PROMINENT-Eye Ancillary Study: Diabetic Retinopathy Outcomes in a Randomized Trial of Pemafibrate Versus Placebo (Protocol AD)
Phase: PHASE3
Conditions: Diabetic Retinopathy, Diabetic Macular Edema
Sponsor: Jaeb Center for Health Research

PROMINENT-Eye 3-14-18 V2.0 
 
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Diabetic Retinopathy  
Clinical Research Network 
(DRCR.net) 
 
 
 
PROMINENT-Eye Ancillary Study: 
Diabetic Retinopathy Outcomes in a 
Randomized Trial of Pemafibrate  
Versus Placebo 
 
 
 
Protocol Amendment 1 
Version 2.0 
 
 
 
March 14, 2018 
 

PROMINENT-Eye 3-14-18 V2.0 
 
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Signature Page 
 
JCHR Principal Investigator 
 
Name, degree 
 
Signature / Date 
 
 
External Sponsor  
(Kowa Research Institute, Inc.) 
 
Name, degree 
 
Signature / Date 
 
 
Center for Cardiovascular Disease 
Prevention  
 
Name, degree 
 
Signature / Date 
 

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Table of Contents 
 
Abbreviations _________________________________________________________________ 5 
INTRODUCTION______________________________________________________________ 6 
1.1 Diabetic Retinopathy Complications and Public Health Impact ........................................ 6 
1.2 Preventing DR Onset and Worsening ................................................................................. 6 
1.3 Limitations of Current Treatments for PDR and DME ...................................................... 6 
1.4 Rationale for PPARα Therapy for DR Worsening ............................................................. 7 
1.5 Pemafibrate and the Ongoing PROMINENT trial .............................................................. 8 
1.6 Summary of Protocol Rationale .......................................................................................... 9 
1.7 Study Objective ................................................................................................................. 10 
1.8 Study Design and Synopsis of Protocol ............................................................................ 10 
1.9 General Considerations ..................................................................................................... 13 
STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT ______________________ 14 
2.1 Identifying Eligible Participants and Obtaining Informed Consent ................................. 14 
2.2 Subject Eligibility and Exclusion Criteria ........................................................................ 14 
2.2.1 Eligibility Criteria .......................................................................................................... 14 
2.2.2 Study Eye Criteria: ......................................................................................................... 14 
2.3 Screening Evaluation and Baseline Testing ...................................................................... 15 
2.3.1 Ocular Historical Information ........................................................................................ 15 
2.3.2 Baseline Testing Procedures .......................................................................................... 15 
FOLLOW-UP VISITS _________________________________________________________ 16 
3.1 Visit Schedule ................................................................................................................... 16 
3.2 Testing Procedures ............................................................................................................ 16 
STUDY PROCEDURES _______________________________________________________ 17 
4.1 Imaging Procedures .......................................................................................................... 17 
4.2 Other Procedures ............................................................................................................... 17 
MISCELLANEOUS CONSIDERATIONS ________________________________________ 18 
5.1 Treatment of DR and DME............................................................................................... 18 
5.2 Risks and Benefits............................................................................................................. 18 
5.3 Study Participant Withdrawal and Losses to Follow-up................................................... 18 
5.4 Discontinuation of Study .................................................................................................. 18 
5.5 Contact Information Provided to the DRCR.net Coordinating Center ............................. 18 
5.6 Subject Reimbursement .................................................................................................... 19 
STATISTICAL CONSIDERATIONS ____________________________________________ 20 
6.1 Primary Outcome .............................................................................................................. 20 
6.2 Sample Size Estimation .................................................................................................... 21 
6.3 Primary Analysis Plan....................................................................................................... 22 
6.3.1 
Principles for Analysis ............................................................................................. 22 
6.3.2 
Confounding ............................................................................................................ 22 
6.3.3 
Per Protocol Analyses .............................................................................................. 22 
6.3.4 
Sensitivity Analyses ................................................................................................. 22 
6.3.5 
Subgroup Analyses .................................................................................................. 23 
6.4 Secondary Outcomes and Safety Outcomes for Treatment Group Comparison .............. 24 
DATA COLLECTION AND MONITORING ______________________________________ 26 
7.1 Case Report Forms ............................................................................................................ 26 
7.2 Study Records Retention................................................................................................... 26 
7.3 Quality Assurance and Monitoring ................................................................................... 26 
7.4 Protocol Deviations ........................................................................................................... 27 

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ETHICS/PROTECTION OF HUMAN PARTICIPANTS ____________________________ 28 
8.1 Ethical Standard ................................................................................................................ 28 
8.2 Institutional Review Boards .............................................................................................. 28 
8.3 Informed Consent Process ................................................................................................ 28 
8.3.1 
Consent Procedures and Documentation ................................................................. 28 
8.3.2 
Participant and Data Confidentiality ........................................................................ 28 
REFERENCES _______________________________________________________________ 30 

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ABBREVIATIONS 
 
ACCORD 
Action to Control Cardiovascular Risk in Diabetes 
ACCORD-Eye 
Action to Control Cardiovascular Risk in Diabetes Eye Trial 
ALT 
Alanine aminotransferase 
anti-VEGF 
Anti-Vascular Endothelial Growth Factor 
AST 
Aspartate aminotransferase 
bid 
Two times per day 
CI 
Confidence Interval 
CK 
Creatine kinase 
CST 
Central Subfield Thickness 
DME 
Diabetic Macular Edema 
DR 
Diabetic Retinopathy 
DRCR.net  
Diabetic Retinopathy Clinical Research Network 
E-ETDRS 
Electronic- Early Treatment Diabetic Retinopathy Study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FIELD 
Fenofibrate Intervention and Event Lowering in Diabetes 
HbA1c 
Hemoglobin A1c 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization   
IRB 
Institutional Review Board  
JCHR 
Jaeb Center for Health Research 
NF-kappa B 
nuclear factor kappa-light-chain-enhancer of activated B cells 
NPDR 
Non-Proliferative Diabetic Retinopathy 
OCT 
Optical Coherence Tomography 
PDR 
Proliferative Diabetic Retinopathy 
PPARα 
Peroxisome Proliferator-Activated Receptor α 
PROMINENT 
Pemafibrate to Reduce Cardiovascular Outcomes by Reducing 
Triglycerides in Patients with Diabetes 
PRP 
Panretinal Photocoagulation 
QALY 
Quality-Adjusted Life-Year 
US 
United States 
UWF 
Ultra-widefield 
 

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INTRODUCTION 
1 
 
2 
1.1 Diabetic Retinopathy Complications and Public Health Impact 
3 
The age-adjusted incidence of diabetes mellitus in the United States has reportedly doubled in 
4 
recent history.1 Estimates suggest that by the year 2040, approximately 642 million individuals 
5 
worldwide will be affected by this chronic disease.2 The increasing global epidemic of diabetes 
6 
implies an increase in rates of associated vascular complications from diabetes.  At present, almost 
7 
8 million people in the United States are estimated to have diabetic retinopathy (DR).3 Despite 
8 
advances in the diagnosis and management of ocular disease in patients with diabetes, eye 
9 
complications from diabetes mellitus continue to be a leading cause of vision loss and new onset 
10 
blindness in working-age individuals throughout the United States.4, 5 
11 
 
12 
1.2 Preventing DR Onset and Worsening 
13 
At this time, the primary method of slowing DR onset and worsening remains that of strict glycemic 
14 
control and blood pressure control.  Results from the Early Treatment Diabetic Retinopathy Study 
15 
(ETDRS) revealed that better glycemic control inhibits DR worsening among all age groups, type 1 
16 
and type 2 diabetes, and all stages of retinopathy.6 The United Kingdom Prospective Diabetes Study 
17 
(UKPDS) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study 
18 
demonstrated that improved blood glucose control can reduce the risk of developing DR in patients 
19 
with type 2 diabetes, with the UKPDS additionally showing the benefit of improved blood pressure 
20 
control.7, 8  The Diabetes Control and Complications Trial (DCCT) found that intensive therapy, 
21 
aimed at keeping glycemic levels as close to normal range values as possible, reduced the risk of 
22 
any DR developing by 76% (95% confidence interval (CI):62% to 85%) among patients with no DR 
23 
at baseline and slowed the worsening of DR by 54% (95% CI: 39% to 66%) among patients with 
24 
mild DR at baseline.9  The benefits of intensive treatment were sustained for approximately 4 years 
25 
after the period of intensive glycemic control with a 75% (P<0.001) risk reduction in the worsening 
26 
of DR.10  This beneficial effect in fact persisted for even as long as 18 and 25 years later in this 
27 
cohort of study participants with type 1 diabetes. 11, 12 This beneficial effect also persisted in type 2 
28 
diabetes.13, 14 
29 
 
30 
Despite improvements in systemic glycemic control,15 there continues to be a substantial proportion 
31 
of diabetic patients who develop DR and its associated sequelae.  In 2005–2008, 28.5% (4.2 
32 
million) of Americans with diabetes aged 40 years or older had DR, and of this group, 655,000 
33 
individuals had advanced DR that could lead to severe vision loss.16  Approximately 40-60% of the 
34 
Wisconsin Epidemiologic Study Diabetic Retinopathy (WESDR) cohort, whose onset of diabetes 
35 
occurred between 1922 and 1980, developed proliferative diabetic retinopathy (PDR) over time, 
36 
with rates of visual impairment (vision of 20/40 or less in the better seeing eye) ranging from 
37 
approximately 5% to 20%.15   
38 
 
39 
1.3 Limitations of Current Treatments for PDR and DME 
40 
Recent advances in therapy for advanced diabetic eye disease include the use of anti-vascular 
41 
endothelial growth factor (anti-VEGF) agents to prevent vision loss from PDR and also to treat 
42 
center-involved DME.  Anti-VEGF therapy has been shown to be highly effective in treating active 
43 
ocular neovascularization as well as in increasing visual gain and decreasing visual loss in eyes with 
44 
center-involved DME.17-19  However, anti-VEGF treatment does have drawbacks including the need 
45 
for recurrent intravitreous injections for medication delivery that are performed as often as once a 
46 
month.  These injections have potential associated side effects including the development of 
47 
endophthalmitis and incremental cost effectiveness ratios when using aflibercept or ranibizumab 
48 
that are far beyond $100,000 per Quality-Adjusted Life-Year (QALY) over a 10-year time horizon 
49 
compared with bevacizumab.20 In addition not all eyes treated with anti-VEGF have resolution of 
50 

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DR or DME.19, 21  Scatter laser photocoagulation or panretinal photocoagulation (PRP) is another 
51 
treatment for PDR that is not invasive and does not need to be repeated as frequently as anti-VEGF 
52 
injections, but laser treatment has other well-documented adverse effects, including exacerbation or 
53 
development of macular edema with transient or permanent central vision loss, peripheral visual 
54 
field defects, night vision loss, loss of contrast sensitivity, potential complications from misdirected 
55 
or excessive burns, increased risk of vitrectomy compared with anti-VEGF treatment, and 
56 
worsening of visual loss in nearly 5 percent of individuals despite appropriate treatment.19, 22  Thus, 
57 
there is an ongoing need to identify novel therapies that are both effective for PDR and DME 
58 
treatment and that also avoid the potential adverse events or costs associated with current ocular 
59 
interventions.  Furthermore, the identification of an oral therapeutic agent that may prevent 
60 
worsening to PDR or DME might allow treatment of a wider segment of the diabetic population at 
61 
risk for diabetic eye complications who do not have access to anti-VEGF or laser treatment or who 
62 
are not suitable candidates for these treatments.  This would be a major public health contribution if 
63 
indeed this potentially effective oral agent could be implemented into clinical care. 
64 
 
65 
1.4 Rationale for PPARα Therapy for DR Worsening 
66 
Two major clinical studies in patients with diabetes have demonstrated beneficial effects on ocular 
67 
outcomes from treatment with oral fenofibrate, which acts via activation of peroxisome proliferator-
68 
activated receptor α (PPARα) and may decrease inflammation through inhibition of NF-kappa B 
69 
activity.23  Fenofibrate is an oral medication of the fibrate class with a well-documented and 
70 
favorable safety profile that is used for treatment of hyperlipidemia.  Fenofibrate reduces low-
71 
density and very low-density lipoprotein and triglyceride levels while increasing high-density 
72 
lipoprotein levels.  In addition to its agonist effects on the PPARα pathway, fenofibrate affects 
73 
human retinal endothelial cells through a PPARα-independent mechanism.  A number of other 
74 
pathways have also been explored with regards to its effects in diabetic retinopathy.  For example, 
75 
Dr. Lois Smith from Harvard has suggested that fenofibrate may inhibit cytochrome P450 
76 
epoxygenase 2C activity resulting in reduction in pathological ocular angiogenesis, using her 
77 
oxygen induced retinopathy in a mouse model.  Others have suggested a decrease in NF-kappa B 
78 
activity may be the potential pathway for reduction of diabetic retinopathy progression.  Other 
79 
mechanisms have also been suggested.24-29 
80 
  
81 
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study randomized 9795 
82 
patients with type 2 diabetes to fenofibrate 200 mg/day versus placebo.30  A subgroup of this cohort 
83 
(N=1012) also agreed to undergo fundus photography at baseline, 2 year, 5 year, and end of study in 
84 
order to document DR severity worsening.  The percentage of patients requiring first laser treatment 
85 
for either DR or DME was significantly lower in the fenofibrate group than in the placebo group 
86 
(3.4% vs 4.9%; HR for first laser treatment: 0.69, 95% CI 0.56-0.84, P = 0.0002).  850 participants 
87 
(84%; 421 allocated to placebo, 429 allocated to fenofibrate) in the photography substudy were 
88 
followed to the end of the study.  Although a difference between the groups overall for the primary 
89 
endpoint of 2-step DR worsening in the substudy was not identified, in the subgroup of participants 
90 
with pre-existing DR (N=193), fenofibrate treatment was associated with a reduction in 2-step DR 
91 
worsening as compared with placebo (3.1% versus 14.6%, P = 0.004).   
92 
 
93 
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial enrolled 10,251 
94 
participants with type 2 diabetes and randomized them to intensive glycemic control (goal HbA1c < 
95 
6.0%) or standard therapy.8  The 5,518 participants with dyslipidemia were further randomized in a 
96 
2x2 factorial design to receive simvastatin in combination with either fenofibrate (at 160 or 54 
97 
mg/day depending on renal function) or placebo.  The ACCORD Eye study enrolled 3,537 
98 
individuals from this group of which 82.3% (N = 2,856) achieved both a baseline and year 4 follow-
99 
up visit and among which 1,593 were included in the fenofibrate portion of the trial.  Among all of 
100 

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the participants in the ACCORD Eye trial, 1,370 (48%) had no diabetic retinopathy in either eye, 
101 
892 (31%) had mild diabetic retinopathy, 553 (19%) had mild to moderately severe NPDR, and 39 
102 
(1%) had severe NPDR or PDR (note: 2 participants were not classified). 
103 
 
104 
At 4 years, DR worsening was significantly less likely with intensive glycemic control as compared 
105 
with standard therapy (7.3% vs. 10.4%; adjusted OR, 0.67, 95% CI, 0.51-0.87, P = 0.003).  DR 
106 
worsening also was significantly less frequent in the fenofibrate as compared with the placebo-
107 
treated group (6.5% versus 10.2%, adjusted OR, 0.60, 95% CI, 0.42-0.87, P = 0.006).  The benefit 
108 
of fenofibrate therapy was seen primarily in study participants with DR at baseline (see table 
109 
below).  In patients with microaneurysms in only 1 or both eyes or with mild nonproliferative 
110 
diabetic retinopathy (NPDR) in only 1 eye, the odds ratio for >3 step progression was 0.27 (95% CI: 
111 
0.12-0.63, p = 0.0009).31 No significant relationship was seen between fenofibrate use and DR 
112 
worsening in eyes with no DR.  Among participants with mild NPDR to moderately severe NPDR 
113 
(N = 279) the rates of progression were 9% to 17%.  Fenofibrate treatment did not appear to affect 
114 
the rate of at least moderate vision loss (fenofibrate group: 23.7%, vs. placebo group: 24.5%, P = 
115 
0.57), nor did it affect changes in macular edema status between baseline and year 4. 
116 
 
117 
*Table taken from Chew EY, Davis MD, Danis RP, et al. The effects of medical management on the progression of 
118 
diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes 
119 
(ACCORD) Eye Study. Ophthalmology. 2014;121(12):2443-51. 
120 
 
121 
In the 8 year follow-up study of ACCORD, 4 years following the cessation of the fenofibrate, the 
122 
rates of diabetic retinopathy progression was 11.8% (47 of 399) in the fenofibrate group and 10.2% 
123 
(37 of 363) in the placebo group with an adjusted odds ratio (OR) of 1.13 (95% CI: 0.71-1.79; P 
124 
=0.60), suggesting the benefit does not persist once the drug is stopped.  Using the Cox proportional 
125 
hazards model resulted in an adjusted HR of 0.76 (95% CI 0.57–1.03, P = 0.08).  When adjusted for 
126 
the competing risk of death, the adjusted HR was 0.83 (95% CI 0.69–1.00, P = 0.04).14   
127 
 
128 
1.5 Pemafibrate and the Ongoing PROMINENT trial  
129 
Pemafibrate is a highly selective and potent modulator of PPARα.  Pemafibrate, a selective 
130 
peroxisome proliferator alpha receptor modulator (SPPARM-α), is approximately 2,500 times more 
131 
potent than fenofibric acid, in terms of the concentration, producing 50% effectiveness (i.e., 
132 
effective concentration in 50% of participants [EC50]) of the PPARα-activating effect.  The 
133 
Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with 
134 
Diabetes (PROMINENT) study is a phase 3 multinational, multicenter, randomized, placebo- 
135 
controlled masked trial to assess whether treatment with pemafibrate will delay the time to 
136 
occurrence of the composite cardiovascular outcome of nonfatal myocardial infarction, nonfatal 
137 

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ischemic stroke, unstable angina requiring unplanned revascularization and/or cardiovascular death.  
138 
The participants are adults with type 2 diabetes who have elevated triglycerides and low high-
139 
density lipoprotein cholesterol, and are at high risk for cardiovascular events, in the context of 
140 
adequate background of lipid-lowering therapy (including stable dose moderate or high intensity 
141 
statin).  Two-thirds of the enrolled study population will have prior evidence of systemic 
142 
atherosclerosis (secondary prevention cohort) while one-third will not (high risk primary prevention 
143 
cohort, age ≥ 50 years [male] or ≥ 55 years [female]).  There are expected to be approximately 
144 
2,500 participants enrolled in the U.S. and Canada.  The trial is an event-driven trial, anticipated to 
145 
involve approximately 10,000 participants to achieve 1,092 cardiovascular events over 
146 
approximately 5 years.   
147 
 
148 
This protocol is an ancillary study to the main PROMINENT trial in which the DRCR.net and 
149 
PROMINENT Study Group will collaborate to evaluate the effect of pemafibrate treatment versus 
150 
placebo on long-term rates of DR worsening in patients with type 2 diabetes at risk for 
151 
cardiovascular events.  Based on data from eyes with baseline retinopathy in the ACCORD Eye 
152 
study (see table below), it is anticipated that approximately 50% of PROMINENT study 
153 
participants will have diabetic retinopathy in at least one eye and be eligible for this PROMINENT-
154 
Eye Study.   
155 
 
156 
Table taken from Chew EY, Davis MD, Danis RP, et al. The effects of medical management on the progression of 
157 
diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes 
158 
(ACCORD) Eye Study. Ophthalmology. 2014;121(12):2443-51. 
159 
 
160 
1.6 Summary of Protocol Rationale 
161 
Despite improved glycemic and systemic control for many patients with diabetes, over the past 
162 
several decades, DR develops and progresses in a large proportion of patients, and visual loss from 
163 
diabetic eye complications continues to be a leading cause of blindness in the US and other 
164 
developed countries worldwide.  Thus, even a modest ability to prevent DR onset or to slow DR 
165 
worsening might substantially reduce the number of patients at risk for diabetes-related vision loss 
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worldwide.  Widespread use of an oral agent effective at reducing worsening of DR might also 
167 
decrease the numbers of patients who undergo treatment for DR and DME and who are 
168 
consequently at risk for side effects that adversely affect visual function.  Two major studies of 
169 
fenofibrate, FIELD and ACCORD-eye, have demonstrated clinically important reduction in 
170 
progression of retinopathy in patients with diabetes assigned to fibrate compared with placebo.  
171 
However, despite the positive clinical trial results, fenofibrate has not gained wide acceptance as a 
172 
preventive agent by either ophthalmologists or primary diabetes care providers.  Thus, it is 
173 
important to provide further evidence demonstrating whether or not selectively increasing PPARα 
174 
activity reduces progression of retinopathy in patients with diabetes and non-proliferative diabetic 
175 
retinopathy at baseline.  Pemafibrate is a more potent and selective PPARα modulator than 
176 
fenofibrate.  Its efficacy is currently being evaluated in the PROMINENT study for prevention of 
177 
cardiovascular events in patients with type 2 diabetes.  Given the large study cohort with a 
178 
substantial proportion likely to have DR and the multi-year duration of the PROMINENT trial, this 
179 
study represents a unique opportunity to assess effects of chronic PPARα activation through 
180 
pemafibrate therapy on DR outcomes.   
181 
 
182 
1.7 Study Objective 
183 
 
184 
 Primary Objective: 
185 
1. To assess whether treatment with pemafibrate (0.2 mg orally BID) compared with placebo 
186 
reduces the hazard rate of diabetic retinopathy worsening in adults with type 2 diabetes and 
187 
diabetic retinopathy without neovascularization in at least one eye who are participating in 
188 
the parent PROMINENT trial. 
189 
 
190 
Secondary Objectives: 
191 
1. To assess whether treatment with pemafibrate (0.2 mg orally BID) compared with placebo 
192 
reduces rates of diabetic macular edema development or visual acuity worsening. 
193 
 
194 
2. To assess whether treatment with pemafibrate compared with placebo affects safety or 
195 
tolerability in the cohort of participants with diabetic retinopathy in at least one eye. 
196 
 
197 
1.8 Study Design and Synopsis of Protocol 
198 
A. Study Design 
199 
• Longitudinal ancillary study to the PROMINENT trial. 
200 
 
201 
B. Major Eligibility Criteria (see section 2.2 for additional eligibility criteria) 
202 
• Already randomized at US or Canadian sites in the PROMINENT study 
203 
a. Enrollment visit into the ancillary study must be conducted within 3 months of 
204 
randomization into the PROMINENT trial. 
205 
• Ability to cooperate with dilated ophthalmic examination and imaging procedures 
206 
• At least one eye meets the following study eye inclusion criteria: 
207 
a. ETDRS Diabetic Retinopathy Severity level between 20 and 53 (minimal to severe 
208 
NPDR), inclusive, according to the investigator and confirmed by central Reading 
209 
Center grading. 
210 
• Major study eye exclusion criteria are: 
211 
a. Neovascularization on clinical exam or fundus photographs 
212 
b. Current central-involved DME based on optical coherence tomography  (OCT) 
213 
central subfield thickness (CST) 
214 
i. Zeiss Cirrus: CST ≥ 290µm in women or ≥ 305µm in men 
215 
ii. Heidelberg Spectralis: CST ≥ 305µm in women or ≥ 320µm in men 
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c. Major non-diabetic intraocular pathology that in the opinion of the investigator 
217 
would substantially and adversely affect visual acuity or lead to ocular 
218 
neovascularization during the course of the study 
219 
d. Anticipated need for intravitreous anti-VEGF, intravitreous corticosteroid, or PRP in 
220 
the next 6 months following randomization 
221 
e. History of intravitreous anti-VEGF or corticosteroid treatment within the prior year 
222 
for any indication. 
223 
f. Any history of PRP or vitrectomy 
224 
 
225 
Participants may have 1 or 2 study eyes based on how many eyes meet eligibility criteria. 
226 
 
227 
C. Estimated Sample Size 
228 
At least 600 individuals are expected to be eligible and to enroll in the study at US and Canadian 
229 
DRCR.net clinical sites that have geographic proximity to the parent PROMINENT clinical site.  
230 
Recruitment will continue until the PROMINENT trial has completed enrollment, with up to a 
231 
maximum of 900 enrolling in PROMINENT-Eye. 
232 
 
233 
D. Protocol Summary 
234 
Participants in the parent PROMINENT study will be referred to partnering DRCR.net sites for 
235 
comprehensive ophthalmologic examination including visual acuity, fundus photography and 
236 
spectral domain optical coherence tomography (OCT) to be performed within 3 months of the 
237 
PROMINENT randomization visit.  Participants who meet eligibility criteria at this visit will be 
238 
eligible for two or three additional study ophthalmic visits through 4 years (see Table in Section E 
239 
below).  Participants who do not meet ocular eligibility will be discontinued from the ancillary 
240 
PROMINENT-Eye Study, but not from the parent study.  If intravitreous anti-VEGF or 
241 
corticosteroid treatment, PRP, or vitrectomy will be administered to a study eye for any indication 
242 
for the first time since entering the study, when possible, all study procedures should be performed 
243 
prior to implementing treatment to establish retinopathy severity before therapy is initiated.  
244 
Participants who receive treatment will continue follow-up through 4 years. 
245 
 
246 
E. Schedule of Study Visit and Examination Procedures 
247 
 
248 
 
Screening/ 
Baselinea 
2 yearb 
± 2 months 
4 yearb 
± 2 monthsc 
Prior to 
DME/PDR 
Treatment 
Initiationd 
Visit and Visit Window 
Best corrected visual 
acuity 
X 
X 
X 
X 
Eye Exame, f 
X 
X 
X 
X 
DRCR.net Fundus 
Photographye,g 
X 
X 
X 
X 
Spectral Domain OCTe 
X 
X 
X 
X 
Collection of Adverse 
Events occurring during 
the visit 
X 
X 
X 
X 
a. 
To be performed within 3 months of the PROMINENT randomization visit 
249 
b. Time from randomization into the PROMINENT trial.  
250 

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c. 
If the PROMINENT trial ends before a participant reaches the 4 year visit, one final visit within 3 months of 
251 
the PROMINENT trial ending will be completed.  
252 
d. All study procedures should be performed prior to the initiation of treatment for DME or DR in a study eye.   
253 
e. 
After pupil dilation  
254 
f. 
Participants may opt out of eye exam particularly if they have recently had an eye exam 
255 
g. The widest camera type available will be used for color fundus photography. 
256 
 
257 
F. Outcomes 
258 
Primary outcome: 
259 
 
260 
The primary outcome is diabetic retinopathy worsening or DME development (composite outcome), 
261 
based on both eyes for bilateral participants and based on the study eye only for unilateral 
262 
participants.  Study eye is defined based on the criteria in section 2.2.2 as the eye(s) having ETDRS 
263 
Diabetic Retinopathy Severity level between 20 and 53 (minimal to severe NPDR), inclusive, 
264 
according to the investigator and confirmed by central Reading Center, without definite central 
265 
subfield involved diabetic macular edema. 
266 
 
267 
Diabetic retinopathy worsening or DME development is defined as any of the following: 
268 
 
269 
• For participants with 2 study eyes: 3-step worsening on the ETDRS Retinopathy Severity Scale 
270 
for Persons (Table 1 in Section 6) at a protocol visit.  This scale takes into account the 
271 
retinopathy level of both study eyes. 
272 
• For participants with one study eye: 2-step worsening on the ETDRS Retinopathy Severity 
273 
Scale for Individual Eyes (Table 2 in Section 6) in the study eye at a protocol visit.  This scale 
274 
only takes into account the retinopathy level of the study eye. 
275 
• Procedure undertaken for the treatment of PDR at any time (even in the absence of photographic 
276 
documentation) including PRP, intravitreous anti-VEGF, or vitrectomy in at least one study eye. 
277 
• Treatment initiated for DME at any time (even in the absence of OCT documentation) including 
278 
anti-VEGF, corticosteroids, focal/grid laser, or vitrectomy in at least one study eye. 
279 
• Development of central-involved DME on OCT with vision loss at the 2-year or 4-year visit.  
280 
Defined as OCT central subfield thickness above the machine and gender-specific thresholds 
281 
(see Section 2.2.2 for details) with at least a 10% increase in thickness from baseline and visual 
282 
acuity 20/32 or worse (letter score ≤ 78) in at least one study eye. 
283 
 
284 
Secondary outcomes include a treatment comparison of the following: 
285 
 
286 
Participant-Level Secondary Outcomes (relates to either eye for bilateral participants and to the 
287 
study eye for unilateral participants): 
288 
 
289 
• Hazard rate of 3-step person-level (for bilateral participants, see Table 1 in Section 6) or 2-step 
290 
eye-level (for unilateral participants, see Table 2 in Section 6) diabetic retinopathy worsening on 
291 
the ETDRS Retinopathy Severity Scale or receiving treatment for PDR in at least one study eye 
292 
at any time (irrespective of DME status or treatment) 
293 
• Hazard rate of developing central-involved DME on OCT with vision loss (as defined above) or 
294 
receiving treatment for DME in at least one study eye at any time (irrespective of diabetic 
295 
retinopathy severity level or treatment) 
296 
• Person-level diabetic retinopathy severity at 2 years and 4 years 
297 
• Percentage of participants with at least a 2-line loss in visual acuity from baseline in at least one 
298 
study eye at 2 years and 4 years 
299 

PROMINENT-Eye 3-14-18 V2.0 
 
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300 
Eye-Level Secondary Outcomes (evaluated only for study eyes): 
301 
 
302 
• Hazard rate of a composite PDR/DME outcome.  Defined as the time to 2-step diabetic 
303 
retinopathy worsening on the ETDRS Retinopathy Severity Scale for Individual Eyes (see 
304 
Table 2 in Section 6) at 2 years or 4 years, development of central-involved DME on OCT 
305 
with vision loss (as defined above) at 2 years or 4 years, or treatment for DME or PDR at 
306 
any time 
307 
• Hazard rate of 2-step diabetic retinopathy worsening or receiving treatment for PDR at any 
308 
time (irrespective of DME status or treatment) 
309 
• Hazard rate of developing central-involved DME on OCT with vision loss at 2 years or 4 
310 
years or receiving treatment for DME at any time (irrespective of diabetic retinopathy level 
311 
or treatment) 
312 
• Eye-level diabetic retinopathy severity at 2 years and 4 years 
313 
• Change in OCT central subfield thickness from baseline at 2 years and 4 years 
314 
• Change in visual acuity letter score from baseline at 2 years and 4 years 
315 
• Percentage of eyes with at least 2-line loss in visual acuity from baseline at 2 years and 4 
316 
years 
317 
 
318 
Safety Outcomes: 
319 
• Adverse events collected as part of this ancillary study including vitreous hemorrhage and 
320 
retinal detachment 
321 
• Changes from randomization in ALT, AST, CK, and creatinine 
322 
 
323 
1.9 General Considerations 
324 
The study is being conducted in compliance with the policies described in the DRCR.net Policies 
325 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with the 
326 
protocol described herein, and in accordance with ICH E6 Good Clinical Practice.  All study 
327 
investigators will attest to complying with these requirements.  
328 
 
329 
The DRCR.net Procedures Manuals provide details of the imaging procedures.   
330 
 
331 
Retinal images and OCT data will be primary source data, and additional data collected will be 
332 
directly entered in electronic case report forms, which will be considered the source data. 
333 
 
334 
There is no restriction on the number of participants to be enrolled by a site. 
335 
 
336 
Assessment of adverse events occurring during the Prominent-Eye clinical visit will be obtained 
337 
through adverse event reporting at the end of each study visit. 
338 
 
339 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
340 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
341 
2013). 
342 
 
343 
The risk level for this ancillary research is considered to be no more than minimal risk. 
344 

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STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 
345 
 
346 
2.1 Identifying Eligible Participants and Obtaining Informed Consent 
347 
At least 600 participants are expected to be enrolled in this study.  Recruitment will continue until 
348 
the PROMINENT trial has completed enrollment, with up to a maximum of 900 participants 
349 
enrolling in PROMINENT-Eye.  Participants in the PROMINENT trial will be referred to 
350 
participating DRCR.net sites based on geographic proximity within the U.S. and Canada.  The 
351 
ancillary study brochure providing an overview of the study will be initially discussed with the 
352 
patient by the PROMINENT investigator and/or coordinator.  Interested participants will be 
353 
provided contact information and encouraged to contact their local PROMINENT-Eye clinical site 
354 
and (if permitted by the IRB) will consent to having their contact information provided to the local 
355 
PROMINENT-Eye clinical site and the DRCR.net Coordinating Center.  The DRCR.net 
356 
PROMENENT-Eye clinical site may also contact the participant to facilitate scheduling with 
357 
participant consent.   
358 
 
359 
At the DRCR.net clinical site, the PROMINENT-Eye study protocol will be discussed with the 
360 
patient by a DRCR.net study investigator and clinic coordinator.  Prior to completing any 
361 
procedures or collecting any data for this study, informed consent will be obtained.  Potential 
362 
eligibility will be assessed at the screening visit.  Patients who are eligible based on the screening 
363 
visit and Reading Center confirmation of DR severity level will return for additional study imaging 
364 
visits as outlined below. 
365 
 
366 
2.2 Subject Eligibility and Exclusion Criteria 
367 
2.2.1 Eligibility Criteria 
368 
• Already randomized at US or Canadian sites in the PROMINENT study 
369 
a. Enrollment visit into the ancillary study must be conducted within 3 months of 
370 
randomization into the PROMINENT trial. 
371 
• Ability to cooperate with dilated ophthalmic examination and imaging procedures 
372 
 
373 
2.2.2 Study Eye Criteria: 
374 
The study participant must have at least one eye meeting all of the inclusion criteria listed below.   
375 
 
376 
The eligibility criteria for a study eye are as follows (both eyes will be considered study eyes if both 
377 
meet the eligibility criteria at the time of enrollment): 
378 
 
379 
• At least one eye meets the following study eye inclusion criteria: 
380 
a. ETDRS Diabetic Retinopathy Severity level between 20 and 53 (minimal to severe 
381 
NPDR), inclusive, on color fundus photographs confirmed by central Reading Center 
382 
grading. 
383 
• Study eye exclusion criteria are: 
384 
a. Neovascularization present. 
385 
b. Current central-involved DME based on optical coherence tomography  (OCT) 
386 
central subfield thickness (CST) 
387 
i. Zeiss Cirrus: CST ≥ 290µm in women or ≥ 305µm in men 
388 
ii. Heidelberg Spectralis: CST ≥ 305µm in women or ≥ 320µm in men 
389 
c. Known major non-diabetic intraocular pathology that in the opinion of the 
390 
investigator would substantially and adversely affect visual acuity or lead to ocular 
391 
neovascularization during the course of the study 
392 

PROMINENT-Eye 3-14-18 V2.0 
 
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d. Anticipated need for intravitreous anti-VEGF, intravitreous corticosteroid, or PRP in 
393 
the next 6 months following randomization 
394 
e. History of intravitreous anti-VEGF or corticosteroid treatment within the prior year 
395 
for any indication. 
396 
f. History of intraocular surgery within prior 4 months or anticipated within the next 6 
397 
months following randomization 
398 
g. Any history of PRP or vitrectomy 
399 
h. History of YAG capsulotomy performed within 2 months prior to screening 
400 
i. Aphakia 
401 
j. Known substantial media opacities that would preclude successful imaging 
402 
 
403 
Participants may have 1 or 2 study eyes based on how many eyes meet eligibility criteria. 
404 
 
405 
2.3 Screening Evaluation and Baseline Testing 
406 
2.3.1 Ocular Historical Information 
407 
An ocular history will be elicited from the potential study participant including prior ocular 
408 
diseases, surgeries, and treatment. 
409 
 
410 
2.3.2 Baseline Testing Procedures 
411 
The following procedures will be performed to assess eligibility and/or to serve as baseline 
412 
measures for the study: 
413 
• The testing procedures are detailed in the DRCR.net Procedures Manuals.  Visual acuity 
414 
testing, ocular exam, fundus photography, and OCT will be performed by DRCR.net 
415 
certified personnel.  
416 
• The fundus photographs will be sent to a Reading Center for grading. 
417 
• OCT images meeting DRCR.net criteria for manual grading will be sent to a Reading 
418 
Center. 
419 
 
420 
1. E-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester (including 
421 
protocol refraction) in each eye 
422 
2. Ocular examination on each eye including dilated ophthalmoscopy 
423 
• Participant can opt out of ocular exam (dilation will be required regardless)  
424 
3. Spectral Domain OCT using Zeiss Cirrus or Heidelberg Spectralis OCT machine on both eyes  
425 
4. DRCR.net protocol fundus photography in both eyes 
426 
• The widest field camera type available will be used for color fundus photography.
427 

PROMINENT-Eye 3-14-18 V2.0 
 
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FOLLOW-UP VISITS  
428 
 
429 
3.1 Visit Schedule 
430 
Each participant will have protocol specific follow-up visits scheduled at 2 years (± 2 months) and 
431 
at 4 years (± 2 months) from the randomization date in the PROMINENT trial.  If the 
432 
PROMINENT study ends prior to a participant’s 4-year visit, the participant will have one closeout 
433 
visit within 3 months of the last PROMINENT visit. 
434 
 
435 
Additional retina evaluation visits may occur as required for usual care of the study participant 
436 
either by the DRCR.net clinical site or by the participant’s non-DRCR.net ophthalmologist.  If the 
437 
participant will be examined by a non-DRCR.net ophthalmologist, the participant will be asked to 
438 
sign a medical records release so any treatment that is documented can be obtained by the 
439 
DRCR.net site.  In addition, participants for whom ocular treatment for DR or DME is planned for 
440 
the first time during the trial (e.g. anti-VEGF or corticosteroid intravitreous injection, PRP, 
441 
focal/grid laser, or vitrectomy) will be asked to return to the DRCR.net clinical site to complete the 
442 
study procedures before the treatment is administered, provided treatment is not urgently needed as 
443 
determined by the treating physician.  If pre-treatment images are not able to be obtained, study 
444 
images should try to be obtained within 1 month after treatment initiation.  Participants who receive 
445 
treatment will continue follow-up through 4 years. 
446 
 
447 
Communication between the PROMINENT clinical site and the PROMINENT-Eye clinical site 
448 
may occur to facilitate compliance with the follow-up schedule if needed. 
449 
 
450 
3.2 Testing Procedures 
451 
The following procedures will be performed at each protocol visit unless otherwise specified.  A 
452 
grid in section 1.3 summarizes the testing performed at each visit.   
453 
 
454 
1. Visual Acuity: 
455 
• A protocol refraction followed by E-ETDRS visual acuity testing in both eyes (best 
456 
corrected). 
457 
2. Ocular examination on each eye including dilated ophthalmoscopy 
458 
• Participant can opt out of ocular exam (dilation will be required regardless)  
459 
3. OCT using Zeiss Cirrus or Heidelberg Spectralis OCT machine on both eyes  
460 
4. DRCR.net protocol fundus photography in both eyes  
461 
• The widest field camera type available will be used for color fundus photography. 
462 
 
463 
All of the testing procedures do not need to be performed on the same day, provided that they are 
464 
completed within the time window of a visit and prior to initiating any treatment. 
 
465 

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STUDY PROCEDURES 
466 
 
467 
4.1 Imaging Procedures 
468 
The DRCR.net protocol images will be obtained by a fundus photographer specifically certified by 
469 
the DRCR.net for these imaging procedures.  The images will be first sent to the DRCR.net 
470 
Coordinating Center (uploaded through the website as available) and then to a Reading Center for 
471 
further evaluation.  During image grading, a map of the ETDRS 7 standard fields will be placed as 
472 
an overlay on each ultra-widefield (UWF) image with peripheral areas outside the ETDRS fields 
473 
darkened so that extent and severity of DR lesions can be graded separately for the areas within and 
474 
outside the ETDRS fields. 
475 
 
476 
OCT will be performed by DRCR.net certified personnel.  Only spectral domain machines are 
477 
permitted.  For a given study participant, the same machine type should be used for the duration of 
478 
the study, unless circumstances do not permit (e.g., replacement of damaged machine).  If a switch 
479 
is necessary, the same machine type should be used for the remainder of the study.  The images will 
480 
be sent to the DRCR.net Coordinating Center (uploaded through the website as available) and may 
481 
be sent to a Reading Center for further evaluation. 
482 
 
483 
Each digital image must be evaluated to be of adequate quality for submission, according to the 
484 
study procedures.  If photograph quality is judged substandard by the operator, then the imaging 
485 
should be repeated until a good quality image is obtained.   
486 
 
487 
4.2 Other Procedures 
488 
Ocular historical information will be collected, including prior treatment for diabetic retinopathy, 
489 
prior nondiabetic ocular diseases, surgeries, and treatment. 
490 
 
491 
4.3 Safety Assessments 
492 
Assessment of subject safety at the study visit will be obtained through adverse event reporting at 
493 
the end of each study visit.  Any adverse events that occurred during the participant’s visit will be 
494 
documented and communicated to the PROMINENT clinical site, and these adverse events will be 
495 
entered into the PROMINENT study database.
496 

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MISCELLANEOUS CONSIDERATIONS 
497 
 
498 
5.1 Treatment of DR and DME 
499 
Treatment of diabetic retinopathy and/or DME including initiation of PRP or anti-VEGF treatment 
500 
is at the discretion of the treating physician.  However, the first time PRP, intravitreous anti-VEGF 
501 
or corticosteroid treatment, focal/grid laser, or vitrectomy is planned, the study procedures should 
502 
be performed prior to treatment initiation, provided treatment is not urgently needed as determined 
503 
by the treating physician. 
504 
 
505 
5.2 Risks and Benefits 
506 
The procedures in this study are part of daily ophthalmologic practice in the United States and pose 
507 
few known risks.  Dilating eye drops will be used as part of the exam.  There is a small risk of 
508 
inducing a narrow-angle glaucoma attack from the pupil dilation.  However, all participants will 
509 
have had prior pupil dilation usually on multiple occasions and therefore the risk is extremely small.  
510 
Fundus photographs have bright lights associated with the camera flashes, which can be 
511 
uncomfortable for study participants, but these carry no known risk to the eye or vision. 
512 
 
513 
There may be few direct benefits from participating in this ancillary study other than the awareness 
514 
of being involved in a large endeavor to answer relevant and timely questions regarding the possible 
515 
benefit of pemafibrate on diabetic retinopathy progression. 
516 
 
517 
In addition, if proliferative diabetic retinopathy is identified on color fundus photos, the 
518 
participant’s non-DRCR.net ophthalmologist (if applicable) and the PROMINENT investigator will 
519 
be notified of this diagnosis so that treatment can be initiated if necessary.   
520 
 
521 
5.3 Study Participant Withdrawal and Losses to Follow-up 
522 
A study participant has the right to withdraw from the study at any time.  If a study participant is 
523 
considering withdrawal from the study, the principal investigator should personally speak to the 
524 
individual about the reasons, and every effort should be made to accommodate him or her.   
525 
 
526 
The goal for the study is to have as few losses to follow-up as possible.  The Coordinating Center 
527 
will assist in the tracking of study participants who cannot be contacted by the site.  The 
528 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 
529 
 
530 
Study participants who withdraw will be asked to have a final closeout visit at which the testing 
531 
described for the protocol visits will be performed. 
532 
 
533 
5.4 Discontinuation of Study 
534 
The study may be discontinued by the Executive Committee of the parent PROMINENT study or 
535 
the Executive Committee of the PROMINENT-Eye study prior to the preplanned completion of 
536 
follow-up for all ancillary study participants. 
537 
 
538 
5.5 Contact Information Provided to the DRCR.net Coordinating Center 
539 
The Coordinating Center will be provided with contact information for each study participant.  
540 
Permission to obtain such information will be included in the Informed Consent Form from the 
541 
PROMINENT study and from the PROMINENT-Eye study.  The contact information will be 
542 
maintained in a secure database and will be maintained separately from the study data. 
543 
 
544 
Contact from the Coordinating Center may be made for each study participant in the first month 
545 
after enrollment, and approximately every six months thereafter.  Additional contacts from the 
546 

PROMINENT-Eye 3-14-18 V2.0 
 
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Coordinating Center will be made if necessary to facilitate the scheduling of the study participant 
547 
for follow-up visits.  A participant-oriented newsletter may be sent once a year.  A study logo item 
548 
may be sent once a year.  
549 
 
550 
Study participants may be provided with a summary of the study results in a newsletter format after 
551 
completion of the study by all participants. 
552 
 
553 
5.6 Subject Reimbursement 
554 
The Coordinating Center will provide each study participant with a $50 merchandise or money card 
555 
per completed protocol visit.  Additional travel expenses may be paid in cases for participants with 
556 
higher expenses. 
557 

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STATISTICAL CONSIDERATIONS 
558 
 
559 
The approach to sample size and statistical analysis is summarized below.  A detailed statistical 
560 
analysis plan will be written and finalized prior to the completion of the study. 
561 
 
562 
6.1 Primary Outcome 
563 
The primary outcome is diabetic retinopathy worsening or DME development (composite outcome), 
564 
based on both eyes for bilateral participants and based on the study eye only for unilateral 
565 
participants.  From a statistical perspective, the primary outcome is a person-level outcome as data 
566 
from both eyes of bilateral participants is combined into a single outcome measurement.  The 
567 
primary outcome is defined as any of the following: 
568 
 
569 
• For participants with 2 study eyes: 3-step worsening on the ETDRS Retinopathy Severity Scale 
570 
for Persons (Table 1) at a protocol visit.  This scale takes into account the retinopathy level of 
571 
both study eyes. 
572 
• For participants with one study eye: 2-step worsening on the ETDRS Retinopathy Severity 
573 
Scale for Individual Eyes (Table 2) in the study eye at a protocol visit.  This scale only takes 
574 
into account the retinopathy level of the study eye. 
575 
• Procedure undertaken for the treatment of PDR at any time (even in the absence of photographic 
576 
documentation) including PRP, intravitreous anti-VEGF, or vitrectomy in at least one study eye. 
577 
• Treatment initiated for DME at any time (even in the absence of OCT documentation) including 
578 
anti-VEGF, corticosteroids, focal/grid laser, or vitrectomy in at least one study eye. 
579 
• Development of central-involved DME on OCT with vision loss at the 2-year or 4-year visit.  
580 
Defined as OCT central subfield thickness above the machine and gender-specific thresholds 
581 
(see Section 2.2.2 for details) with at least a 10% increase in thickness from baseline and visual 
582 
acuity 20/32 or worse (letter score ≤ 78) in at least one study eye. 
583 
 
584 
Table 1: Summary of ETDRS Final Retinopathy Severity Scale for Persons 
585 
 
586 
Level in each eye 
Description 
Scale step 
10/10 
No DR 
1 
20/< 20 
Microaneurysms only, one eye 
2 
20/20 
Microaneurysms only, both eyes 
3 
35/< 35 
Mild NPDR, one eye 
4 
35/35 
Mild NPDR, both eyes 
5 
43/< 43 
Moderate NPDR, one eye 
6 
43/43 
Moderate NPDR, both eyes 
7 
47/< 47 
Moderately severe NPDR, one eye 
8 
47/47 
Moderately severe NPDR, both eyes 
9 
53/< 53 
Severe or very severe NPDR, one eye 
10 
53/53 
Severe or very severe NPDR, both eyes 
11 
60 or 61/< 60 
Mild PDR and/or PRP, one eye 
12 
60 or 61/60 or 61 
Mild PDR and/or PRP, both eyes 
13 
65/< 65 
Moderate PDR, one eye 
14 
65/65 
Moderate PDR, both eyes 
15 
71+/< 71 
High-risk PDR, one eye 
16 
71+/71+ 
High-risk PDR, both eyes 
17 
 
587 

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Table 2: Summary of ETDRS Final Retinopathy Severity Scale for Individual Eyes 
588 
 
589 
Level in the eye 
Severity 
Scale Step 
10 
DR absent 
1 
20 
Microaneurysms only  
2 
35 
Mild NPDR (hard exudates, soft exudates, and/or mild 
hemorrhage)  
3 
43 
Moderate NPDR (mild intraretinal microvascular abnormalities 
or moderate hemorrhage) 
4 
47 
Moderately severe NPDR (mild venous beading, moderate 
intraretinal microvascular abnormalities or severe hemorrhage) 
5 
53 
Severe or very severe NPDR (moderate/severe venous beading, 
severe intraretinal microvascular abnormalities and/or very 
severe hemorrhage) 
6 
60, 61 
Scars of photocoagulation for PDR (60) or mild PDR (61) 
7 
65 
Moderate PDR 
8 
71, 75 
High-Risk PDR 
9 
81, 85 
High-Risk PDR with vitreous hemorrhage  
10 
 
590 
6.2 Sample Size Estimation 
591 
Based on data from eyes with baseline retinopathy in the ACCORD study, it is anticipated that 
592 
approximately 50% of PROMINENT study participants will have minimal to severe NPDR (levels 
593 
20-53) in at least one eye.  Among participants with minimal to severe NPDR in at least one eye, 
594 
the percentage of patients with either a 3-step patient-level progression or photocoagulation was 
595 
approximately 5% in the fenofibrate group and 12% in the placebo group.  For the entire ACCORD 
596 
cohort (i.e. with and without baseline retinopathy), the rate of DME worsening on color 
597 
photographs was approximately 3% over 4 years in both the fenofibrate and control groups.  
598 
However, the percentage of patients with baseline retinopathy and worsening DME without 
599 
worsening retinopathy is not reported.  In addition, DME progression in ACCORD was assessed by 
600 
color photographs while in the current study it will be assessed by OCT, which has been shown to 
601 
be more sensitive at detecting DME.32  Therefore, it is unknown what impact the primary outcome 
602 
components, besides retinopathy progression, will have on the projected outcome, resulting in 
603 
uncertainty around these estimates. 
604 
 
605 
The table below shows the required sample size for 80% power with a type I error rate of 5% and a 
606 
null hypothesis of no difference between groups (two-tailed test) for a time-to-event outcome (log-
607 
rank test).  These calculations were based on the 4-year outcome rate in the placebo group and the 
608 
resulting hazard ratio when comparing the outcome rate in the pemafibrate group.  The outcome 
609 
times are assumed to follow an exponential distribution and the estimates include adjustment for 
610 
15% attrition over 4 years, also assumed to follow an exponential distribution. 
611 
 
612 
Table 3. Required Number of Participants for Primary Analysis 
613 
 
614 
Hazard 
Ratio 
Placebo Event Rate 
16% 
14% 
12% 
10% 
8% 
0.30 
270 
310 
364 
438 
552 
0.40 
398 
458 
536 
646 
812 
0.50 
618 
710 
832 
1000 
1256 

PROMINENT-Eye 3-14-18 V2.0 
 
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615 
The projected 4-year outcome rates of 5% in the pemafibrate group and 12% in the placebo group 
616 
yield a hazard ratio of approximately 0.4, resulting in a required sample size of 536 participants. 
617 
 
618 
Assuming 600 participants are enrolled of whom 15% are lost to follow up over 4 years, the 
619 
detectable hazard ratio with 80% power is 0.49 for a placebo event rate of 16% to 0.32 for a placebo 
620 
event rate of 8%.  In other words, the study is powered for a reduction in the rate of diabetic 
621 
retinopathy worsening by 1/2 to 2/3, depending on the event rate in the placebo group.  The placebo 
622 
event rate could be higher than 16% because the 12% estimate from ACCORD accounts for events 
623 
due only to progression of retinopathy on photographs and does not include treatment-related and 
624 
DME-related events, which are other components of the composite outcome.  There are no existing 
625 
data on which to base estimates for rates of these outcomes.  In the event that the outcome rates in 
626 
the placebo group are higher than projected, the study will be powered to detect smaller reductions 
627 
in the hazard of diabetic retinopathy worsening.  Therefore, the estimates given here are 
628 
conservative. 
629 
 
630 
6.3 Primary Analysis Plan 
631 
6.3.1 Principles for Analysis 
632 
The primary treatment group comparison will be based on the hazard ratio from a Cox proportional 
633 
hazards regression model that adjusts for the baseline person-level retinopathy, which accounts for 
634 
the retinopathy level in the non-study eye of unilateral participants (see Table 1).  The primary 
635 
analysis is an intention-to-treat analysis.  Data from participants who are not observed to meet 
636 
outcome criteria and who are lost to follow up will be censored at the time of the last completed 
637 
visit.  All model assumptions, including proportional hazards, will be verified.  If model 
638 
assumptions are not reasonably satisfied, alternative approaches will be explored. 
639 
 
640 
6.3.2 Confounding 
641 
Imbalances between groups in important covariates are not expected to be of sufficient magnitude 
642 
to produce confounding.  However, the presence of confounding will be evaluated in regression 
643 
models by including factors potentially associated with the outcome for which there is an imbalance 
644 
between groups. 
645 
 
646 
6.3.3 Per Protocol Analyses 
647 
Per protocol analyses mimicking the primary intention-to-treat analyses will be performed on the 
648 
following cohorts: 
649 
 
650 
• Participants with no major protocol deviations as defined by the PROMINENT trial. 
651 
• Participants with ≥ 80% compliance during the treatment period as defined by the 
652 
PROMINENT trial. 
653 
 
654 
6.3.4 Sensitivity Analyses 
655 
The following sensitivity analyses will be conducted: 
656 
 
657 
• Repeat the primary analysis while censoring data from participants who receive treatment 
658 
for DME when the OCT central subfield thickness in the treated eye did not meet the 
659 
outcome criteria for DME with vision loss when the treatment was given.  Participants who 
660 
do not have an OCT scan from the visit at which treatment is given also will be censored in 
661 
this analysis. 
662 
 
663 

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6.3.5 Subgroup Analyses 
664 
The treatment effect in subgroups defined by baseline factors will be assessed in pre-planned 
665 
subgroup analyses.  These analyses will be conducted to determine whether the treatment effect in 
666 
any subgroup differs from the overall treatment effect.  The study is not expected to have sufficient 
667 
statistical power for definitive conclusions in subgroups and statistical power will be low to 
668 
formally test for the presence of subgroup effects.  Interpretation of subgroup analyses will depend 
669 
on whether the overall analysis demonstrates a significant treatment effect.  In the absence of a 
670 
significant treatment effect in the primary analysis, assessment of subgroups will be considered 
671 
exploratory and used to suggest hypotheses for further investigation in future studies. 
672 
 
673 
The general approach for these analyses will be to add an interaction term for the subgroup factor 
674 
by treatment group into the proportional hazards model used for the primary analysis. 
675 
 
676 
The planned subgroups for analyses are as follows: 
677 
• Baseline person-level retinopathy level: Steps 2-4, Steps 5-6, Steps 7-9, and Steps 10-11 
678 
 
679 
Statistical analyses will only be conducted for a subgroup if there are at least 20 participants in each 
680 
treatment group for that subgroup.  The above subgroups are considered those of primary interest 
681 
for which a rationale for a subgroup effect is hypothesized.  The hypothesized mechanism and 
682 
direction of effect are listed in the table below. 
683 
 
684 
Factor 
Hypothesized direction/mechanism of association 
Retinopathy Level 
Participants with more severe retinopathy have higher risk for 
retinopathy worsening and may have disease that is too advanced for the 
treatment to work.  Therefore, it is possible that the treatment effect is 
greater in eyes with less severe disease.  
 
685 
The following baseline subgroup factors also will be evaluated in exploratory analyses: 
686 
 
687 
• Prior DME treatment: yes vs. no 
688 
• Age: < 65 vs. ≥ 65 
689 
• HbA1c: < 7.5% vs. ≥ 7.5% 
690 
• Sex 
691 
• Race/Ethnicity 
692 
• Hyperlipidemia status: ≥ HDL (high-density lipoprotein) median of the sample cohort and ≥ 
693 
TG (triglyceride) median; ≥ HDL median and < TG median; < HDL median and ≥ TG 
694 
median; < HDL median and < TG median 
695 
• Number of study eyes: 1 vs. 2 
696 
 
697 
There is no known mechanism supporting an interaction of these effects with treatment group.  If a 
698 
significant subgroup effect for any of these factors is found, it will be interpreted as hypothesis 
699 
generating only and in need of confirmation from further studies.  In particular, there are no data to 
700 
suggest that the treatment effect will vary by sex or race/ethnicity, although both of these factors 
701 
will be evaluated. 
702 
 
703 
For all analyses, P-values will be computed for factors based on continuous or ordinal data when 
704 
available in addition to the categorizations listed above. 
705 
 
706 

PROMINENT-Eye 3-14-18 V2.0 
 
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6.4 Secondary Outcomes and Safety Outcomes for Treatment Group Comparison 
707 
Secondary outcomes will be compared at the 2-year and 4-year visits with the exception of time-to-
708 
event outcomes in which the hazard rates will be compared over 4 years only.  Safety outcomes 
709 
collected as part of this ancillary study will be compared at 4 years only.  To control for potential 
710 
correlations arising from participants with two study eyes, eye-level outcomes will be compared 
711 
using linear mixed models (continuous outcomes), logistic regression using generalized estimating 
712 
equations (binary outcomes), or Cox proportional hazards regression with a robust sandwich 
713 
estimate of the covariance matrix (time-to-event outcomes).33  Participant-level outcomes will be 
714 
compared similarly but without adjustment for inter-eye correlation. 
715 
 
716 
All analyses will include adjustment for the baseline level of the outcome, where appropriate.  In 
717 
addition, participant-level and eye-level secondary outcomes will be adjusted for baseline person-
718 
level diabetic retinopathy severity.  The treatment groups will be compared on the following 
719 
outcomes of interest: 
720 
 
721 
Participant-Level Secondary Outcomes (relates to either eye for bilateral participants and to the 
722 
study eye for unilateral participants): 
723 
 
724 
• Hazard rate of 3-step person-level (for bilateral participants, Table 1) or 2-step eye-level (for 
725 
unilateral participants, Table 2) diabetic retinopathy worsening on the ETDRS Retinopathy 
726 
Severity Scale or receiving treatment for PDR in at least one study eye at any time (irrespective 
727 
of DME status or treatment) 
728 
o Percentage of participants with diabetic retinopathy worsening at 2 years and 4 years 
729 
will be enumerated without statistical comparison 
730 
o Percentage of participants receiving treatment for PDR in at least one study eye at or 
731 
prior to 2 years and 4 years will be enumerated without statistical comparison 
732 
• Hazard rate of developing central-involved DME on OCT with vision loss (as defined in Section 
733 
6.1) or receiving treatment for DME in at least one study eye at any time (irrespective of 
734 
diabetic retinopathy severity level or treatment) 
735 
o Percentage of participants with central-involved DME on OCT with vision loss in at 
736 
least one study eye at 2 years and 4 years will be enumerated without statistical 
737 
comparison 
738 
o Percentage of participants receiving treatment for DME in at least one study eye at or 
739 
prior to 2 years and 4 years will be enumerated without statistical comparison 
740 
• Person-level diabetic retinopathy severity at 2 years and 4 years 
741 
• Percentage of participants with at least a 2-line loss in visual acuity from baseline in at least one 
742 
study eye at 2 years and 4 years 
743 
 
744 
Eye-Level Secondary Outcomes (evaluated only for study eyes): 
745 
 
746 
• Hazard rate of a composite PDR/DME outcome.  Defined as the time to 2-step diabetic 
747 
retinopathy worsening on the ETDRS Retinopathy Severity Scale for Individual Eyes 
748 
(Table 2) at 2 years or 4 years, development of central-involved DME on OCT with vision 
749 
loss (as defined in Section 6.1) at 2 years or 4 years, or treatment for DME or PDR at any 
750 
time 
751 
o Percentage of eyes with 2-step diabetic retinopathy worsening or development of 
752 
central-involved DME on OCT with vision loss at 2 years and 4 years will be 
753 
enumerated without statistical comparison 
754 

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o Percentage of eyes receiving treatment for PDR or DME at or prior to 2 years and 4 
755 
years will be enumerated without statistical comparison 
756 
• Hazard rate of 2-step diabetic retinopathy worsening or receiving treatment for PDR at any 
757 
time (irrespective of DME status or treatment) 
758 
o Percentage of eyes with 2-step diabetic retinopathy worsening at 2 years and 4 years 
759 
will be enumerated without statistical comparison 
760 
o Percentage of eyes receiving treatment for PDR at or prior to 2 years and 4 years will 
761 
be enumerated without statistical comparison 
762 
• Hazard rate of developing central-involved DME on OCT with vision loss at 2 years or 4 
763 
years or receiving treatment for DME at any time (irrespective of diabetic retinopathy level 
764 
or treatment) 
765 
o Percentage of eyes with central-involved DME on OCT with vision loss at 2 years 
766 
and 4 years will be enumerated without statistical comparison 
767 
o Percentage of eyes receiving treatment for DME at or prior to 2 years and 4 years 
768 
will be enumerated without statistical comparison 
769 
• Eye-level diabetic retinopathy severity at 2 years and 4 years 
770 
• Change in OCT central subfield thickness from baseline at 2 years and 4 years 
771 
• Change in visual acuity letter score from baseline at 2 years and 4 years 
772 
• Percentage of eyes with at least 2-line loss in visual acuity from baseline at 2 years and 4 
773 
years 
774 
 
775 
Safety Outcomes: 
776 
• Adverse events collected as part of this ancillary study including vitreous hemorrhage and 
777 
retinal detachment 
778 
• Changes from randomization in ALT, AST, CK, and creatinine 
779 
 
780 
To help control the type I error rate at 5%, P-values for secondary outcomes and safety outcomes 
781 
will be adjusted using the adaptive false discovery rate method of Benjamini and Hochberg in 
782 
separate sets  (i.e., one adjustment for patient-level secondary outcomes, one adjustment for eye-
783 
level secondary outcomes, and one adjustment for safety outcomes).34  It is recognized that this does 
784 
not completely control the type I error rate. 
785 
 
786 
All model assumptions will be verified.  These include but are not limited to proportional hazards, 
787 
linearity, normality of residuals, and homoscedasticity.  If model assumptions are not reasonably 
788 
satisfied, then a transformation of the data or an alternative approach may be considered.  Methods 
789 
for handling missing secondary outcome data will be included in the detailed Statistical Analysis 
790 
Plan. 
791 
 
792 
Adverse events reported in this ancillary study as defined in section 4.3 will be enumerated in 
793 
patient listings and summarized in tables by System Organ Class, using MedDRA terms.  Changes 
794 
in ALT, AST, CK, and creatinine will be depicted as shift tables (i.e., as a shift to high, low, or 
795 
normal) for each parameter at 4 years. 
796 

PROMINENT-Eye 3-14-18 V2.0 
 
26 of 31 
DATA COLLECTION AND MONITORING 
797 
 
798 
7.1 Case Report Forms 
799 
The key study data are collected through a combination of electronic case report forms (CRFs) and 
800 
grading of retinal images. 
801 
 
802 
When data are directly collected in electronic case report forms, this will be considered the source 
803 
data.  Each participating site will maintain appropriate medical and research records for this trial, in 
804 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
805 
confidentiality of participants. 
806 
 
807 
7.2 Study Records Retention 
808 
Study documents should be retained by the investigator for the latest of 3 years following the end of 
809 
the current DRCR.net grant, 2 years after the last approval of a marketing application, and until 
810 
there are no pending or contemplated marketing applications, or until at least 2 years have elapsed 
811 
since the formal discontinuation of clinical development of the investigational product.  These 
812 
documents should be retained for a longer period, however, if required by local regulations.  No 
813 
records will be destroyed without the written consent of the Jaeb Center for Health Research.  It is 
814 
the responsibility of the sponsor to inform the investigator when these documents no longer need to 
815 
be retained. 
816 
 
817 
7.3 Quality Assurance and Monitoring 
818 
Designated personnel from the JCHR Coordinating Center will be responsible for maintaining 
819 
quality assurance and quality control systems to ensure that the clinical portion of the trial is 
820 
conducted and data are generated, documented and reported in compliance with the protocol, Good 
821 
Clinical Practice (GCP) and the applicable regulatory requirements. 
822 
 
823 
A risk-based monitoring plan will be developed and revised as needed during the course of the 
824 
study, consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations — A 
825 
Risk-Based Approach to Monitoring” (August 2013). 
826 
 
827 
The data of most importance for monitoring at the site are participant eligibility and image outcome 
828 
data.  Therefore, the risk-based monitoring plan will focus on these areas.  As much as possible, 
829 
remote monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
830 
verity and completeness of the key site data when possible.  Elements of the risk-based monitoring 
831 
will include: 
832 
 
833 
• Qualification assessment, training, and certification for sites and site personnel 
834 
• Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
835 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
836 
review of entered data and edits, statistical monitoring, study closeout 
837 
• On-site monitoring (site visits): source data verification, site visit report 
838 
• Communications with site staff 
839 
• Patient retention and visit completion 
840 
• Quality control reports 
841 
• Management of noncompliance 
842 
• Documenting monitoring activities 
843 
• Adverse event reporting and monitoring 
844 

PROMINENT-Eye 3-14-18 V2.0 
 
27 of 31 
 
845 
JCHR Coordinating Center representatives or their designees may visit the study facilities at any 
846 
time in order to maintain current and personal knowledge of the study through review of the 
847 
records, comparison with source documents, observation and discussion of the conduct and progress 
848 
of the study. 
849 
 
850 
7.4 Protocol Deviations 
851 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
852 
requirements.  The noncompliance may be either on the part of the participant, the investigator, or 
853 
the study site staff.  As a result of deviations, corrective actions are to be developed by the site and 
854 
implemented promptly. 
855 
 
856 
The site principal investigator/study staff is responsible for knowing and adhering to their IRB 
857 
requirements.  Further details about the handling of protocol deviations will be included in the 
858 
monitoring plan. 
859 

PROMINENT-Eye 3-14-18 V2.0 
 
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ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
860 
 
861 
8.1 Ethical Standard 
862 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
863 
Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR 
864 
Part 56, and/or the ICH E6. 
865 
 
866 
8.2 Institutional Review Boards 
867 
The protocol, informed consent form, recruitment materials, and all participant materials will be 
868 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form 
869 
must be obtained before any participant is enrolled.  Any amendment to the protocol will require 
870 
review and approval by the IRB before the changes are implemented to the study.  All changes to 
871 
the consent form will be IRB approved; a determination will be made regarding whether previously 
872 
consented participants need to be re-consented. 
873 
 
874 
8.3 Informed Consent Process 
875 
8.3.1 Consent Procedures and Documentation 
876 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
877 
study and continues throughout the individual’s study participation.  Extensive discussion of risks 
878 
and possible benefits of participation will be provided to the participants and their families.  
879 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
880 
document.  The investigator will explain the research study to the participant and answer any 
881 
questions that may arise.  All participants will receive a verbal explanation in terms suited to their 
882 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
883 
research participants.  Participants will have the opportunity to carefully review the written consent 
884 
form and ask questions prior to signing. 
885 
The participants should have the opportunity to discuss the study with their surrogates or think 
886 
about it prior to agreeing to participate.  The participant will sign the informed consent document 
887 
prior to any procedures being done specifically for the study.  The participants may withdraw 
888 
consent at any time throughout the course of the trial.  A copy of the informed consent document 
889 
will be given to the participants for their records.  The rights and welfare of the participants will be 
890 
protected by emphasizing to them that the quality of their medical care will not be adversely 
891 
affected if they decline to participate in this study. 
892 
 
893 
8.3.2 Participant and Data Confidentiality 
894 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
895 
the sponsor(s) and their agents.  Therefore, the study protocol, documentation, data, and all other 
896 
information generated will be held in strict confidence.   
897 
The study monitor, other authorized representatives of the sponsor or, representatives of the IRB 
898 
may inspect all documents and records required to be maintained by the investigator, including but 
899 
not limited to medical records (office, clinic, or hospital).  The clinical study site will permit access 
900 
to such records. 
901 
The study participant’s contact information will be securely stored at each clinical site for internal 
902 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
903 
location for as long a period as dictated by local IRB and Institutional regulations. 
904 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
905 
will be transmitted to and stored at the JCHR Coordinating Center.  This will not include a link to 
906 
the participant’s contact or identifying information.  Rather, individual participants and their 
907 
research data will be identified by a unique study identification number.  The study data entry and 
908 

PROMINENT-Eye 3-14-18 V2.0 
 
29 of 31 
study management systems used by clinical sites and by JCHR Coordinating Center research staff 
909 
will be secured and password protected.  At the end of the study, all study databases will be de-
910 
identified and archived at the JCHR Coordinating Center. 
 
911 

PROMINENT-Eye 3-14-18 V2.0 
 
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International Diabetes Federation: Facts and figures.  
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Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 
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5. 
Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J Med. 2005;353:839-41. 
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Davis MD, Fisher MR, Gangnon RE, et al. Risk factors for high-risk proliferative diabetic 
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7. 
Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and 
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8. 
Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy 
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12. 
Dcct Edic Research Group, Aiello LP, Sun W, et al. Intensive diabetes therapy and ocular 
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Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive 
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Klein R, Klein BE. Are individuals with diabetes seeing better?: a long-term 
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Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the 
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Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, 
Glassman AR, et al. Panretinal Photocoagulation vs Intravitreous Ranibizumab for 
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20. 
Sampat KM, Garg SJ. Complications of intravitreal injections. Curr Opin Ophthalmol. 
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Hiukka A, Maranghi M, Matikainen N, Taskinen MR. PPARalpha: an emerging therapeutic 
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Noonan JE, Jenkins AJ, Ma JX, Keech AC, Wang JJ, Lamoureux EL. An update on the 
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Ding L, Cheng R, Hu Y, et al. Peroxisome proliferator-activated receptor alpha protects 
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Roy S, Kim D, Hernandez C, Simo R, Roy S. Beneficial effects of fenofibric acid on 
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Gong Y, Shao Z, Fu Z, et al. Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C 
Activity to Suppress Pathological Ocular Angiogenesis. EBioMedicine. 2016;13:201-11. 
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Farris RA, Price ET. Reverse Translational Study of Fenofibrate's Observed Effects in 
Diabetes-Associated Retinopathy. Clin Transl Sci. 2017;10(2):110-6. 
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Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser 
treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 
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Chew EY, Davis MD, Danis RP, et al. The effects of medical management on the 
progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control 
Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology. 
2014;121(12):2443-51. 
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Davis MD, Bressler SB, Aiello LP, et al. Comparison of time-domain OCT and fundus 
photographic assessments of retinal thickening in eyes with diabetic macular edema. Invest 
Ophthalmol Vis Sci. 2008;49(5):1745-52. 
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Lee EW, Wei LJ, Amato DA. Cox-type regression analysis for large numbers of small 
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