Efficacy of Dapagliflozin in the Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration
Phase: PHASE2
Conditions: Retinal Degeneration, Retinal Diseases, Eye Diseases, Geographic Atrophy, Pathological Conditions, Anatomical
Sponsor: Washington University School of Medicine

Eﬃcacy of Dapagliﬂozin in the Progression of Geographic 
Atrophy secondary to Age-Related Macular Degenera>on 
 
 
 
 
NCT Number: 
Pending 
 
 
 
 
 
 
 
Date of Document: 
September 8, 2025 

 
 
 
 
 
 
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Efficacy of Dapagliflozin in the Progression of 
Geographic Atrophy secondary to Age-Related 
Macular Degeneration 
 
 
 
Principal Investigator:   
 
 
 
 
 
 
 
 
Version Date/Number: 
 V.10 
 
 
 

 
 
 
 
 
 
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2 
TABLE OF CONTENTS 
A 
INTRODUCTION ............................................................................................................................... 4 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
A2 
PRIMARY HYPOTHESIS ................................................................................................................... 4 
B 
INTRODUCTION ............................................................................................................................... 4 
B1 
PRIOR LITERATURE AND STUDIES .................................................................................................. 4 
B2 
RATIONALE FOR THIS STUDY ......................................................................................................... 5 
C 
STUDY OBJECTIVES........................................................................................................................ 6 
C1 
PRIMARY AIM ................................................................................................................................ 6 
C2 
SECONDARY AIM ........................................................................................................................... 6 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................... 7 
D 
INVESTIGATIONAL AGENT .......................................................................................................... 7 
D1 
PRECLINICAL DATA ....................................................................................................................... 7 
D2 
CLINICAL DATA TO DATE .............................................................................................................. 8 
D3 
DOSE RATIONALE AND RISK/BENEFITS ......................................................................................... 8 
3.a 
Benefit/Risk and Ethical Assessment ........................................................................................ 8 
3.b 
Potential Benefits to Subjects ................................................................................................... 9 
3.c 
Potential Risks to Subjects ........................................................................................................ 9 
E 
STUDY DESIGN ................................................................................................................................11 
E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................11 
E2 
SUBJECT SELECTION AND WITHDRAWAL......................................................................................11 
2.a 
Inclusion Criteria ....................................................................................................................12 
2.b 
Exclusion Criteria ....................................................................................................................12 
2.c 
Ethical Considerations ............................................................................................................12 
2.d 
Subject Recruitment Plans and Consent Process ....................................................................13 
2.e 
Randomization Method and Masking ......................................................................................14 
2.f 
Early Withdrawal of Subjects ..................................................................................................15 
2.g 
When and How to Withdraw Subjects ......................................................................................15 
2.h 
Lost to Follow-Up ....................................................................................................................15 
E3 
STUDY DRUG ................................................................................................................................16 
3.a 
Description ..............................................................................................................................16 
3.b 
Treatment Regimen ..................................................................................................................16 
3.c 
Method for Assigning Subjects to Treatment Groups ..............................................................16 
3.d 
Preparation and Administration of Study Drug .......................................................................16 
3.e 
Subject Compliance Monitoring ..............................................................................................16 
3.f 
Prior and Concomitant Therapy ..............................................................................................16 
3.g 
Blinding of Study Drug ............................................................................................................17 
3.h 
Receiving, Storage, Dispensing and Return ............................................................................17 
F 
STUDY PROCEDURES ....................................................................................................................17 
F1 
SCREENING FOR ELIGIBILITY ........................................................................................................17 
F2 
INFORMED CONSENT.....................................................................................................................17 
F3 
VITAL SIGNS .................................................................................................................................18 
F4 
MEDICAL HISTORY .......................................................................................................................18 
F5 
CONCOMITANT MEDICATIONS (CON MEDS) .................................................................................18 
F6 
PHYSICAL EXAMINATION..............................................................................................................19 
F7 
LOCAL BASIC METABOLIC PANEL (BMP) AND COMPLETE BLOOD COUNT (CBC) .......................19 
F8 
STUDY DRUG INITIAL DISPENSING AND REFILL ............................................................................19 
F9 
DRUG ACCOUNTABILITY ..............................................................................................................19 

 
 
 
 
 
 
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F10 
OPHTHALMOLOGIC EXAM.............................................................................................................20 
F11 
RETINAL EXAM .............................................................................................................................20 
F12 
FUNCTIONAL EYE EXAMS .............................................................................................................20 
F13 
SCHEDULE OF MEASUREMENTS ....................................................................................................20 
F14 
SAFETY AND ADVERSE EVENTS ....................................................................................................21 
14.a 
Definitions of Adverse Events ..................................................................................................21 
14.b 
Classification of Events ...........................................................................................................22 
14.c 
Reporting Procedures ..............................................................................................................23 
14.d 
Adverse Event Reporting Period ..............................................................................................24 
F15 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ..........................................................24 
15.a 
Primary Outcome Endpoint .....................................................................................................24 
15.b 
Secondary Efficacy Endpoints .................................................................................................25 
G 
STATISTICAL PLAN ........................................................................................................................25 
G1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................................25 
G2 
ANALYSIS PLAN............................................................................................................................25 
2.a 
Descriptive Statistics ...............................................................................................................25 
2.b 
Efficacy Analysis ......................................................................................................................25 
2.c 
Subset Analyses........................................................................................................................26 
2.d 
Safety Analysis .........................................................................................................................26 
G3 
STATISTICAL METHODS ................................................................................................................26 
G4 
MISSING OUTCOME DATA ............................................................................................................28 
4.a 
Handling Missing Data in Efficacy Analyses ..........................................................................28 
4.b 
Handling Missing Data in Descriptive Analyses .....................................................................28 
4.c 
Handling Missing or Partially Missing Dates .........................................................................28 
G5 
UNBLINDING PROCEDURES ...........................................................................................................28 
H 
DATA HANDLING AND RECORD KEEPING .............................................................................29 
H1 
CONFIDENTIALITY AND SECURITY ................................................................................................29 
H2 
TRAINING......................................................................................................................................29 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................................................29 
H4 
RECORDS RETENTION ...................................................................................................................29 
I 
STUDY MONITORING, AUDITING, AND INSPECTING ..........................................................29 
I1 
STUDY MONITORING PLAN ...............................................................................................................29 
I2 
AUDITING AND INSPECTING ..............................................................................................................30 
J 
STUDY ADMINISTRATION ...........................................................................................................30 
J1 
FUNDING SOURCE AND CONFLICTS OF INTEREST ..............................................................................30 
K 
REFERENCES ...................................................................................................................................30 
 
 
 
 
 

 
 
 
 
 
 
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A Introduction 
A1 Study Abstract 
Age-related macular degeneration (AMD) is the leading cause of blindness in people 
over 50 years of age in the United States. Dry AMD is a specific form characterized by 
lipoprotein-rich deposits that form under the retina. With disease progression, in some 
patients dry AMD progresses to an atrophic form of disease called geographic atrophy 
(GA). GA is slowly progressive and can lead to vision loss. Recent literature has 
demonstrated that SGLT2 inhibitors (SGLT2i) such as dapagliflozin can target the 
ApoM/S1P pathway, increasing activity under inflammatory conditions. Apolipoprotein M 
is a lipoprotein associated with high-density lipoprotein (HDL). Dysregulated cholesterol 
efflux (CE) and reverse cholesterol transport (RCT) are critical in AMD pathogenesis. 
ApoM may have beneficial effects on dry AMD through its regulation of CE and RCT. 
The current US FDA-approved treatments for GA, a C3 or C5 complement inhibitor, 
have shown only modest efficacy, but they are associated with risks including retinal 
vasculitis, a 2-3-fold increase in chance of conversion wet AMD, and risk of infectious 
endophthalmitis associated with the monthly or bimonthly injections to maintain efficacy. 
Due to these concerns, many physicians, including those at Washington University, are 
currently hesitant to adopt this treatment and are looking for new treatment options to 
slow the progression of GA. The purpose of this study is to assess the effect of oral 
SGLT2i dapagliflozin on the progression of GA. This study will consist of a prospective, 
interventional randomized double-blind placebo-controlled study of patients with 
advanced dry AMD (as evidenced by presence of GA) who will be randomized to either 
dapagliflozin or placebo. Patient demographics and baseline ocular health will be 
recorded, and comprehensive ocular examination coupled with various ophthalmic 
imaging modalities and visual function tests such as ultra-wide field fundoscopic photos, 
fundus autofluorescence, optical coherence tomography (OCT), dark adaptation, and will 
be taken at the initial visit, 6 months, and 1 year. Primary outcome of interest will be 
progression of GA lesion area over the 1-year period, and secondary outcomes include 
structural and functional testing for visual function such as change in drusen volume as 
measured by OCT, dark adaptation, and low luminance BCVA to determine the effect of 
dapagliflozin on the progression of dry AMD.   
A2 Primary Hypothesis 
The primary hypothesis is that the rate of progression of the GA lesion over one year (as 
measured by FAF will be decreased post-dapagliflozin intervention.  
 
B Introduction 
B1 Prior Literature and Studies 
Age-related macular degeneration (AMD) is a condition characterized by the gradual 
deterioration of the macula, a small central area of the retina responsible for sharp 
vision. It predominantly affects individuals over 50 and is the leading cause of blindness 

 
 
 
 
 
 
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in developed countries (Apte et al. 2018). In the United States, approximately 6% of 
those aged 65-74 and 20% of those over 75 are affected by AMD (Leibowitz et al., 
1980). Given the global increase in life expectancy, the elderly population is projected to 
grow substantially in the upcoming years (Ortma & Velkof, 2014). To be sure, according 
to U.S. Census Bureau projections, the number of Americans over 65 will more than 
double, reaching 80 million by mid-century (Day, 1993). Unless effective prevention or 
treatment strategies are implemented, the incidence of AMD cases leading to visual 
impairment is expected to rise with the aging population. 
 
AMD is divided into two primary subtypes: non-neovascular ("dry") and neovascular 
("wet"). Non-neovascular dry AMD constitutes approximately 90% of cases and is 
characterized by a gradual degeneration of the macula. Over time, this can lead to the 
atrophy of the central retina, culminating in central vision loss. Neovascular AMD, 
although less common, is more likely to cause sudden and often significant central vision 
loss (Holz et al., 2014). Dry AMD significantly contributes to moderate and severe 
central vision loss and is typically present in both eyes (Maguire & Vine, 1986; Potter & 
Thallemer, 1981; Sarks et al., 1988; Schatz & McDonald, 1989; Sunness et al., 1999). In 
dry AMD, the macula experiences a thinning of the retinal pigment epithelial cells (RPE), 
along with other age-related changes in adjacent retinal layers (Holz et al., 2014). It is 
characterized by the presence of drusen, yellow crystalline deposits that form beneath 
the RPE (Holz et al., 2014). In severe cases, dry AMD leads to noticeable thinning 
and/or atrophy of the macula, resulting from the loss of RPE and associated capillaries 
(choriocapillaris). This advanced stage of dry AMD is known as geographic atrophy 
(GA). The progressive deterioration of light-sensitive photoreceptor cells in GA leads to 
severe visual impairment in affected eyes. In some cases, dry AMD can transition into 
the wet form of the disease, which can similarly lead to faster progression of vision loss 
(Holz et al., 2014). 
B2 Rationale for this Study 
 
Although early or intermediate dry AMD is the most prevalent form of the disease, there 
is currently no approved therapy available. The absence of treatment options for dry 
AMD is a pressing unmet medical need, and a significant concern for the growing elderly 
population. For advanced AMD, current therapies, including anti-VEGF 
pharmacotherapy for neovascular AMD, and new complement pathway antagonists for 
geographic atrophy come with notable side effects such as potential choroidal 
neovascularization and intraocular inflammation with pegcetacoplan. Treatments for 
neovascular AMD and GA are associated with a procedural risk of infectious 
endophthalmitis. This creates a substantial treatment gap in preventing the progression 
of geographic atrophy and subsequent vision loss. 
 
Extensive research, including studies conducted by our group, has identified cholesterol 
accumulation as a key factor in the development and progression of AMD. Additionally, 
we have found significantly lower serum levels of ApoM in AMD patients. When 
comparing serum ApoM levels in patients without AMD (n = 944) to those diagnosed 
with AMD in either one or both eyes, be it dry or wet AMD (n = 53), we observed 
markedly lower levels in AMD patients (Mann-Whitney test; p<0.0001). 
 
Despite recognizing the role of lipid accumulation in driving disease progression and 
vision loss, no treatments currently exist for addressing the root cause of cholesterol 

 
 
 
 
 
 
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buildup in AMD. Recent work at Washington University by the Javaheri laboratory has 
unveiled a link between SGLT2i and ApoM. ApoM, primarily produced by the liver and to 
a lesser extent by the kidney, directly binds to sphingosine-1-phosphate (S1P) 
(Christoffersen et al., 2011), a bioactive lipid that activates G-protein coupled receptors 
(S1P receptors) present in various cell types, including RPE cells. ApoM exerts multiple 
effects, including antioxidant and anti-atherogenic properties (Elsoe et al., 2012; 
Christoffersen et al., 2008))) regulation of inflammation, endothelial protection 
(Christoffersen et al., 2011; Christensen et al., 2016) and cell survival (Ruiz et al., 2017). 
The Javaheri laboratory has identified ApoM as a regulator of lysosomal function and 
autophagy in the murine heart (Guo et al., 2023). Further studies have shown that in 
patients diagnosed with acute COVID-19, randomization to SGLT2i increased ApoM 
levels (Ripoll et al., in review). Further, ApoM is known to promote macrophage 
cholesterol efflux (Yao et al, Wolfrum et al.). Despite the existing knowledge linking 
ApoM to reverse cholesterol transport, lysosomal function, and autophagy, there is 
limited understanding of ApoM's role in eye diseases and AMD. 
 
Dapagliflozin, a commonly used sodium-glucose co-transporter inhibitor (SGLT2) 
inhibitor in chronic heart failure, chronic kidney disease, and diabetes, has garnered 
interest due to its substantial cardiorenal protective effects in these patients. SGLT2 is 
the major transporter responsible for renal sodium and glucose reabsorption in the 
proximal convoluted tubule of the kidney. Additionally, SGLT2 inhibitors have pleiotropic 
effects that favorably impact various processes, including energy metabolism, 
endothelial function, oxidative stress, inflammation, and autophagy (Bonnet and Scheen 
2018, Solini et al 2017, Kim et al 2020, Maayah et al 2020, Ghanim et al 2020, Lambers 
Heerspink et al 2013, Solini et al 2017). 
 
In multiple experimental systems, including heart failure models and doxorubicin 
administration, the Javaheri laboratory has demonstrated that SGLT2 inhibitors like 
empagliflozin and dapagliflozin increase circulating ApoM levels (Guo et al 2025). To 
date, the use of SGLT2 inhibitors has not been explored as a therapeutic option for 
slowing the progression of dry AMD. Consequently, this study could significantly 
broaden our options for slowing the disease progression and mitigating the devastating 
vision loss associated with dry AMD. Therefore, we hypothesize that dapagliflozin, a 
potent, highly selective, and orally active inhibitor of human renal SGLT2, holds the 
potential to slow the progression of advanced dry AMD and delay the onset of 
debilitating blindness. 
C Study Objectives 
The objectives of this study are to evaluate the safety and efficacy of dapagliflozin, an 
SGLT2 inhibitor, administered orally in subjects with geographic atrophy secondary to 
dry age-related macular degeneration (AMD). 
C1 Primary Aim 
Primary Efficacy Endpoint:  
Mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) 
at three time points: Baseline, 6 Month Visit, and 12 Month Visit 
C2 Secondary Aim 
Secondary Efficacy Endpoint include: 

 
 
 
 
 
 
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1) The mean change in size of drusen volume from Baseline to 12 Month Visit 
 
2) The mean change in best corrected visual acuity (ETDRS letters) from Baseline 
to 12 Month Visit  
 
3) The mean change in rod intercept time on dark adaptation from Baseline to 12 
Month Visit 
 
4) The mean change in low luminance best corrected visual acuity (ETDRS letters) 
from Baseline to 12 Month Visit 
C3 Rationale for the Selection of Outcome Measures 
In advanced stages of dry AMD, using surrogate markers or anatomical indicators can 
be beneficial if they accurately represent visual function or predict future vision 
deterioration. For geographic atrophy (GA), the advanced phase of dry AMD, the 
degeneration of photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris 
typically advances from the parafovea to the fovea, resulting in significant vision loss. 
Therefore, preventing the expansion of GA towards the fovea offers promise for 
preserving central vision. Precise measurement of GA area and reliable projections of its 
growth have led the FDA to consider reduced progression of GA enlargement as a 
suitable substitute primary endpoint for GA-focused clinical trials. Techniques like fundus 
autofluorescence are commonly utilized for lesion area analysis in GA assessment, and 
the rate of area growth has shown significant connections with GA progression. Some 
studies have suggested that applying a square root transformation to GA measurements 
can lessen the correlation between initial measurements and growth rate, thus allowing 
for a better association with GA progression (Abidi et al.). 
 
Furthermore, the choice of secondary outcome measures is aimed at evaluating both the 
structural and functional aspects of dry AMD. In dry AMD, conventional visual acuity 
(VA) has traditionally served as the primary measure. However, in early AMD, VA often 
remains unaffected and doesn't accurately reflect the severity of the condition. 
Additionally, typical AMD indicators like drusen accumulation do not consistently 
correlate with VA. Moreover, drusen can regress spontaneously without discernible 
functional consequences. Additionally, VA decline is gradual and typically becomes 
evident in the later stages of advanced dry AMD. Given these considerations, while VA 
and drusen volume may not be a sufficient primary endpoint for clinical trials focused on 
dry AMD, they may still be valuable as a secondary measure (Abidi et al.). Currently, 
there's no established functional vision assessment that has been validated for use as a 
primary endpoint in dry AMD trials. Thus, we plan to utilize functional capacity measures 
in dry AMD, such as dark adaptation, best corrected visual acuity, and low luminance 
best corrected visual acuity, as secondary endpoints. 
D Investigational Agent 
D1 Preclinical Data 
Dapagliflozin is an FDA approved drug with a new drug application (NDA) that explains 
in more detail the preclinical and clinical information. Broadly, this information below is 
cited from this NDA on its page 23: 

 
 
 
 
 
 
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“During the first review cycle, the nonclinical studies did not identify a carcinogenic 
hazard associated with dapagliflozin. However, due to an imbalance in bladder cancer 
that did not favor dapagliflozin in the Applicant’s clinical program, the Agency 
recommended that the Applicant conduct additional nonclinical studies focused on 
evaluating potential bladder tumor promotion with dapagliflozin in a rodent model. In this 
NDA resubmission, the Applicant submitted additional nonclinical studies that addressed 
whether dapagliflozin or its major metabolite (dapagliflozin 3-O-glucuronide) directly 
promoted tumor growth of human bladder tumor cell lines in vitro or in vivo (xenograft 
studies). Although the Applicant retrospectively demonstrated that dapagliflozin did not 
induce a transcriptional profile typical of tumor promoters in various rat tissues, the 
bladder was not among the tissues profiled. Additionally, the Applicant demonstrated 
that varying glucose concentrations in growth medium did not alter the growth in 
transitional cell carcinoma cell lines, and that hyperplastic bladders were not observed in 
a SGLT2 knockout mouse model. The results of these studies were consistent with what 
the Agency had already concluded (i.e., dapagliflozin did not appear to be a direct tumor 
promoter or inducer). However, these studies did not address whether dapagliflozin may 
act as a tumor promoter through changes in urinary volume, flow, and composition within 
the microenvironment of the bladder. Since the CRL, the Agency has repeatedly 
recommended acceptable models for evaluating transitional cell tumor growth within the 
bladder (e.g., transplanting human bladder tumor cells to mouse bladders [orthotopic 
models] or selectively inducing bladder tumors in rodents in which a genotoxic agent had 
been administered, such as hydroxybutyl nitrosamine [BBN]). These studies were never 
conducted. However, at the December 12, 2013 EMDAC meeting, the Applicant stated 
that they are currently working with experts in the field and are committed to conducting 
these studies. (NDA) 
D2 Clinical Data to Date  
Sources of clinical data are similarly cited in the NDA of dapagliflozin on page 25-28. 
Below is an excerpt from the NDA regarding the clinical data for dapagliflozin:  
 
“The dapagliflozin clinical development program consisted of 37 Phase 1 studies (26 
from the original NDA submission and eleven new studies in the 30-MU) and 26 Phase 
2b and Phase 3 clinical trials (fifteen from the original submission, plus six new core 
studies and five supportive studies in the 30-MU). A description of the Phase 2b/3 
clinical development program is presented in Table 3. These trials included diverse 
populations of patients with T2DM. There were drug-naïve patients at an early stage of 
disease and patients taking oral antidiabetic agents and/or insulin at later stages of the 
disease. The effects of dapagliflozin were also evaluated in patients with moderate renal 
insufficiency, established cardiovascular disease, and hypertension. Integrated safety 
datasets from 21 of the 26 studies were included in the 30-MU. Review of these 21 trials 
(referred to as the All Phase 2b/3 study pool from this point forward) comprises the main 
safety review for this NDA resubmission. These trials are identified in the table below.” 
D3 Dose Rationale and Risk/Benefits  
3.a 
Benefit/Risk and Ethical Assessment  
Dapagliflozin has global marketing approval in more than 90 countries. More detailed 
information about the known and expected benefits and risks and reasonably expected 

 
 
 
 
 
 
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9 
AEs of dapagliflozin may be found in the Investigator’s Brochure. The following is a 
summary of benefit-risk considerations relevant to the dry AMD population.  
3.b 
Potential Benefits to Subjects  
All patients in the study are expected to be treated optimally according to background 
local standard of care therapy, including treatments to control co-morbidities. 
Dapagliflozin or matching placebo will be administered in addition to these treatments. 
These patients will receive close medical attention at clinic visits, irrespective of blinded 
treatment allocation. The direct benefits to participation in the study may be a slowing of 
the progression of dry-AMD to preserve central vision longer if the medication proves to 
efficacious, though patients will be informed that they may be randomized to a group that 
does not have the medication (placebo group). There may be a possible benefit of 
improvement in visual acuity, low luminance visual acuity, or dark adaptation for the 
patient. 
3.c 
Potential Risks to Subjects  
The safety profile of dapagliflozin is already well established from prior clinical studies in 
various clinical settings. These studies have demonstrated that dapagliflozin is generally 
safe and well tolerated.  
Dapagliflozin, as an inhibitor of SGLT2, increases urinary glucose excretions, which is 
commonly believed to increase the risk of urinary tract infections. Urinary tract infections 
have been reported in dapagliflozin-treated patients in a slightly higher proportion than in 
placebo-treated patients in some global Phase III studies, although the rates of urinary 
tract infections (and serious urinary tract infections) observed in large clinical trials of 
dapagliflozin and other SGLT2i have been similar to placebo (Wiviott et al 2019, 
McMurray et al 2019). Increased urinary glucose excretion may also lead to an 
increased risk of developing genital infections. Genital infections are considered 
common side effects (in ≥1/100 to <1/10 patients).  
Dapagliflozin reduces BP and may reduce blood volume from its diuretic effect, though 
this could also be an important mechanism of a potential treatment effect. A pooled 
analysis of patients with T2DM and HF in the dapagliflozin development program, 
showed no increase of volume depletion events, but an increase in renal events, mainly 
creatinine increases, in patients treated with dapagliflozin (n=171) compared with 
patients treated with placebo (n=149). About half of the patients were on loop diuretics 
(Kosiborod et al 2017). In the dapagliflozin T2DM program, the rate of events related to 
volume depletion and impaired renal function has been similar between dapagliflozin 
and placebo.  
Dapagliflozin has not been shown to induce hypoglycemia in non-diabetic patients. In 
clinical pharmacology studies, healthy subjects have been treated with single oral doses 
of up to 500 mg and multiple oral doses of 100 mg up to 14 days without any 
hypoglycemic events. However, in patients with T2DM and on insulin or sulfonylurea 
medication, there is an increased risk of hypoglycemia. Patients with T2DM will be 
monitored in the hospital as part of standard of care, which in North America, Latin 
America, Europe, and India includes blood glucose monitoring.  

 
 
 
 
 
 
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There have been reports of ketoacidosis, including DKA, in patients with T2DM taking 
dapagliflozin and other SGLT2 inhibitors. Diabetic ketoacidosis is considered a rare (in 
≥1/10000 to <1/1000 patients) adverse drug reaction for dapagliflozin in patients with 
T2DM.  
Patients treated with dapagliflozin who present with signs and symptoms consistent with 
ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of 
breath, should be assessed for ketoacidosis, even if blood glucose levels are below 14 
mmol/L (250 mg/dL). If ketoacidosis is suspected, interruption of dapagliflozin treatment 
should be considered, and the patient should be evaluated promptly.  
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting 
from pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis, or pancreatic 
surgery), insulin dose reduction, reduced caloric intake, or increased insulin 
requirements caused by infections, illness or surgery and alcohol abuse. Dapagliflozin 
should be used with caution in patients in these circumstances.  
Since this protocol suggests utilizing dapagliflozin in a new patient population, 
the risk profile is best addressed by calling attention to the strong safety profile 
seen in the large-scale, long-term randomized controlled trials. The DECLARE-TIMI 
58 trial, which included 17,160 patients with type 2 diabetes, stratified results by age, 
included patients ≥65 and ≥75 years old. The study found no increased risk of major 
adverse cardiovascular events (MACE), fractures, and hypoglycemia compared to 
placebo (Wiviott et al., 2019). Notably, dapagliflozin did not increase hypoglycemia risk, 
making it a safer alternative to sulfonylureas or insulin in older adults, who are at higher 
risk of falls, cognitive decline, and frailty-related complications (Perkovic et al., 2019). 
Additionally, the DAPA-HF trial confirmed no excess risk of renal decline, hypotension, 
or ketoacidosis in older adults with heart failure, further supporting the cardiorenal safety 
of dapagliflozin in aging populations (McMurray et al., 2019). Diabetic ketoacidosis 
(DKA), a rare but serious adverse event, has not been significantly observed in non-
diabetic populations, making dapagliflozin a viable candidate for expanded indications 
beyond diabetes. In a pooled analysis of 15 Phase I-III trials, empagliflozin did not show 
any increased incidence of any adverse events, and this data based on >15,000 patient-
years’ exposure supports the favorable benefit-risk profile of SGLT2 inhibitors. (Kohler et 
al.  2017). Finally, pooled analysis of 9 Phase III studies confirmed that long-term use 
(104 weeks), which exceeds this study design of 52 weeks, in elderly patients did not 
lead to excess dehydration, renal complications, or severe genitourinary infections 
(Fioretto et al., 2016).  
 
Given its robust clinical trial data, real-world safety evidence, and broad regulatory 
acceptance, dapagliflozin is well-positioned for experimental expansion in safe use in 
aging populations, such as those populations that have geographic atrophy.  
 
Pupillary dilation will be performed using 1% tropicamide and 2.5% phenylephrine, 
standard mydriatics in clinical and research settings. While generally safe, side effects of 
pupillary dilation may include temporary blurred vision, difficulty with near focus, light 
sensitivity, and mild irritation for several hours. The most serious risk is acute angle-
closure glaucoma in individuals with narrow angles. AMD patients often receive pupillary 
dilation every 6 months as per standard of care, which is the frequency for this study. 

 
 
 
 
 
 
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11
Nevertheless, all participants will be screened beforehand, and potential risks will be 
discussed during the consent process. 
 
E Study Design  
E1 Overview or Design Summary 
This is a single-center, parallel-group, randomized, double-blind, placebo-controlled, 
Phase II trial in approximately 70 adults with dry advanced AMD or geographic atrophy. 
The study is evaluating the effect of dapagliflozin 10 mg versus placebo, given once 
daily by mouth for 1 year in addition to background local standard of care therapy, 
including treatments to control co-morbidities. Patients should start study drug the same 
day as randomization.  
 
 
 
E2 Subject Selection and Withdrawal  
In this study, patients will be recruited from sites with adult patients at outpatient clinics 
of retina specialists at the Retina Clinic at Barnes Jewish Hospital Center for Outpatient 
Health. Each patient should meet all the inclusion criteria and none of the exclusion 
criteria for this study to be randomized to study drug. Under no circumstances can there 
be exceptions to this rule. Patients’ eligibility criteria may be reassessed on one 
subsequent day following the initial Screening/Baseline Visit. However, if they still do not 
meet the inclusion criteria after this reassessment, they must be considered screen 
failures. 
In this study, “enrolled” patients are those who sign the consent form. “Randomized” 
patients are those who undergo randomization and receive a randomization number. 
Withdrawal can occur at any time during the study.  
 

 
 
 
 
 
 
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12
2.a 
Inclusion Criteria 
1. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol 
2. Are reliable and willing to make themselves available for the duration of the study 
and are willing to follow study procedures 
3. Participant is male or, if female, participant is surgically sterilized or amenorrheic for 
at least one year 
4. ≥50 years old 
5. Evidence of dry advanced AMD with the presence of non-foveal Geographic Atrophy 
(GA)  
a) The geographic atrophy must not involve the center point of the fovea. 
b) Total area of geographic atrophy must be between 2.5 mm2 and 17.5 mm2 (1 – 4 
disc areas, respectively).  
c) If the geographic atrophy consists of multiple lesions, at least one lesion must 
have an area of ≥1.25 mm² (equivalent to 0.5 disc areas). 
6. BCVA between 20/25 and 20/320 
7. Must be treatment-naïve for AMD, except for oral supplements 
 
2.b 
Exclusion Criteria 
Prior investigational drug use within 60 days 
Use of other SGLT2 inhibitors 
History of symptomatic hypotension or symptomatic hypotension (symptoms of 
hypotension + SBP < 90mmHg) at baseline 
Type I and Type II Diabetes Mellitus  
End stage renal disease or estimated glomerular filtration rate less than 25 mL/min/1.73 
m2 per MDRD calculation 
History of heart failure 
History of a serious hypersensitivity reaction to dapagliflozin or any of the excipients in 
FARXIGA 
Other concomitant disease or condition that investigator deems unsuitable for the study, 
including drug or alcohol abuse or psychiatric, behavioral, or cognitive disorders, 
sufficient to interfere with the patient’s ability to understand and comply with the study 
instructions or follow-up procedures 
Any prior treatment for AMD (dry or wet) or any prior intravitreal treatment for any 
indication in either eye, except oral supplements of vitamins or mineral 
Any intraocular surgery or thermal laser within 3 months of date of randomization 
Any ocular or periocular infection (including blepharitis), or ocular surface inflammation 
in the past 12 weeks 
Any prior thermal laser in the macular region, regardless of indication (self-report) 
Any evidence of choroidal neovascularization in study eye  
Enrollment in another interventional trial during the trial period 
 
2.c 
Ethical Considerations  
Dapagliflozin has global marketing approval in more than 90 countries. More detailed 
information about the known and expected benefits and risks and reasonably expected 
AEs of dapagliflozin may be found in the Investigator’s Brochure. The summary of 
benefit-risk considerations is summarized in Section D3. 
 

 
 
 
 
 
 
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16
E3 Study Drug  
3.a 
Description  
Dapagliflozin and its matching placebo tablets will be packed in bottles. The tablets may 
contain lactose, which may cause gastrointestinal discomfort in lactose-intolerant 
individuals.  
3.b 
Treatment Regimen  
At randomization (Day 1), eligible patients will be randomly assigned to 1 of 2 
treatments:  
• 
Dapagliflozin 10 mg, given once daily per oral use  
• 
Placebo—one tablet to match dapagliflozin 10 mg, given once daily per oral use  
The study drug should be taken by mouth as soon as possible after randomization and 
then once daily in the morning, at approximately the same time every day, during the 
treatment period of 1 year. If the patient, for any reason is not administered the study 
drug in the morning, any other time point during the day may be applied, provided the 
study drug is routinely administered in approximately 24-hour intervals.  
3.c 
Method for Assigning Subjects to Treatment Groups  
All patients will be randomly assigned to study drug a centralized randomization program 
in Redcap. Randomization to study drug will be performed in balanced blocks to ensure 
approximate balance between the treatment groups (1:1).  
 
3.d 
Preparation and Administration of Study Drug  
Patients will be randomized 1:1 to either dapagliflozin 10 mg or placebo once daily per 
oral use by the contracted preparation organization. Every attempt should be made to 
have patients on dapagliflozin 10 mg or matching placebo during the course of the study. 
The study drug should be taken as soon as possible after randomization and then once 
daily in the morning, at approximately the same time every day, during the 12 month 
treatment period. 
3.e 
Subject Compliance Monitoring  
Patients will be asked at each of the pre-defined visits regarding compliance to their 
medication regimen. Severe non-compliance with the study protocol may result in 
discontinuation from the study drug. 
 
3.f 
Prior and Concomitant Therapy  
All patients will be treated according to local guidelines on standard of care treatment for dry AMD. 
Subjects enrolled must be treatment-naïve (no previous treatment for AMD) in either eye except 
for oral supplements of vitamins and minerals. Any treatment with any investigational agent for any 
condition in the past 60 days, or treatment with an investigational agent for any condition during 
the trial, is not permitted. 
However, concomitant treatment with open label SGLT2i (e.g., dapagliflozin, empagliflozin, 
canagliflozin, ertugliflozin, tofogliflozin and luseogliflozin and fixed-dose combinations containing 
these drugs), is prohibited. Background medications should be part of clinical practice and will not 

 
 
 
 
 
 
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17
be provided by the investigator. Medication other than that described above, which is considered 
necessary for the patient’s safety and well-being, may be given at the discretion of the Investigator 
and recorded. 
3.g 
Blinding of Study Drug  
Blinding of the study drug will be ensured using a double-blind technique of matching 
placebo as managed by the pharmacy. No member of the study team, personnel, or 
delegates will have access to the randomization scheme during the study.  
 
3.h 
Receiving, Storage, Dispensing and Return  
The study team will maintain a drug accountability log to track the dispensing, use, and 
return of the study drug. Participants will be instructed to return all unused study drug, 
empty containers, and partially used doses at each study visit. Compliance with study 
drug administration will be assessed through pill counts. 
 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to the patients.  
 
All study drugs should be kept in a secure place under appropriate storage conditions. 
The study drug label on the bottle specifies the appropriate storage conditions.  
 
Any study drug deliberately or accidentally destroyed must be recorded. When the study 
drug is destroyed at site: study site personnel, will account for all study drug at the site, 
unused study drug, and for appropriate destruction. Certificates of delivery, destruction, 
and return should be signed.  
F Study Procedures  
F1 Screening for Eligibility 
The population of interest is a group of patients >50 years old with advanced dry AMD 
as evidenced by presence of geographic atrophy secondary to AMD. The PI and Sub-I's 
will identify patients who are seen at the practices of Dr. Rajendra Apte, Dr. Kumar Rao, 
Dr. Kisha Piggott according to the inclusion and exclusion criteria referenced in section 
5.2.  
F2 Informed Consent  
The Investigator or their designated representative will discuss the study’s purpose, 
including its potential risks and benefits, with the participant and address any questions 
they may have. Participants will be made aware that their involvement is entirely 
voluntary. They must sign an informed consent form (ICF) that complies with 21 CFR 50, 
applicable local laws, ICH guidelines, privacy and data protection standards, and the 
requirements of the IRB/IEC. Consent must be secured before any study-specific 
activities (e.g., procedures outlined in the protocol) are performed, and this process must 
be recorded in the participant’s source documents. The medical record should note that 
written consent was obtained prior to enrollment, including the date of consent, and the 
person obtaining it must also sign the ICF. Participants will receive a copy of the signed 
ICF.  

 
 
 
 
 
 
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18
 
Only participants who provide IRB/IEC-approved informed consent (witnessed if required 
by law or regulation) may be enrolled. Details about known common side effects of the 
investigational treatment, as outlined in the Investigator’s Brochure (IB), will be included 
in the ICF and discussed with participants during the consent process and throughout 
the study as necessary. Any newly identified safety information about the investigational 
drug that emerges between IB updates will be shared appropriately—such as through an 
Investigator Notification (IN) or aggregated safety report—and may necessitate revising 
the ICF, followed by a discussion with the participant. Declining to participate in these 
optional assessments will in no way affect the participant’s ability to join the main 
research study. A copy of the signed consent will be given to the participant. 
F3 Vital Signs 
Vital signs will include measurement of blood pressure and pulse rate. 
 
After the participant has been sitting for 3 minutes, with back supported and both feet 
placed on the floor, blood pressure and pulse rate will be measured using an automated 
device. For virtual visits requiring blood pressure and pulse check, participants will be 
guided through this process with their home machine.  
 
If SBP is less than 90 mmHg at the at Screening/Baseline Visit (see Exclusion Criteria 
Section 5.2 of the protocol for details), two additional readings can be obtained, so that 
up to three consecutive assessments are made, with the participant seated quietly for 
approximately five minutes preceding each repeat assessment.  
In case of repeated vital assessments, the electronic case report form (eCRF) should 
contain the qualifying results. 
 
For patients whose SBP is measured below 90 mmHg across three consecutive 
readings, reassessment of the blood pressure may be conducted on a single separate 
day to reassess eligibility. If SBP is still less than 90 mmHg, patient will be considered a 
screen fail and will not be eligible for participation in the trial. 
 
Blood pressure measurements should be performed immediately following the informed 
consent process, and if blood pressure does not meet the inclusion criteria, no additional 
screening procedures will be conducted. 
F4 Medical History 
A detailed medical history will be collected by interview and medical record review at the 
Screening/Baseline Visit to document current medical conditions and allergies. Date of 
onset for medical conditions will be recorded in the CRFs but can be approximate if 
detailed records are not available.  
F5 Concomitant Medications (Con Meds) 
A comprehensive medication history will be collected, covering all current medications, 
such as prescription drugs, over-the-counter medications, supplements, and 
investigational products, with details on dosage, duration, and indication. Initiation dates 
can be approximated if detailed records are not available.  

 
 
 
 
 
 
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19
F6 Physical Examination 
A targeted physical examination, encompassing an assessment of general appearance, 
cardiovascular, abdominal, genitourinary, and integumentary systems, will be conducted 
to evaluate baseline clinical characteristics and monitor for potential adverse events. All 
findings identified at baseline will be recorded in the Case Report Forms (CRFs), and 
any findings from follow-up visits that deviate from the baseline and meet the criteria for 
an adverse event will be reported accordingly. 
F7 Local Basic Metabolic Panel (BMP) and Complete Blood 
Count (CBC) 
Approximately 10 mL (equivalent to 2 teaspoons) of blood will be collected for a BMP 
and CBC analysis run at Barnes Jewish laboratory. The BMP and CBC will be evaluated 
at the Baseline Visit, the 6 Month Visit, and the 9 Month Visit to monitor key metabolic 
parameters throughout the study. Additional BMP and CBC assessments may be 
conducted at the discretion of the Investigator for participants reporting adverse events, 
as needed to ensure safety and evaluate potential study-related effects. 
F8 Study Drug Initial Dispensing and Refill 
A 90-day supply of study drug will be initially dispensed at the Day 1 Visit following 
randomization. The study drug will be dispensed to participants in labeled containers 
with unique identification numbers. Additional 90-day supplies will be provided by the 
study team at the 3 Month Visit, 6 Month Visit, and 9 Month Visit. For participants who 
elect to conduct their 3 Month Visit and 9 Month Visit virtually, study drug will be 
provided via mail delivery. 
 
Participants will be provided with written instructions for the proper storage and handling 
of the study drug. The study drug must be stored in its original container at the specified 
temperature and kept out of reach of children or pets. 
F9 Drug Accountability 
Participants will be instructed to return all unused study drug, empty containers, and 
partially used doses at each study visit. Compliance with study drug administration will 
be assessed through pill counts. Participants who do not take the study drug as 
instructed or fail to return unused study drug may be withdrawn from the study.  
 
The study site will maintain detailed drug accountability logs, including the quantity of 
study drug received, dispensed, returned, and destroyed. Any discrepancies in drug 
accountability will be documented and reported to the IRB as required 
 
Participants must maintain a compliance rate of at least 80% over each assessment 
period (e.g., between study visits). Compliance is defined as the percentage of doses 
taken as prescribed out of the total expected doses, calculated as follows: 
 
 
 
If a participant’s compliance falls below 80% during any assessment period, the 
Investigator will counsel the participant on the importance of adherence and provide 

 
 
 
 
 
 
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20
strategies to improve compliance (e.g., reminders, support tools). Should the participant 
fail to achieve at least 80% compliance by the subsequent visit, they will be withdrawn 
from the study. Withdrawal due to non-compliance will be documented in the 
participant’s Case Report Form (CRF), including the calculated compliance percentage, 
dates of assessment, and any remedial actions attempted. 
F10 Ophthalmologic Exam 
A special microscope called a slit lamp will be used to look closely at the anterior parts of 
the eye like the eyelids, cornea, iris, and lens. To examine the back of the eye, including 
the retina and optic nerve, pupil dilation will be achieved using 1% tropicamide and 2.5% 
phenylephrine administered topically, and then the doctor will use a bright light and a 
handheld lens in a technique called indirect ophthalmoscopy. 
F11 Retinal Exam  
The retinal exam focuses on checking the back part of the eye, and includes fundus 
photography, which takes detailed color pictures of the retina to look for signs of 
disease. It also includes optical coherence tomography (OCT), which creates cross-
sectional images of the retina to see the layers of the retina in high detail. 
Autofluorescence is used with OCT to highlight areas where retinal cells may have 
subject to stress or damage, helping to detect early signs of diseases in macular 
degeneration. 
F12 Functional Eye Exams 
Functional eye exams measure the function of your eyes as opposed to structure, such 
as how well your eyes see in different lighting conditions. They include tests like dark 
adaptation, which checks how quickly your eyes adjust to darkness, and low-luminance 
visual acuity, which measures how clearly you see in dim light—both useful for detecting 
early vision changes. 
F13 Schedule of Measurements 
 
Visit Name 
Baseline 1 
Day 
11 
Day 
305 
3 
Month5 
6 
Month 
9 
Month5 
12 
Month  
(End 
of 
Study) 
Visit Windows 
(Days) 
-14-1 
1 
30 
(± 3) 
90 
(± 7) 
180 
(± 10) 
270 
(± 10) 
360 
(± 10) 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Review 
X 
 
 
 
 
 
 
Con Med 
Assessment 
X 
 
X 
X 
X 
X 
X 
Ophthalmologic 
Exam2 
X 
 
 
 
X 
 
X 
Retinal Exam 3 
X 
 
 
 
X 
 
X 

 
 
 
 
 
 
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21
Functional Eye 
Exams4 
X 
 
 
 
X 
 
X 
Physical Exam 
X 
 
 
 
X 
 
X 
Study Drug Initial 
Dispense and 
Administration 
 
X 
 
 
 
 
 
Medication Refill 
 
 
 
X 
X 
X 
 
Drug 
Accountability 
 
 
 
X 
X 
X 
X 
X 
Local BMP and 
CBC 
X 
 
 
 
X 
 
X 
Blood Pressure, 
HR 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
X 
 
X 
X 
X 
X 
X 
 
1 Baseline and Day 1 visits can be completed on the same day 
2 Ophthalmologic Exam includes slit lamp exam, biomicroscopy, indirect ophthalmoscopy 
with pupillary dilation.  
3 Retinal Exam includes fundus photography and optical coherence tomography (with 
autofluorescence). 
4 Functional eye exams include dark adaptation and low-luminance visual acuity  
5 30 Day, 3 Month, and 9 Month Visits are optionally virtual, patient can elect to return in 
person for a research visit or choose a virtual visit if they can provide a home blood 
pressure and pulse rate. Refill of study medication will be mailed to participant’s home 
in the case of a 3 or 9 month virtual visit.  
F14 Safety and Adverse Events  
14.a Definitions of Adverse Events 
An Adverse Event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram). In clinical studies, an AE can include an undesirable 
medical condition occurring at any time, including run-in or washout periods, even if no 
study treatment has been administered.  
The term AE is used to include both serious and non-serious AEs.  
A Serious Adverse Event (SAE) is an AE occurring during any study phase (i.e., run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria:  
• 
Results in death  
• 
Is immediately life-threatening  
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  

 
 
 
 
 
 
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22
• 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions  
• 
Is a congenital abnormality or birth defect  
• 
Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above.  
14.b Classification of Events 
Definition: any unfavorable medical occurrence in a human subject including 
any abnormal sign, symptom, or disease. 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
To assist with grading of adverse event severity, the following definitions are 
provided: 
Mild = Aware of sign or symptom, but easily tolerated 
Moderate = Discomfort enough to cause interference with usual activity 
Severe = Incapacitating with inability to work or do usual activity 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for 
the terms listed that should be used are those provided by the Department of 
Health and Human Services’ Office for Human Research Protections (OHRP).  A 
copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
The causality of SAEs (their relationship to all study treatment/procedures) will be 
assessed by the Investigator(s). 
When making an assessment of causality consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
 
• 
Time Course. Exposure to suspect drug. Has the subject actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the 
same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience. Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? Investigator would not normally 
recommend or support a re-challenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship. 
 
In difficult cases, other factors could be considered such as: 

 
 
 
 
 
 
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23
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence 
for a ‘reasonable possibility’ of a causal relationship for the individual case. The 
expression ‘reasonable possibility’ of a causal relationship is meant to convey, in 
general, that there are facts (evidence) or arguments to suggest a causal relationship. 
 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
 
Causal relationship in cases where the disease under study has deteriorated due to lack 
of effect should be classified as no reasonable possibility. 
14.c Reporting Procedures 
All reportable severe adverse events (SAEs) have to be reported, whether or not 
considered causally related to the study drug. The representative is responsible for 
informing the IRB/IEC and/or the Regulatory Authority of the SAE as per local 
requirements.  
If any reportable SAE occurs in the course of the study, then Investigators or other site 
personnel inform the appropriate designated representatives within one day i.e., 
immediately but no later than 24 hours of when he or she becomes aware of it.  
The designated representative works with the Investigator to ensure that all the 
necessary information is provided to the database within one calendar day of initial 
receipt for fatal and life-threatening events and within 5 calendar days of initial receipt 
for all other reportable SAEs.  
For fatal or life-threatening reportable SAEs where important or relevant information is 
missing, active follow-up is undertaken immediately. Site personnel inform the 
investigator of any follow-up information on a previously reported SAE within one 
calendar day i.e., immediately but no later than 24 hours of when he or she becomes 
aware of it.  
The reference document for definition of expectedness is the Investigator’s Brochure for 
dapagliflozin.  
Investigator and other site personnel must inform the FDA, via a MedWatch/AdEERs 
form, of any serious or unexpected AEs that occur in accordance with the reporting 
obligations of 21 CFR 312.32. It is the responsibility of the Investigator or designated 
delegate to compile all necessary information and ensure that the FDA receives a report 
according to the FDA reporting requirement timelines. The conduct of the study will 
comply with all FDA safety reporting requirements.   
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM 
REPORTING REQUIREMENTS FOR HRPO.  It is the responsibility of the investigator to 
report any unanticipated problem to the FDA as follows: 

 
 
 
 
 
 
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24
• 
Report any unexpected fatal or life-threatening adverse experiences associated 
with use of the drug (i.e., there is a reasonable possibility that the experience 
may have been caused by the drug) by telephone or fax no later than 7 calendar 
days after initial receipt of the information.  A life-threatening adverse experience 
is defined as any adverse drug experience that places the subject (in the view of 
the investigator) at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might 
have caused death. 
• 
Report any serious, unexpected adverse experiences, as well as results from 
animal studies that suggest significant clinical risk within 15 calendar days after 
initial receipt of this information.  A serious adverse drug experience is defined as 
any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
An unexpected adverse drug experience is defined as any adverse drug experience, the 
specificity or severity of which is not consistent with the current investigator brochure (or risk 
information, if an IB is not required or available). 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Pulmonary, Allergy and Rheumatology Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 301-796-9728 
14.d Adverse Event Reporting Period 
Reportable adverse events will be collected from first dose of study treatment through 30 days 
following the last study treatment. 
F15 Study Outcome Measurements and Ascertainment 
The objectives of this study are to evaluate the safety and efficacy of dapagliflozin when 
given to subjects with geographic atrophy secondary to dry age-related macular 
degeneration (AMD). Primarily, Optos wide-field images with autofluorescence, OCT, 
AdaptDxTm dark adaptation, and standard ophthalmic exam will be obtained as per the 
schedule of measurements in F2. 
 
15.a Primary Outcome Endpoint 
Mean rate of change in GA over 12 months measured by FAF at three time points: 
Baseline, 6 Month Visit, and 12 Month Visit 
 

 
 
 
 
 
 
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25
15.b Secondary Efficacy Endpoints 
 
1. The mean change in size of drusen volume from Baseline to 12 Month Visit 
2. The mean change in best corrected visual acuity (ETDRS letters) from Baseline to 12 
Month Visit 
3. The mean change in rod intercept time on dark adaptation from Baseline to 12 Month 
Visit 
4. The mean change in low luminance best corrected visual acuity (ETDRS letters) from 
Baseline to 12 Month Visit 
 
G Statistical Plan  
G1 Sample Size Determination and Power 
This is a Phase II pilot study (double-masked, placebo-controlled single center clinical 
trial) evaluating the efficacy of SGLT2 inhibitor dapagliflozin for the treatment of dry 
AMD. Up to a maximum of 70 patients total (35 patients in each arm) will be randomized 
with the assumption that 5 in each arm may be lost to follow-up, resulting in 30 evaluable 
subjects in each arm at the end of the study. Based on the uncertainty of the proportion 
of patients enrolled who will be evaluable, definitive power analyses are not feasible. 
Therefore, sample power calculations were performed on a range of possibilities. 
Assuming the average rate of progression in the year in the control group is ~0.33 
mm/year (from GATHER1 trial), we estimate that the effect size that corresponds with a 
30% rate reduction is ~0.5 - ~1 based on interpatient variation. A sample size of 30 
patients evaluable for the primary endpoint will allow us to detect an effect size of >0.7 
with 80% power at two-sided 0.05 alpha. A sample size of 15 evaluable patients will 
allow us to detect an effect size >1.0. This study is designed to generate preliminary 
data for future, larger trials rather than confirm hypotheses and, thus, not definitively 
powering the study is acceptable. 
G2 Analysis Plan 
2.a 
Descriptive Statistics 
Descriptive statistics will be provided on demographic information, treatment 
administration, baseline characteristics, and protocol deviations, as well as for selected 
endpoints at relevant time points. No tests of significance will be carried out to compare 
treatment groups on baseline data because any observed differences between them 
must be attributed to chance. 
 
2.b 
Efficacy Analysis 
The efficacy analysis will be conducted on all randomized and treated subjects 
according to the intention-to-treat principle. For normal endpoints, treatment groups will 
be compared through an analysis of variance and mixed model for repeated measures 
including stratification factors. 
 
The overall (one-sided) false positive error rate in this trial, accounting for the conduct of 
pairwise comparisons with control, is 0.025 for the analysis of the primary endpoint. 

 
 
 
 
 
 
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26
 
2.c 
Subset Analyses 
The trial is not sized to test for the presence of treatment by subset interactions. Thus, 
true treatment by subset interactions will likely be missed, unless they are quite 
substantial. Conversely, should any particular subset of subjects seem to benefit more or 
less from therapy than the total population, this will not be taken as evidence of a true 
treatment by subset interaction, given the likelihood that such an observation could be 
due to chance alone. With these caveats in mind, exploratory subset analyses will be 
performed to identify any major effect that might be worth testing in future trials. 
Clinically meaningful subsets will be looked at, including stratification factors. 
 
2.d 
Safety Analysis 
The safety analysis will be conducted on all subjects who had at least one administration 
of trial drug. 
 
Adverse events will be summarized using MedDRA terms. The incidence and severity of 
adverse events will be listed and grouped by body system. All laboratory data will be 
listed and values falling outside normal ranges will be identified. Summary statistics (i.e., 
mean, median, standard deviation, minimum and maximum) will be presented for all 
continuous variables. Summary statistics will be given on the number of subjects for 
whom the trial medication had to be permanently stopped. 
G3  Statistical Methods  
Data will be analyzed using SAS Studio, SPSS, or R. Descriptive analyses will be 
performed on baseline, safety and efficacy data. All tables will be created for the 
treatment arm (dapagliflozin) and overall.  
Descriptive statistics will be tabulated as follows:  
Categorical data will be summarized in contingency tables presenting frequencies and 
percentages.  
Continuous data will be summarized using number of non-missing values (n), mean, 
standard deviation, median, minimum, 1st quartile (Q1), 3rd quartile (Q3), and maximum 
values.  
Listings with individual subjects’ data will be provided for all CRF (including derived data) 
and central laboratory data or other external data. Data collected in the CRF that are not 
present in a table will also be listed (e.g. time and method of tonometry, comments 
fields, data on Fatal Outcomes page, Unscheduled Visit pages, etc.).  
The primary efficacy endpoint is mean rate of change in GA over 12 months measured 
by fundus autofluorescence (FAF) at three time points: Baseline, 6 Month Visit, and 12 
Month Visit. To eliminate the dependency of GA growth rates on the Baseline lesion size 
(Feuer et al., 2013), instead of using the observed GA area measurement, the square 
root of the GA area will be used in the analysis. For analyses of the primary endpoint, a 
Mixed-Effects Repeated Measures (MMRM) model will be used to assess the 

 
 
 
 
 
 
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27
differences between the treatment groups in rate of change of GA area over 12 months. 
Models will be fitted by using restricted maximum likelihood (REML) and include 
Baseline VA (< 50 letters vs. ≥ 50 letters), size of the Baseline GA (< 4 disc area vs. ≥ 4 
disc area), and pattern of FAF at the junctional zone of GA (none/focal vs. 
banded/diffuse) as used in the randomization as covariates. Fixed effects will include 
treatment, visit, the Baseline VA (< 50 letters vs. ≥ 50 letters), size of the Baseline GA (< 
4 disc area vs. ≥ 4 disc area), pattern of FAF at the junction zone of GA (none/focal vs. 
banded/diffuse), treatment by visit interaction, and the stratification factors by visit 
interactions. An unstructured (co)variance structure will be used to model the within-
subject errors. If this analysis fails to converge, alternative structures (e.g., 
heterogeneous autoregressive or heterogeneous compound symmetry, in this order) will 
be considered. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. The test of the mean rate of change over 12 months will be 
assessed by testing the appropriate contrast of the model parameter estimates.  
Secondary efficacy endpoints are as specified:  
• 
The mean change in size of drusen volume from Baseline to 12 Month Visit 
• 
The mean change in rod intercept time on dark adaptation from Baseline to 12 
Month Visit 
• 
Mean change in best corrected visual acuity (ETDRS letters) from Baseline to 12 
Month Visit  
• 
Mean change in low luminance best corrected visual acuity (ETDRS letters) from 
Baseline to 12 Month Visit  
Secondary efficacy analysis will be conducted for intention-to-treat (ITT) population for 
these pre-specified secondary endpoints. The analyses described above will also be 
repeated in a supportive manner for the per-protocol (PP) population.  
Descriptive tables will be provided for secondary endpoints based on the observed data, 
but due caution will be exercised in interpreting descriptive tables because of the 
potential impact of missing data.  
Any hypothesis testing performed as part of analyzing secondary efficacy endpoints will 
be considered exploratory.  
For analyses of the secondary endpoints, a similar Model for Repeated Measures 
(MRM) will be used to assess the differences between the treatment groups at 12 Month 
visit. The model will be fitted by using restricted maximum likelihood (REML). The model 
will include Baseline VA (< 50 letters vs. ≥ 50 letters), size of the Baseline GA (< 4 disc 
area vs. ≥ 4 disc area), size of baseline drusen, and pattern of FAF at the junctional 
zone of GA (none/focal vs. banded/diffuse) as used in the randomization as covariates. 
Fixed effects will include treatment, visit, the Baseline VA (< 50 letters vs. ≥ 50 letters), 
size of the Baseline GA (< 4 disc area vs. ≥ 4 disc area), pattern of FAF at the junction 
zone of GA (none/focal vs. banded/diffuse), treatment by visit interaction, and the 
stratification factors by visit interactions. An unstructured (co)variance structure will be 
used to model the within-subject errors. If this analysis fails to converge, alternative 
structures (e.g., heterogeneous autoregressive or heterogeneous compound symmetry, 
in this order) will be considered. The Kenward-Roger approximation will be used to 

 
 
 
 
 
 
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28
estimate denominator degrees of freedom. Significance tests will be based on 
appropriate treatment contrasts at 12 Month Visit.  
G4  Missing Outcome Data 
4.a 
Handling Missing Data in Efficacy Analyses  
Methods that take into account the presence of missing data and that yield valid 
estimates under the assumption of data missing at random (MAR) will be used. In 
particular, a Model for Repeated Measures fitted by Restricted Maximum Likelihood 
method will be used in the primary analysis, whereas-observed data will be used with no 
imputation.  
Of note, the proper approach to address missingness is the prevention of missing data, 
and efforts will be to be taken to implement proactive approaches to minimize the 
number of patients who are not assessed at 12 months.  
4.b 
Handling Missing Data in Descriptive Analyses  
When summarizing categorical variables, subjects with missing data are generally not 
included unless otherwise specified. When needed, the category of “Missing” is created 
and the number of subjects with missing data is presented.  
When summarizing continuous variables, subjects with missing data are not included in 
calculations. No imputations are made.  
4.c 
Handling Missing or Partially Missing Dates  
Missing or partially missing dates will not be imputed at data level. However, 
assumptions for missing or partially missing dates for important variables will be made to 
allow inclusion of appropriate data records in the analyses. In general, the assumptions 
about the missing or partially missing dates, when needed, are made conservative to 
avoid overestimation of treatment effect and underestimation of adverse effects.  
If a medication date or time is missing or partially missing, so it cannot be determined 
whether it was taken prior or concomitantly, it will be considered both as a prior and a 
concomitant medication.  
If the partial adverse effect onset date information does not indicate whether the AE 
started prior to treatment or after treatment, the AE will be classified as after the start of 
treatment.  
G5  Unblinding Procedures  
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the Investigator(s) or pharmacists at the study site upon 
request. 
The treatment code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment 
randomization. The date and reason that the blind was broken must be recorded in the 
source documentation and CRF as applicable. The Investigator is to document and 

 
 
 
 
 
 
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29
report the action to the appropriate representative, without revealing the treatment given 
to the patient.  
The designated safety representative retains the right to break the code for SAEs that 
are unexpected and are suspected to be causally related to the study drug and that 
potentially require expedited reporting to regulatory authorities.  
H Data Handling and Record Keeping  
H1 Confidentiality and Security 
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. Largely, patient data will only be accessible to those with clearance. Efforts 
will be made to keep clinical information masked and protected through secure 
electronic passwords only available to those with clearance. 
H2 Training  
Before the first patient is entered into the study, a delegate from the study team will 
review and discuss the requirements of the Clinical Study Protocol and related 
documents with the investigational staff and train them in any study specific procedures 
and system(s) utilized. Training will be conducted via Skype, Zoom, or another 
telecommunications application.  
The PI will ensure that appropriate training relevant to the study is given to all study staff, 
and that any new information relevant to the performance of this study is forwarded to 
the staff involved.  
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).  
H3 Case Report Forms and Source Documents 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. The Investigator must permit study-related monitoring, 
audits, IRB/IEC review, and regulatory agency inspections and provide direct access to 
source data documents.  
H4 Records Retention 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period or transferred to another location or party without written notification from 
authorized parties. 
I Study Monitoring, Auditing, and Inspecting  
I1 
Study Monitoring Plan  
During the study, a research representative is on site and will be available to:  

 
 
 
 
 
 
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30
• 
Provide information and support to the Investigator(s)  
• 
Confirm that facilities remain acceptable  
• 
Confirm that the investigational team is adhering to the protocol, that data are 
being accurately and timely recorded in the CRFs, and that study drug 
accountability checks are being performed  
The study site will maintain detailed drug accountability logs, including the quantity of 
study drug received, dispensed, returned, and destroyed at the specified visit times. Any 
discrepancies in drug accountability will be documented and reported to the IRB as 
required. At the end of the study or upon participant withdrawal, any unused study drug 
will be collected and destroyed in accordance with local regulations and requirements. 
I2 
Auditing and Inspecting  
Authorized representatives of a regulatory authority or an IRB/IEC may perform audits or 
inspections at the site, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice, and any applicable regulatory requirements.  
J Study Administration 
J1 Funding Source and Conflicts of Interest 
The funding source will come from the AMD/Retinal Disease Research Fund which has 
been awarded to principal investigator Dr. Rajendra Apte. There are no conflicts of 
interest for team members of this study relating to the experimental drug. 
 
 
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