Clinical trial NCT02684578
Conditions: Age-Related Macular Degeneration Macular Degeneration, Age-Related Dry Macular Degeneration Geographic Atrophy
Sponsor: University of California, San Francisco
Start date: 2016-04-01; Completion date: 2022-10-01
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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 2: 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.
Interventions: intervention 1: Metformin
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
METFORMIN CLINICAL TRIAL: 
 
METformin administration FOR the 
MINimization of geographic atrophy 
progression in patients with dry Age-Related 
Macular Degeneration (NCT02684578) 
 
PROTOCOL 
 
 
Version 1.20 
06 June 2019


2 
 
 
 
TABLE OF CONTENTS 
 
CHAPTER 1: BACKGROUND AND SUMMARY 
1.1 1 Background 
1.1.1 Why is this study important? 
1.1.2 Pathophysiology of Geographic Atrophy in AMD 
1.1.3 Current Standard of Care for Patients with GA 
1.1.4 Metformin Overview 
1.2 2 Justification: Mechanisms of action by which metformin may decrease progression 
of Geographic Atrophy in Patients with dry AMD 
1.3 3 Study Design Overview 
1.4 4 Study Aims 
 
CHAPTER 2: SUBJECT ENROLLMENT 
2.1 Eligibility Assessment 
2.1.1 Inclusion Criteria 
2.1.2 Exclusion Criteria 
2.2 Informed Consent 
2.3 Procedures at the Enrollment Visit 
 
CHAPTER 3: TREATMENT AND FOLLOW-UP 
3.1 Treatment Group 
3.2 Observation Group 
3.3 Compliance 
3.4 Follow-up visit Schedule 
3.5 Follow-up visit Testing Procedures 
 
CHAPTER 4: MANAGING RISK 
4.1 Safety: The Use of Metformin in Non-diabetic Patients 
4.2 Risks to Study Subjects (lactic acidosis, GI discomfort [insert other metformin risks], loss of 
confidentiality, risks of examination procedures, risk in delay of use if other treatment comes out 
during study time period) 
4.2.1 Withdrawal of Study Subjects 
4.2.2 Reporting Adverse Events 
4.2.3 Discontinuation of Study 
4.3 Data Safety Management Board 
4.4 Study Costs 
 
CHAPTER 5: SAMPLE SIZE APPROXIMATION AND STATISTICAL ANALYSIS 
5.1 Sample Size Calculation 
5.2 Primary Analysis 
5.3 Secondary Analyses 
CHAPTER 6: REFERENCES 


3 
 
 
 
CHAPTER 1: Background & Summary 
 
1.1 Background: 
 
1.1.1 Why is this study important? 
Age-related macular degeneration is currently the leading cause of severe vision 
loss in people over the age of 50. In the United States, AMD affects at least 11 million 
individuals and 1.2 million individuals are legally blind as a result (1). AMD is classified 
into two types: “wet” AMD, characterized by choroidal neovascularization, and “dry” 
AMD, characterized by the presence of drusen under the macula and eventually in later 
stages, by geographic atrophy of retinal pigment epithelial (RPE) cells associated with 
subsequent loss of overlying photoreceptors. While there are currently a few treatment 
options shown to decrease the progression of the wet form of AMD, there are no proven 
medical treatments to reverse or slow the progression of dry AMD. While wet AMD 
generally results in much more rapid loss of central vision, only about 10% of AMD 
cases take this form, and dry AMD always precedes the neovascular form. The number of 
people in the US with AMD is estimated to double by the year 2050, as the population 
ages (2). This condition is not only devastating to patients facing blindness, but it is also a 
major economic burden with the global cost of visual impairment due to AMD estimated 
to be $343 billion (3). 
 
1.1.2 Clinical Observations and Current Standard of Care for Patients with GA 
Geographic atrophy in patients with AMD has discrete characteristics and is thus 
diagnosed readily. In areas of atrophy, decreased retinal thickness is apparent on optical 
coherence tomography. GA also appears in fundus photography, as the areas of thinning 
retina appear lighter that the surrounding unaffected retina, and choroidal vessels may be 
more easily visualized in these thin atrophic areas. Moreover, fundus autofluorescence 
can be a valuable tool used to confirm the diagnosis of GA and track GA progression, as 
atrophic areas appear hypofluorescent (4). 
In terms of patient experience, GA generally initially arises in the area 
surrounding the fovea, sparing central vision (5). This manifests itself in the form of 
impaired vision in dim light, dark adaptation difficulty, less contrast sensitivity, and 
worsening near vision usually apparent during reading. As the disease process evolves 
with enlargement of GA, the fovea may not be spared in the later stages, and atrophy at 
this point leads to loss of central vision (4). 
The current standard of care for patients with GA simply involves observation and 
close monitoring by retina specialists, as there is no proven intervention to stop or slow 
the progression of GA. Follow-up of these patients ensures that should patients develop 
neovascularization, the correct course of action is taken, since this form of AMD can be 
treated via intravitreal anti-VEGF treatments, photodynamic therapy, or photocoagulation 
(6). Actual management of dry AMD is limited to modification in lifestyle including diet 
and exercise regimens, cessation of smoking, vitamin supplements and low-vision 
rehabilitation in the later stages (7). 


4 
 
1.1.3 Pathophysiology of Geographic Atrophy in AMD 
Though the pathophysiology of GA in AMD is still not fully understood, a 
growing body of evidence exists to support the role of chronic inflammation potentially 
caused by metabolic product accumulation in the extracellular space between the RPE 
cells and Bruch’s membrane (7). Thus, it is hypothesized that the activation of the 
complement system via increase in oxidative stress may play a significant role in the 
etiology of this disease. 
This theory is supported by several findings, including the discovery of 
complement system proteins within the drusen of patients with AMD. Moreover, genes 
involved in the complement activation cascade, including CFH, CFHR1, CFHR3, CFB, 
C2, and C3 have been implicated in AMD pathogenesis in several genetic studies. Most 
sequence variants of these complement-pathway associated genes result in increased 
susceptibility to AMD development, as unlike the unchanged genes, these gene variants 
fail to inhibit the complement pathway. On the other hand, CFHR1 and CFHR3 variants 
were found to be protective. Despite sequence similarity to CFR, these genes appear to 
act downstream of C3, the target of CFH’s inhibition (8). Further genetic support for this 
pathophysiology is provided by a study showing that in populations of European descent, 
polymorphisms in the Complement factor H locus and the Complement factor 
B/Complement component 2 locus may be responsible for up to 75% of AMD cases (9). 
 
1.1.4 Metformin Overview 
Metformin is a potent antihyperglycemic drug that is recommended by the 
American Diabetes Association as the first line of oral defense in the treatment of type 2 
diabetes (10). This drug, belonging to the biguanide class, was first described in scientific 
literature in 1921, and became available for human use in the United Kingdom in 1958 
(11, 12). It received FDA approval in the United States in 1994. 
The effect of metformin is primarily the acute decrease in hepatic glucose and 
secondary improvement of glucose uptake. Unlike most treatments for T2DM, metformin 
has a very low risk for hypoglycemia. It has relatively mild side-effects, with the most 
common being gastrointestinal distress. GI side effects are dose-dependent, and can 
usually be overcome via stepwise dose increases (13). The most serious side effect is 
lactic acidosis, and while this can be life-threatening it is uncommon, with Brown et al in 
1998 reporting an observed rate of 9.7 cases in >41,000 person-years of experience (14). 
While the mechanisms of action by which metformin works to treat patients with T2DM 
are not fully understood, its inhibition of mitochondrial complex I and the resulting 
activation of AMPK is thought to play a major role in the decrease of hepatic glucose 
production (15). 
 
1.2 Justification: Mechanisms of action by which metformin may decrease progression of 
Drusen accumulation and Geographic Atrophy in Patients with dry AMD 
 
There are multiple potential mechanisms by which metformin could act to reduce the progression 
of drusen accumulation and geographic atrophy in patients with AMD. These include but are not 
limited to some of the following, many of which are intertwined or related. Due to metformin 
affecting several different pathways and processes, it likely utilizes varying mechanisms of 
action to produce beneficial phenotypes. 


5 
 
 
 
Reduction of Oxidative Stress 
• There are multiple studies supporting the role of oxidative stress in AMD and its 
development (16) 
• Several trials involving antioxidants, vitamins, and mineral supplements can potentially 
slow AMD progression (17, 18, 19), although long term (after 10 years) this effect of 
slowed progression was only seen in NV AMD, but not central GA 
• Metformin is used to reduce oxidative stress, and specifically it has been shown to reduce 
the levels of oxidative stress markers in diabetics compared to baseline values and 
compared to control subjects who underwent lifestyle modifications without medication 
(20) 
Reduction of Inflammation 
• Drusen, deposits present beneath the retinal pigment epithelium in AMD, contain a 
variety of pro-inflammatory proteins, including fibrinogen, vitronectin, and complement 
components, as well as C-Reactive Protein (CRP). 
• High levels of C reactive protein have been associated with a greater future risk of AMD 
(21), and higher levels are also associated with AMD progression (22, 23) 
• CRP is a mediator of complement action Genentech is studying lampalizumab for 
AMD which affects complement pathway (Phase 3 Clinical Trial: 
https://www.clinicaltrials.gov/ct2/show/NCT02247479) 
• Metformin has been shown to decrease CRP levels in women with PCOS (off label use of 
the drug), (24); it also decreased CRP in patients with T2D (25, 26) 
mTOR Pathway 
• The mTOR pathway is potentially activated in AMD. Evidence for this theory includes 
one study in which mitochondrial DNA were selectively ablated in mice RPE cells, 
resulting in RPE morphological changes similar to those seen in AMD. The most 
prominent early RPE changes were hypertrophy and dedifferentiation, which coincided 
with activation of the mTOR pathway in OXPHOS-deficient RPE cells (27) 
• Metformin inhibits mTOR. One proposed mechanism of action: it accumulates in the 
mitochondria where it inhibits complex 1. This decreases ATP production and conversely 
increases AMP levels. High AMP levels activate AMPK, which then inhibits the mTOR 
signaling pathway. Alternatively, some think that metformin may activate AMPK directly 
at this point in the pathway (28) 
Mitochondrial function 
• In AMD, damaged mitochondria result in a deficit in RPE oxidative phosphorylation, 
eventually leading to photoreceptor degeneration and RPE morphological changes (27). 
Moreover, damaged mitochondrial DNA has been linked to AMD; thus mitochondria 
might be a good target for AMD treatment (29, 30) 


6 
 
• Metformin decreases mitochondrial respiration (31). Thus it is possible that metformin 
could decrease the oxidative stress that causes the damage to mtDNA in patients with 
AMD. 
Potential for Weight Loss 
• Obesity/Higher BMI is a risk factor for AMD (32) 
• Metformin has been shown to reduce weight in non-diabetic obese patients (both insulin 
sensitive and insulin resistant) over a period of 6 months (33) 
• Metformin has been shown to reduce weight in non-diabetic adult and children taking 
antipsychotic meds (34) 
• Metformin’s use for the sole purpose of weight reduction is still controversial based upon 
insufficient evidence supporting its efficacy (35) 
 
1.3 Study Design Overview 
 
Major Eligibility Criteria: See Chapter 2 
• People aged 55 or older with AMD with soft drusen, at least one of which is greater than 
or equal to 63 microns in diameter, and/or with geographic atrophy in one or both eyes 
 
Study Groups: 
Subjects will be randomly assigned (1:1) to either: 
• Metformin Treatment Group: this group will take Metformin daily throughout the 
duration of the 18 month interventional study period (see detailed dosage information in 
Chapter 3). In addition to taking this drug, this group will maintain the standard of care 
exam schedule for patients with dry AMD, including follow-up exams on a 6 month 
basis. This group will have an eGFR test at baseline and at one year to monitor kidney 
function. 
• Observation Group: the subjects assigned to this group will follow standard of care 
protocol for dry AMD, which simply consists of monitoring the progression on a 6 month 
basis. 
 
Sample Size: See details in Chapter 5 
• 186 subjects from all study sites 
 
Visit Schedule (timed from randomization) 
• Enrollment exam/ 0 months 
• 1 week phone call—to ensure that treatment group has picked up prescription and 
subjects have begun taking metformin 
• 6 month follow-up exam 
• 12 month follow-up exam 
• 18 month follow-up 
• 24 month follow-up/ Final exam 
 
1.4 Study Aims 
• To determine whether oral Metformin HCl is an effective treatment for slowing the 


7 
 
progression of drusen accumulation or geographic atrophy in patients with dry Age-
related Macular Degeneration 


8 
 
 
CHAPTER 2: SUBJECT ENROLLMENT 
 
2.1 Eligibility Assessment 
 
2.1.1 Inclusion Criteria 
• Subject must be >/= 55 years of age 
• Subject must have evidence of dry AMD, defined by the characteristic presence of 
drusen and/or pigmentary changes with or without geographic atrophy. 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. 
• 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 
 
2.1.2 Exclusion Criteria 
• Subjects with a baseline size of GA > 17.5mm2 (7.0 Macular Photocoagulation Study 
Disc Areas).  
• 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 
-eGFR levels below 45 
• Subjects with moderate to severe heart failure (Class III or IV, New York Heart 
Association Functional Classifications) 
• Subjects with Child’s class C cirrhosis 
• Subjects who are: pregnant women, adults who cannot consent for themselves, and those 
who use alcohol in excess 
o Excess alcohol use is defined by binge drinking (pattern of drinking that brings 
blood alcohol concentration levels to 0.08 g/dL) on 5 or more days in the past 
month 
• 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): 
a. Non-proliferative diabetic retinopathy involving 10 or more hemorrhages or 


9 
 
microaneurysms, or active proliferative diabetic retinopathy 
b. Branch or central retinal vein or artery occlusion 
c. Macular hole 
d. Pathologic myopia 
e. Uveitis 
f. Pseudovitelliform maculopathy 
g. Intraoperative surgery within the last 90 days prior to study eye enrollment 
 
2.2 Informed Consent 
During a standard ophthalmic exam in clinic, a study investigator will determine if a patient 
meets the eligibility criteria for this study. S/he will then explain this study to the patient and if 
the patient would like to proceed with participation in this clinical trial, the investigator will 
obtain written consent at that visit. If the patient requires additional time to consider participation 
and discuss the study with others, this will be accommodated for, and the patient can be enrolled 
at his or her next exam. 
 
2.3 Procedures at the Enrollment Visit 
Prior to subject enrollment, an eGFR test must be read to confirm that levels do not indicate 
compromised kidney function. This test will done to confirm eligibility of the patient, but will be 
repeated at the 12 month study visit in order to maintain proper kidney functioning if randomized 
to the treatment group. 
After consent and HIPAA forms have been signed, the patient will then be eligible for 
randomization. It is important for study investigators to emphasize prior to consent that every 
patient is randomly selected to be in one of two study groups: treatment or observation. The 
patient will be randomized at the time of enrollment, and the study population will be 
randomized in a 1:1 ratio. If the study subject is randomized to the treatment group, s/he will 
receive a prescription for Metformin from the study investigator at this visit or after the 
investigator receives results from the blood test if recent creatinine levels are not available in the 
patient’s chart. If the patient consents to be a part of the optional genetic research, a 0.6 tsp blood 
draw will be performed to measure baseline genetics before study procedures begin. 
 
CHAPTER 3: TREATMENT AND FOLLOW-UP 
 
3.1 Treatment Group 
The treatment group is the experimental group that will be taking Metformin twice daily for 
18 months. Subjects in this group will begin taking Metformin at a dose of 500 mg per day for 
the first week of the study, 500 mg twice daily for the second week of the study and finally they 
will increase the dosage to 1000 mg twice daily (1000 mg taken in the morning and 1000 mg 
taken in the evening). This stepwise increase in dose has been shown to mitigate gastrointestinal 
distress or discomfort, a side effect of metformin that usually resolves on its own after the first 
few weeks of taking the drug. The final dose of 2000 mg per day will not change until the 18th 
month of study, unless GI side effects become intolerable to any individual study subjects. In 
the event that this occurs, dosage will be adjusted such that the subject’s side-effects subside. At 
18 months, subjects will stop taking Metformin.


10 
 
3.2 Observation Group 
One half of the study subjects will be assigned to the observation group. This group will 
receive no treatment for their AMD, and must not receive intraocular medication during the 18 
month interventional study period. Because there are currently no treatment options for patients 
with dry AMD and thus standard of care is to observe the progression of these patients, 
randomization of study subjects to the observation group is ethical since no care is being 
withheld. If a patient in this study group develops neovascularization for which their 
ophthalmologist advises treatment, the subject will exit the study in order to ensure that his or 
her care is not compromised. 
 
3.3 Compliance 
Study subjects will receive a call from study personnel 1 week post-enrollment to ensure that 
s/he has obtained their metformin from the pharmacy if s/he is in the treatment group and to 
encourage compliance. As a part of standard of care, clinic staff will also call patients prior to 
each clinic visit to remind them of their upcoming exams. 
 
3.4 Follow-up visit Schedule 
Study subjects will have a total of 5 ophthalmic exams during which information and images are 
collected and used in this study, at time point 0 months (enrollment), 6 months, 12 months, 18 
months, and 24 months. The interventional portion of the study will last 18 months. All subjects in 
the treatment group will stop metformin use at 18 months. All study subjects will then come for a 
final visit at 24 months where normal study follow-up testing will be completed. These are timed 
specifically such that they are a part of each patient’s standard of care schedule. Thus, no extra 
visits are required for subjects enrolling in this study. 
 
3.5 Follow-up visit Testing Procedures 
Each exam will include standard ophthalmic work-up, including the evaluation of visual acuity 
using ETDRS and low luminance testing using a neutral density filter. ETDRS testing will be 
optional for those subjects presenting without geographic atrophy smaller than 1.25 mm2 (0.5 
Macular Photocoagulation Study disc areas) in size. Furthermore, at each exam fundus 
autofluorescence imaging, optical coherence tomography (OCT), and fundus photography will 
be done to monitor these patients’ AMD as a part of standard of care. These are the same 
images that will be used to assess change in area of GA and the volume of drusen. In addition, 
during the first study exam (month zero) and month 18 exam, each patient will be asked to 
complete the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25), a 25 
question survey of visual function and quality of life developed by the NEI and the Low 
Luminance Questionnaire, a 32 question survey used for assessing self-reported vision problems 
under low vision and at night. To confirm that a study subject’s kidney is functioning properly 
and to remain in accordance with FDA regulations, an eGFR test will be done at enrollment and 
at 1 year (month 12). 
 
If site resources allow and the patient consents, a blood test will be done at the enrollment visit 
and at month 18. 0.6 tsp of blood will be drawn from the patient in order to perform un-biased 
next generation sequencing on the specimen in order to identify any patterns in gene activation 
among different groups of patients so that novel disease mechanisms and/or therapeutic 
avenues can be identified and further explored. 
 


11 
 
3.6 Specimen Banking Procedures 
In the optional section of the informed consent form, the subject will have the opportunity to 
consent to two additional blood tests, one at the enrollment visit and the other at the 18 month 
visit. The specimens will be banked at 400 Parnassus Avenue San Francisco, CA 94143. The 
specimens will be stored indefinitely unless instructed to destroy the specimens by the subject 
in writing to 400 Parnassus. The anticipated future research is concretely undecided; however, it 
will be a genetic analysis of the patients with the hopes of identifying novel disease mechanisms 
that will translate to therapeutic avenues. The specimens will be stored with a unique study ID 
that contains no identifiers tracing back to the subject. The freezer is stored in a locked room 
with limited key access. The bank is unfunded therefore its longevity is not ensured. Should the 
PI leave the institution the specimens from this study will be destroyed immediately thereafter. 


12 
 
 
CHAPTER 4: MANAGING RISK 
 
4.1 Safety: The Use of Metformin in Non-diabetic Patients 
In the presence of normal renal function, there are no differences between single- or 
multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal 
subjects nor is there any accumulation of metformin in either group at usual clinical doses (36). 
Additionally, although the drug is indicated for use in diabetics to lower blood sugar, several 
studies have been conducted involving the use of Metformin in non-diabetic patients. It has been 
safely studied with few adverse effects in non-diabetic populations to assess its effect on weight 
loss, cancer treatment, polycystic ovary syndrome, and more (37, 38). In fact, metformin is now 
recommended by the American Diabetes Association for prevention of diabetes in pre-diabetic 
populations (39). Finally, in a study done by Bannister et al (2014), type 2 diabetics on 
metformin monotherapy had longer survival than matched controls with no DM2, suggesting the 
potential for metformin to convey benefits in both populations (40). 
The greatest risk for patients taking metformin is the extremely rare but serious side- 
effect of lactic acidosis. Most reported cases of lactic acidosis occur in patients with 
compromised renal function. To avoid this risk, we have strict eligibility criteria that disqualify 
patients who have moderate to severe kidney disease from participating in this study. This is 
characterized by stage 3 or higher chronic kidney disease. In fact, these criteria are very cautious 
given recent data suggesting that the contraindication levels should begin at stage 4 and higher 
CKD (41, 42). 
 
4.2 Risks to Study Subjects 
As in all research studies, subjects are at risk for loss of confidentiality. Data to be 
collected in this study are unlikely to affect reputation, insurability, etc., if they were lost or 
disclosed. However, standard consequences of loss of privacy, due to patient identifiers being 
revealed, would result if study data were no longer private. The study investigators and personnel 
take many measures to ensure that subjects’ personal health information remains confidential. 
This includes storing and transmitting data on secure UCSF servers. Data transmitted to the 
coordinating center from outside sites will be done in a secure manner, via the use of password 
protected files. For data that is analyzed outside of locked clinic/office areas, all patients will be 
identified with a unique identifier, not by name or medical record. 
 
Study subjects randomized to the treatment group face additional risks associated with taking 
metformin, including the following: 
 
Common side effects of metformin (not severe): 
• 
Diarrhea 
• 
Nausea 


13 
 
• 
Gas 
• 
Head Pain 
• 
Stomach Cramps 
• 
Swelling of the Abdomen 
• 
Taste Problems 
• 
Vomiting 
 
Infrequent side effects of metformin (not severe): 
• 
Chills 
• 
Dizzy 
• 
Excessive Sweating 
• 
Fingernail and/or Toenail Disease 
• 
Flu-Like Symptoms 
• 
Heart Throbbing or Pounding 
• 
Incomplete or Infrequent Bowel Movements 
• 
Indigestion 
• 
Inflammation of the Nose 
• 
Muscle Pain 
• 
Rash 
• 
Temporary Redness of Face and Neck 
• 
Inadequate Vitamin B12 
 
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) 
o Intravascular administration of iodinated contrast media to patients who are taking 
metformin can result in lactic acidosis, only if the contrast medium causes renal 
failure and the patient continues to take metformin in the presence of renal 
failure.44 
• 
Low Blood Sugar 
• 
Megaloblastic Anemia 
• 
Reaction due to an Allergy 
• 
Drug-drug interactions with other cationic drugs such as: 
o Procainamid 
o Digozin 
o Quinidine 
o Trimethoprim 
o Vancomycin 
o Cimetidine45 
 
LABEL WARNING: 
• Lactic Acidosis is a rare, but serious, metabolic complication that can occur due to 
metformin accumulation during treatment with GLUCOPHAGE or GLUCOPHAGE XR; 
when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur 


14 
 
in association with a number of pathophysiologic conditions, including diabetes mellitus, 
and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is 
characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, 
electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate 
ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma 
levels >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients 
receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient- 
years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 
patient-years exposure to metformin in clinical trials, there were no reports of lactic 
acidosis. Reported cases have occurred primarily in diabetic patients with significant 
renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often 
in the setting of multiple concomitant medical/surgical problems and multiple 
concomitant medications. Patients with congestive heart failure requiring pharmacologic 
management, in particular those with unstable or acute congestive heart failure who are at 
risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of 
lactic acidosis increases with the degree of renal dysfunction and the patient’s age. (36) 
 
4.2.1 Withdrawal of Study Subjects 
Study subjects have the right to withdraw from this study for any reason, at any time. If a 
subject indicates that s/he wants to withdraw from the study, the investigator personally should 
attempt to speak with them to determine the reason. When a subject withdraws before 
completing the study, the reason for withdrawal is to be documented in the CRF and in the 
source document. 
 
In addition, the investigators will discontinue patients from the study treatment or the 
study or both in the following circumstances: 
• The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication. In this case, 
discontinuation from the study occurs prior to introduction of the new agent. 
• The investigator decides that the patient should be withdrawn from the study. If a SAE or 
a clinically significant laboratory value is the basis for this decision, the investigator will 
discontinue the study therapy and take appropriate measures. The investigator must 
immediately notify the study sponsor. 
• The patient or attending physician requests withdrawal of the patient from the study. 
• The investigator or the study sponsor stops the study or stops the patient’s participation in 
the study for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and good clinical practice (GCP). 
• The study therapies have shown unacceptable toxicity, such as lack of recovery of more 
than 4 weeks since last study treatment dose. 
• The patient becomes pregnant or fails to use adequate birth control (for women with 
reproductive potential). 
• The patient is noncompliant with study procedures. 
 
4.2.2 Reporting Adverse Events 
During the study, site personnel will note any change in the condition(s) and the 
occurrence and nature of any adverse events. For 30 days after the last dose of oral metformin is 


14 
 
taken patients should be closely followed for study treatment-related adverse events in order to 
detect delayed toxicity.  If treatment-related toxicity is present beyond 30 days post last 
treatment, patients must be followed every 30 days until the toxicity resolves, another therapy is 
initiated, or death. 
 
If a patient experiences an adverse event after the ICD is signed but the patient never 
receives study specific metformin treatment the event will ONLY be reported if the investigator 
believes that the event may have been caused by a protocol procedure. In addition, all AEs 
occurring after the patient receives the first study specific metformin treatment must be reported 
to the UCSF CHR via the CRF. 
 
The Investigators will report to the CHR their assessment of the potential relatedness of 
each AE to protocol procedure, studied disease state, study drug via the CRF. For each adverse 
event recorded on the Adverse Event CRF, the investigator will make an assessment of 
seriousness, severity, and causality. For patients receiving combination therapy, causality will be 
assessed individually for each protocol-mandated therapy. 
 
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product/therapy, regardless of causal attribution. An adverse event can therefore be any of the 
following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a therapeutic treatment, 
whether or not considered related to the treatment 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
• Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment 
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to the study DSMB and UCSF CHR via the CRF the circumstances 
and data leading to any such dosage reduction or discontinuation of treatment. 
 
Events leading to the clinical outcome of death from progressive disease will be included as part 
of the safety and efficacy analyses for this study, and will not be recorded as adverse events 
unless the investigator believes that the event may have been caused by the study treatment. 
 
Serious adverse event (SAE) collection begins after the patient has signed informed consent and 
has received study treatment. If a patient experiences an SAE after signing informed consent, but 
prior to receiving study treatment, the event will NOT be collected unless the investigator feels 
the event may have been caused by a protocol procedure. 
 
Study site personnel must alert the CHR of any SAE within 24 hours of investigator awareness 
of the event. Alerts issued via telephone are to be immediately followed with official notification 
on study-specific SAE forms. 


15 
 
 
An SAE is any adverse event from this study that results in one of the following outcomes: 
• death (excluding death due to progression of study disease, unless related to study drug) 
• initial or prolonged inpatient hospitalization 
• a life-threatening experience (that is, immediate risk of dying) 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• considered significant by the investigator for any other reason. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
Serious adverse events (SAEs) occurring after a patient has taken the last dose of study drug will 
be collected for 30 days after the last dose of study drug, regardless of the investigator’s opinion 
of causation. Thereafter, SAEs are not required to be reported unless the investigator feels the 
events were related to either study drug, or drug delivery system, or a protocol procedure. 
 
Any SAE occurring prior to enrollment that the investigator believes may have been caused by a 
protocol procedure must be reported to the study sponsor or its designee within 24 hours of 
investigator awareness of the event and recorded on the CRF. 
 
Study-specific clinical outcomes of death from progressive disease should be reported as SAEs 
only if the investigator deems them related to use of the study treatment.  Hospitalizations for the 
purpose of study-specific interventions are also not considered SAEs or AEs. 
 
IMMEDIATE REPORTING REQUIREMENTS 
From Investigator to CHR: 
Certain events require immediate reporting to allow the CHR to take appropriate measures to 
address potential new risks in a clinical trial. The investigator must report such events to the 
CHR immediately; under no circumstances should reporting take place more than 24 hours after 
the investigator learns of the event. The following is a list of events that the investigator must 
report to the CHR within 24 hours after learning of the event, regardless of relationship to study 
drug: 
• Serious adverse events 
• Non-serious adverse events of special interest 
• Pregnancies 
The investigator must report new significant follow-up information for these events to the CHR 
immediately (i.e., no more than 24 hours after becoming aware of the information). New 
significant information includes the following: 
• New signs or symptoms or a change in the diagnosis 
• Significant new diagnostic test results 
• Change in causality based on new information 
• Change in the event’s outcome, including recovery 
• Additional narrative information on the clinical course of the event 


16 
 
 
 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
 
Investigator Follow-Up: 
The investigator should follow all unresolved treatment-related adverse event until the event has 
resolved to baseline grade or better, the event is assessed as stable by the investigator, new 
therapy is initiated, the patient is lost to follow-up, or the patient withdraws consent. Every effort 
should be made to follow all serious adverse events considered to be linked to trial-related 
procedures until a final outcome can be reported. 
 
During the study period, resolution of adverse events (with dates) should be documented on the 
Adverse Event CRF and in the patient’s medical record to facilitate source data verification 
(SDV). If, after follow- up, return to baseline status or stabilization cannot be established, an 
explanation should be recorded on the Adverse Event CRF. 
 
INTERIM ANALYSIS 
Interim analyses of efficacy are not planned for this study. 
 
DOSE MODIFICATIONS 
Doses of metformin will remain at 2000 mg/day unless minor side-effects, namely GI discomfort 
or distress, become intolerable to the patient. In the event that this is the case, the dose will be 
decreased to the point at which these side-effects subside. 
 
4.2.3 Discontinuation of Study 
The study may be discontinued by the study PI or the Data and Safety Monitoring Board 
prior to the preplanned completion of enrollment and follow-up for all subjects in the 
event of unforeseen adverse outcomes affecting the safety of study subjects. 
 
4.3 Data Safety Management Board 
Because this study is defined as “greater than minimal risk,” IRB protocols require the 
establishment of a Data Safety Management Board (DSMB). This board is responsible for 
oversight of this study. 
Composition: 
Jeremy Keenan, MD 
jeremy.keenan@ucsf.edu 
Associate Professor of Ophthalmology at UCSF and the Proctor Foundation, specializing 
in cornea and uveitis 
Director of International Programs at the Proctor Foundation 
 
Phoebe Lin, MD, PhD 
linp@ohsu.edu 
Ophthalmologist specializing in vitreoretinal disease and surgery and uveitis and ocular 
inflammation 
Assistant Professor of Ophthalmology, Casey Eye Institute of the Oregon Health and 
Sciences University 


17 
 
Office: 503-494-0007; Fax: 503-494-7233; Cell: 312-404-8816 
 
Steven Yeh, MD 
steven.yeh@emory.edu 
Louise M. Simpson Professor of Ophthalmology at Emory Eye Center of Emory 
University 
Section of Vitreoretinal Surgery & Diseases 
Director, Section of Uveitis and Vasculitis 
 
Independence: The DSMB members will not participate in the study as investigators, 
nor will they have conflicts of interest regarding the study or the study drug being tested. 
Data: The DSMB will review the medical charts of study subjects to ensure that there 
has been no addition of medical conditions since enrollment that would deem subjects 
ineligible for participation. This includes diagnosis or progression of chronic kidney 
disease with creatinine levels ≥1.5 mg/dL for males and ≥1.4 mg/dL for females, Child’s 
Class C cirrhosis, or New York Heart Association’s Class III or IV Heart Failure. If any 
ineligibility factors are met, subjects will be withdrawn from the study to protect their 
health. Furthermore, if a subject develops neovascularization requiring intervention with 
intravitreal drugs as evident from fundus photos taken at follow-up exams, the subject 
will be withdrawn from the study to avoid confounding factors that may affect 
progression of Geographic Atrophy. This will be monitored by study investigators but 
also confirmed by the DSMB. 
Frequency of Review: The DSMB will formally meet twice during the course of this 
study, but will be continuously monitoring for adverse events throughout the duration of 
the study. These meetings will occur when we have hit 25% of our target accrual number, 
and then again when 75% accrual has been reached. 
Authority: The DSMB will have the authority to recommend changes in the study on the 
level of individual patients and in regards to the study overall. They also hold the power 
to advise discontinuation of the study in the event that patient safety is compromised via 
study participation. 
 
 
4.4 Study Costs 
This is an unfunded study. As such, study subjects or their insurance carriers assume the 
responsibility of paying for a prescription for Metformin HCl for the entirety of the study 
duration (18 months), should the subject be randomized into the treatment group. All other 
examinations and procedures during which information and images are captured and analyzed 
for this study are standard of care practices. As such, the patient or patient’s insurance carrier 
would be covering the cost of these items whether or not s/he is enrolled in this study. 
 
CHAPTER 5: SAMPLE SIZE APPROXIMATION AND STATISTICAL ANALYSIS 
 
5.1 Sample Size Calculation 
According to Yehoshua et al (2014) the changes in mean square root area of GA independent of 
starting size over 26 weeks were 0.19 ± 0.12 and 0.18 ± 0.15 for treatment and control groups 
respectively (43). Over 52 weeks these were 0.37 ± 0.22 and 0.37 ± 0.21 for treatment and 
control groups respectively. Extrapolating from the 6- and 12-month data for the control group, 


18 
 
at 18 months one would expect the progression of change in mean square root area to be 0.55 (±0.3 
SD). Given this mean and standard deviation, 90 participants with GA (45 per group) would 
provide 80% power to determine effect size of 33% (ie, 0.55 vs 0.37), assuming a two-sided 
alpha of 0.05. To account for an estimated 10% drop-out rate, we have rounded this number for 
patients with GA greater than 1.25 mm2 (0.5 Macular Photocoagulation Study disc areas) to 
N=100, with 50 subjects in each group. We include in our total study group an additional 86 
subjects without GA greater than 1.25 mm2 (0.5 Macular Photocoagulation Study disc areas); 
this is based on the following rationale:  we assume progression in the composite dry AMD 
endpoint (described below) of 72% over 18 months, based on a rate of 60% progression over 1 
year (47) , which would correspond to 72% over 18 months (calculation:  40% of patients do not 
progress in the first year; then 60% of those patients will progress during year 2 (and thus 30% 
during months 12 to 18), for an 18-month progression rate of:  60% + (40% * 30%) = 72%). We 
then assume that treatment reduces progression to 40% over 18 months instead of 72% for 
controls. With power 80% power and alpha 0.05, we would need 39 patients per group (Stata 
code:  power logrank .28 .60, power(0.8)). Multiplying by 1.1 to account for 10% loss to follow-
up yields 43 subjects per group, for a total of 86 patients without GA greater than 1.25 mm3.  
  
 
5.2 Primary Outcome Measure 
• For patients with GA greater than 1.25 mm2 (0.5 Macular Photocoagulation Study disc 
areas): 
• 
We will measure the rate of change in area of geographic atrophy as 
determined by masked readers of fundus autoflorescence images. To measure 
this, we will calculate the growth square root of area (mm). Previous studies 
have demonstrated that taking the square root of area measurements before 
calculation of enlargement rates of GA removed the dependence of growth 
on baseline area and resulted in a homogeneous test-retest variance across the 
range of lesion sizes (43). 
• For patients without GA greater than 1.25 mm2 (0.5 Macular Photocoagulation Study 
disc areas): 
• 
We will track a composite outcome measure consisting of prevention of 
drusen growth (drusen volume increase), prevention of GA development, and 
prevention of macular neovascularization development (47) over the course 
of the study period, as determined by masked readers of optical coherence 
tomography images. 
 
5.3 Secondary Analyses 
• Prevention of drusen growth (increase in drusen volume) without progression to 
GA or macular neovascularization (47). 
• Changes in best corrected visual acuity (BCVA) over the study period between the 
treatment and observation groups 
• Comparison of changes in scores over the study period on the National Eye Institute 
Visual Function Questionnaire 25 (NEI-VFQ-25) between treatment and observation 
groups 
• Ocular safety will be assessed at each follow-up exam 
 
 


19 
 
 
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