 12 months, 18 months, 24 months |
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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):
Rare side effects of metformin (severe):
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. | Posted | Count of Participants | Participants | 0 months, 6 months, 12 months, 18 months, 24 months |
|
|
24 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 0 | 32 | 5 | 32 | 16 | 32 |
| EG001 | Observation | 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. | 2 | 34 | 3 | 34 | 4 | 34 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
| ||
| Constipation | Gastrointestinal disorders | Systematic Assessment |
| ||
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
| ||
| Ascending thoracic aortic aneurysm without rupture | Vascular disorders | Systematic Assessment |
| ||
| Deep vein thrombosis | Vascular disorders | Systematic Assessment |
| ||
| Gastroenteritis | Gastrointestinal disorders | Systematic Assessment |
| ||
| Infectious or inflammatory pancolitis | Gastrointestinal disorders | Systematic Assessment |
| ||
| Small bowel obstruction | Gastrointestinal disorders | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal discomfort | Gastrointestinal disorders | Systematic Assessment |
| ||
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
| ||
| Chest pain | General disorders | Systematic Assessment |
| ||
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
| ||
| Fatigue | General disorders | Systematic Assessment |
| ||
| Fall due to dizziness | General disorders | Systematic Assessment |
| ||
| Nausea | General disorders | Systematic Assessment |
| ||
| Rash on back and abdomen | Skin and subcutaneous tissue disorders | Systematic Assessment |
| ||
| Leg pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Dry eyes | Eye disorders | Systematic Assessment |
| ||
| Development of choroidal neovascularization | Eye disorders | Systematic Assessment |
| ||
| Development of subretinal hemorrhage | Eye disorders | Systematic Assessment |
| ||
| Common cold | General disorders | Systematic Assessment |
| ||
| Cough | General disorders | Systematic Assessment |
| ||
| Subjective complaint of elevated blood pressure | General disorders | Systematic Assessment |
| ||
| Constipation | Gastrointestinal disorders | Systematic Assessment |
| ||
| Irritability and anxiety | Psychiatric disorders | Systematic Assessment |
| ||
| Heartburn | General disorders | Systematic Assessment |
| ||
| Increased lipase | Gastrointestinal disorders | Systematic Assessment |
| ||
| Hepatic fibrosis of unknown origin | Hepatobiliary disorders | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jay Stewart | University of California, San Francisco | 628-206-3123 | jay.stewart@ucsf.edu |
| Apr 12, 2023 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D008268 | Macular Degeneration |
| D057092 | Geographic Atrophy |
| ID | Term |
|---|---|
| D012162 | Retinal Degeneration |
| D012164 | Retinal Diseases |
| D005128 | Eye Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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| Male |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
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| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
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| Participants |
|
|
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| Participants |
|
|
| Counts |
|---|
| Participants |
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