Clinical trial NCT02634333
Conditions: Diabetic Retinopathy Diabetic Macular Edema
Keywords: anti-vascular endothelial growth factor nonproliferative diabetic retinopathy
Sponsor: Jaeb Center for Health Research
Start date: 2016-01-01; Completion date: 2022-05-11
Enrollment: 399 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative factor in human eye diseases characterized by neovascularization including proliferative diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME). While there is strong evidence that PDR outcomes are markedly reduced in eyes that are treated with monthly anti-VEGF therapy (A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus: RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I), it is unknown whether or not an earlier but less frequent dosing regimen would result in similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently would result in favorable visual acuity outcomes.

If this study demonstrates that intravitreous aflibercept treatment is effective and safe for reducing the onset of PDR or center involved- DME (CI-DME) in eyes that are at high risk for these complications, a new strategy to prevent vision threatening complications of diabetes will be available for patients. The application of intravitreous aflibercept earlier in the course of disease (i.e., at the time when an eye has baseline severe non-proliferative diabetic retinopathy) could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual outcomes, if PDR and DME are prevented.

The primary objectives of this protocol are to 1) determine the efficacy and safety of intravitreous aflibercept injections versus sham injections (observation) for prevention of PDR or CI-DME in eyes at high risk for development of these complications and 2) compare long-term visual outcomes in eyes that receive anti-VEGF therapy early in the course of disease with those that are observed initially, and treated only if high-risk PDR or CI-DME with vision loss develops.

Secondary objectives include:

* Comparing other visual acuity outcomes between treatment groups, such as proportion of eyes with at least 10 or at least 15 letter loss from baseline, or gain or loss of at least 5 letters at the consecutive study visit just before and at the 2- or 4-year visit
* Comparing optical coherence tomography (OCT) outcomes, such as mean change in OCT central subfield thickness and volume from baseline
* Comparing proportion of eyes with at least 2 and 3-step worsening or improvement of diabetic retinopathy severity level (scale for individual eyes) by central reading center from baseline
* Comparing associated treatment and follow-up exam costs between treatment groups
* Comparing safety outcomes between treatment groups

Detailed description:

Arms: arm 1: Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. arm 2: Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Interventions: intervention 1: Prompt Sham intervention 2: Prompt aflibercept intervention 3: Deferred laser intervention 4: Deferred aflibercept
Intervention descriptions: intervention 1: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. intervention 2: Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. intervention 3: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met intervention 4: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.

Protocol documents:
Prot_000.pdf: 
Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19                  
 
 
 
 
 
Diabetic Retinopathy Clinical Research 
Network 
Intravitreous Anti-VEGF Treatment for 
Prevention of Vision Threatening 
Diabetic Retinopathy in Eyes at High 
Risk  
 
 
Version 6.0 
 
December 9, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19                  
 
 
 
 
 
Table of Contents 
1 
 
2 
Chapter 1. Background Information and Study Synopsis ................................................... 1-1 
3 
1.1 
Background Information ............................................................................................... 1-1 
4 
1.1.1 Diabetic Retinopathy Complications and Public Health Impact ................................ 1-1 
5 
1.1.2 PDR and Its Treatment................................................................................................ 1-1 
6 
1.1.3 DME and Its Treatment .............................................................................................. 1-2 
7 
1.1.4 Rationale for Prevention of PDR and DME in Eyes at High Risk ............................. 1-2 
8 
1.1.5 Aflibercept .................................................................................................................. 1-3 
9 
1.1.6 Summary of Study Rationale ...................................................................................... 1-4 
10 
1.2 
Study Objective ............................................................................................................. 1-5 
11 
1.3 
Study Design and Synopsis of Protocol ........................................................................ 1-5 
12 
1.4 
General Considerations ................................................................................................. 1-9 
13 
Chapter 2. Study Participant Eligibility and Enrollment .................................................... 2-1 
14 
2.1 
Identifying Eligible Subjects and Obtaining Informed Consent ................................... 2-1 
15 
2.2 
Subject Eligibility Criteria ............................................................................................ 2-1 
16 
2.2.1 Individual-level Criteria .............................................................................................. 2-1 
17 
2.2.2 Study Eye Criteria ....................................................................................................... 2-2 
18 
2.2.3 Non-Study Eye Criteria............................................................................................... 2-4 
19 
2.3 
Screening Evaluation and Baseline Testing .................................................................. 2-5 
20 
2.3.1 Historical Information ................................................................................................. 2-5 
21 
2.3.2 Baseline Testing Procedures ....................................................................................... 2-5 
22 
2.3.2.1 Screening Visit ......................................................................................................... 2-5 
23 
2.3.2.2 Randomization Visit ................................................................................................ 2-5 
24 
2.4 
Randomization of Eligible Study Participants .............................................................. 2-6 
25 
Chapter 3. Follow-up Visits and Testing ............................................................................... 3-1 
26 
3.1 
Visit Schedule ............................................................................................................... 3-1 
27 
3.1.1 Assessment Visits ....................................................................................................... 3-1 
28 
3.1.2 Additional Study Visits ............................................................................................... 3-1 
29 
3.2 
Testing Procedures ........................................................................................................ 3-2 
30 
Chapter 4. Treatment Regimen .............................................................................................. 4-1 
31 
4.1 
Treatment Groups .......................................................................................................... 4-1 
32 
4.2 
Injection Procedure ....................................................................................................... 4-1 
33 
4.2.1  
Intravitreous Aflibercept Injection (Eylea®) ......................................................... 4-1 
34 
4.2.2  
Intravitreous Injection Technique .......................................................................... 4-1 
35 
4.2.3 
Sham Injection Technique ..................................................................................... 4-1 
36 
4.2.4 
Deferral of Injections Due to Pregnancy ............................................................... 4-1 
37 
4.2.5 
Non-Study Eye Injections ...................................................................................... 4-1 
38 
4.3 
Follow-Up Treatment Protocol for Prevention of PDR/DME ...................................... 4-2 
39 
4.3.1 
Injections at 4 and 8 Weeks and Each 4-Month Interval Visit until 2 Years ......... 4-2 
40 
4.3.2 
Injections at and After the 2-Year Visit ................................................................. 4-2 
41 
4.4 
Treatment for CI-DME.................................................................................................. 4-2 
42 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19                  
 
 
 
 
 
4.4.1 
Initiation of Focal/Grid Photocoagulation While Receiving Anti-VEGF Injections
43 
 
4-3 
44 
4.4.2 
Continuation of Prevention Treatment Protocol .................................................... 4-3 
45 
4.5 
Treatment for PDR ........................................................................................................ 4-3 
46 
4.5.1 
Primary Outcome for PDR..................................................................................... 4-3 
47 
4.5.2 
Initiating Treatment for PDR ................................................................................. 4-4 
48 
4.5.3 
Intravitreous Injection for PDR at 4 weeks, 8 weeks and 12 weeks ...................... 4-4 
49 
4.5.4 
Intravitreous Injection for PDR at and after 16 weeks .......................................... 4-4 
50 
4.5.5 
Continuation of Prevention Treatment Protocol .................................................... 4-6 
51 
4.6 
Panretinal Photocoagulation Technique ........................................................................ 4-6 
52 
4.7 
Surgery for Vitreous Hemorrhage, Traction Detachment, and Other Complications of 
53 
DR 
4-7 
54 
Chapter 5. Miscellaneous Considerations in Follow-up ....................................................... 5-1 
55 
5.1 
Endophthalmitis ............................................................................................................ 5-1 
56 
5.2 
Treatment in Non-study Eye ......................................................................................... 5-1 
57 
5.3 
Diabetes Management ................................................................................................... 5-1 
58 
5.4 
Study Participant Withdrawal and Losses to Follow-up ............................................... 5-1 
59 
5.5 
Discontinuation of Study ............................................................................................... 5-1 
60 
5.6 
Contact Information Provided to the Coordinating Center ........................................... 5-1 
61 
5.7 
Study Participant Reimbursement ................................................................................. 5-2 
62 
Chapter 6. Adverse Events ...................................................................................................... 6-1 
63 
6.1 
Definition ...................................................................................................................... 6-1 
64 
6.2 
Recording of Adverse Events ........................................................................................ 6-1 
65 
6.3 
Reporting Serious or Unexpected Adverse Events ....................................................... 6-2 
66 
6.4 
Data and Safety Monitoring Committee Review of Adverse Events ............................ 6-2 
67 
6.5 
Risks .............................................................................................................................. 6-3 
68 
6.5.1 
Potential Adverse Effects of Aflibercept ............................................................... 6-3 
69 
6.5.2 
Potential Adverse Effects of Intravitreous Injection .............................................. 6-3 
70 
6.5.3 
Risks of Eye Examination and Tests ..................................................................... 6-4 
71 
Chapter 7. Statistical Methods ................................................................................................ 7-1 
72 
7.1 
Primary Objectives and Key Outcomes ........................................................................ 7-1 
73 
7.2 
Sample Size ................................................................................................................... 7-2 
74 
7.2.1 
Projected Control Group Proportion ...................................................................... 7-2 
75 
7.2.2 
Projected Treatment Group Rate ........................................................................... 7-3 
76 
7.2.3 
Sample Size Estimates ........................................................................................... 7-4 
77 
7.2.4 
Power for the Visual Acuity Outcome ................................................................... 7-4 
78 
7.3 
Primary Analysis Plan ................................................................................................... 7-5 
79 
7.3.1 
Principles for Analysis ........................................................................................... 7-5 
80 
7.3.2 
Per-protocol Analysis............................................................................................. 7-6 
81 
7.3.3 
Interim Analysis Plan ............................................................................................. 7-6 
82 
7.4 
Secondary Outcomes for Treatment Group Comparison .............................................. 7-6 
83 
7.5 
Economic Analysis ........................................................................................................ 7-7 
84 
7.6 
OCT Angiography Ancillary Study .............................................................................. 7-8 
85 
7.7 
Safety Analysis Plan...................................................................................................... 7-8 
86 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19                  
 
 
 
 
 
7.8 
Additional Tabulations and Analyses ........................................................................... 7-9 
87 
Chapter 8. References .............................................................................................................. 8-1 
88 
 
89 


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CHAPTER 1. BACKGROUND INFORMATION AND STUDY SYNOPSIS 
90 
 
91 
1.1 
Background Information 
92 
1.1.1 Diabetic Retinopathy Complications and Public Health Impact 
93 
The age-adjusted incidence of diabetes mellitus in the United States has reportedly doubled in 
94 
recent history.1 Estimates suggest that by the year 2035, approximately 592 million individuals 
95 
worldwide will be affected by this chronic disease.2 The increasing global epidemic of diabetes 
96 
implies an increase in rates of associated vascular complications from diabetes. At present at 
97 
least 5 million people over the age of 40 in the United States are estimated to have diabetic 
98 
retinopathy (DR) in the absence of diabetic macular edema (DME), and an additional 800,000 
99 
have DME, according to data from the Centers for Disease Control.3 Despite advances in 
100 
diagnosis and management of ocular disease in patients with diabetes, eye complications from 
101 
diabetes mellitus continue to be a leading cause of vision loss and new onset blindness in 
102 
working-age individuals throughout the United States.4, 5 
103 
 
104 
1.1.2 PDR and Its Treatment 
105 
Worsening DR is characterized by the development of increasing areas of retinal vascular non-
106 
perfusion causing ischemia or infarction of retina tissue.  The anatomic sequel of retinal vascular 
107 
ischemia is retinal neovascularization (NV) or proliferative diabetic retinopathy (PDR), a major 
108 
cause of preventable and potentially irreversible vision loss in patients with diabetes.  Data from 
109 
the Wisconsin Epidemiologic Study of Diabetic Retinopathy published in 1985 suggest that 
110 
given long enough duration of diabetes, approximately 60% of patients with diabetes mellitus 
111 
will develop PDR.6  Although current rates may be lower, they are still substantial. More 
112 
recently, the Protein Kinase C β Inhibitor Diabetic Retinopathy Study (PKC-DRS) and Diabetic 
113 
Retinopathy Study (DRS)-2 study groups reported that eyes with moderate to severe non-
114 
proliferative DR enrolled in 2 separate phase 3 trials of the protein kinase C inhibitor, 
115 
ruboxistaurin, demonstrated  approximate rates of 60% and 40%, respectively, of worsening of 3 
116 
steps on the Early Treatment for Diabetic Retinopathy Study (ETDRS) person scale across both 
117 
eyes, 2 steps on the ETDRS individual eye scale, or application of PRP over 3 years.7, 8  
118 
 
119 
It is also well-documented that worsening to PDR is associated with worse visual outcomes in 
120 
many eyes.  According to the DRS without intervention, nearly half of eyes with high-risk PDR 
121 
will experience profound vision loss from associated complications including vitreous 
122 
hemorrhage or traction retinal detachment, but rates are reduced dramatically with panretinal 
123 
photocoagulation (PRP).9 The ETDRS demonstrated PRP reduces the risk of severe vision loss 
124 
to 4% for eyes with or approaching high risk PDR.10  Although remarkably effective at reducing 
125 
visual loss if applied in a timely and appropriate manner, PRP treatment destroys viable retinal 
126 
tissue and is associated with well-documented potential side effects that may lead to transient or 
127 
permanent loss of visual function, including exacerbation of existing macular edema,11 
128 
peripheral visual field defects, night vision loss, loss of contrast sensitivity, potential 
129 
complications from misdirected or excessive burns. In addition, subsequent need for vitrectomy 
130 
for vitreous hemorrhage or traction retinal detachment has been reported in at least 5% of 
131 
individuals despite appropriate laser treatment.12, 13  
132 
 
133 
Intravitreous anti-vascular endothelial growth factor (anti-VEGF) in eyes with PDR led to 
134 
decreased risk of DR worsening (need for PRP, vitreous hemorrhage, or vitrectomy for 
135 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
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complications of PDR) compared with no anti-VEGF therapy in a secondary outcome reported 
136 
by the Diabetic Retinopathy Clinical Research Network (DRCR.net) in a trial evaluating 
137 
ranibizumab for DME.14, 15 However, some eyes still worsen despite anti-VEGF therapy and DR 
138 
severity can worsen when anti-VEGF therapy is discontinued.   
139 
 
140 
The efficacy and safety of intravitreous anti-VEGF for treatment of PDR have been evaluated 
141 
over a 2 year period in the ongoing DRCR.net trial, Prompt PRP versus Intravitreous 
142 
Ranibizumab with Deferred PRP for PDR (Protocol S, NCT01489189).  This study randomized 
143 
eyes with PDR either with or without DME to either standard care PRP delivered at baseline or 
144 
to treatment with ranibizumab as per a predefined treatment algorithm with deferred PRP given 
145 
only if these eyes met failure or futility criteria. The study demonstrated that anti-VEGF 
146 
treatment led to visual acuity at 2 years that was non-inferior to that obtained with PRP. The 
147 
mean VA letter change was +2.8±15.2, ranibizumab group, versus +0.2±13.7, PRP group 
148 
(difference +2.2, 95% confidence interval [CI]: -0.5 to +5.0).  Other, secondary outcomes 
149 
appeared to favor the ranibizumab-treated group, including mean change in visual acuity letter 
150 
area under the curve over 2 years (difference +4.2, 95% CI: +3.0 to +5.4, P < 0.001), visual field 
151 
sensitivity loss (mean difference 368 dB; 95% CI: 213 to 531, P < 0.001) and rates of vitrectomy 
152 
(difference in surgical rates 11% (P < 0.001).  Ranibizumab was well-tolerated with few ocular 
153 
events (1 case of endophthalmitis) and no substantial differences identified in rates of systemic 
154 
adverse events between the treatment groups.16   
155 
 
156 
1.1.3 DME and Its Treatment 
157 
DME is another manifestation of DR that produces loss of central vision.  DME is currently a 
158 
leading cause of moderate vision loss in patients with diabetes.17 Without intervention, 33% of 
159 
221 eyes included in the ETDRS with center-involved DME (CI-DME) experienced “moderate 
160 
visual loss” (defined as a 15 or more letter score decrease in visual acuity) over a 3 year period.18  
161 
The DRCR.net study “Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination 
162 
with Laser Photocoagulation for Diabetic Macular Edema” (Protocol I) indicated that treatment 
163 
for DME with intravitreous anti-VEGF therapy (0.5 mg ranibizumab) with prompt or deferred 
164 
focal/grid laser provides visual acuity outcomes at 1 year and 2 years that are superior to 
165 
focal/grid laser alone or focal/grid laser combined with intravitreous corticosteroids,14  providing 
166 
definitive confirmation of the important role of VEGF in DME and the superiority of anti-VEGF 
167 
agents in the treatment of DME.  Additional phase 3 studies have since confirmed the superiority 
168 
of anti-VEGF agents to manage DME.19-21 
169 
 
170 
1.1.4 Rationale for Prevention of PDR and DME in Eyes at High Risk 
171 
Worse baseline NPDR severity is strongly associated with increased risk of worsening to PDR.  
172 
Data from the ETDRS suggest that eyes with severe non-proliferative diabetic retinopathy 
173 
(NPDR) have a 52% risk of progressing to PDR within 1 year and a 60% risk of worsening to 
174 
PDR with high risk characteristics within 5 years.10 Although PRP is performed in some select 
175 
cases of severe NPDR, there is no clear treatment mandate generalizable to most eyes with 
176 
severe NPDR that are at high risk of worsening to PDR.  However, the high risk of vision loss 
177 
from untreated PDR and potential complications from PDR treatment with PRP support a 
178 
rationale to explore possible therapeutic modalities for prevention of PDR.    
179 
 
180 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
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A higher risk of incident DME in eyes with more severe levels of baseline NPDR also has been 
181 
reported.22  Although there is similarly no clear current mandate to treat eyes with severe NPDR 
182 
in the hopes of preventing DME, there is scientific rationale to support this approach.  It is 
183 
possible that the prevention of CI-DME onset in eyes at high risk might prevent vision loss 
184 
associated with the development of CI-DME.  Furthermore, it is possible that an initial, 
185 
infrequently dosed anti-VEGF treatment regimen that prevents CI-DME onset might avoid 
186 
adverse events associated with more frequent dosing required for treatment once CI-DME is 
187 
present.  
188 
 
189 
Multiple studies have implicated VEGF as a major causative factor in human eye diseases 
190 
characterized by neovascularization including PDR and vascular permeability including DME.23-
191 
33 Thus, inhibition of VEGF might be expected to reduce the risk of both PDR and DME onset in 
192 
eyes with DR at high risk for worsening and over the long-term, reduce the risk of vision loss 
193 
from these conditions.  Indeed, as written above, substantial reductions in PDR-related outcomes 
194 
such as worsening on fundus photographs or clinical examination from NPDR to PDR, having 
195 
PRP, experiencing vitreous hemorrhage, or undergoing vitrectomy for PDR, have been reported 
196 
from studies comparing eyes treated with ranibizumab to those given laser or no treatment to 
197 
manage DME.34, 35,19,20  Furthermore, anti-VEGF treatment appears not only to prevent 
198 
worsening to PDR, but also to result in some improvement in the DR severity level as 
199 
demonstrated by DRCR.net Protocol I, RIDE/RISE trials with ranibizumab, and VIVID/VISTA 
200 
trials with aflibercept 14, 19, 20     
201 
 
202 
While there is strong evidence that PDR outcomes are markedly reduced in eyes that are treated 
203 
with monthly anti-VEGF therapy (RIDE/RISE) and moderately reduced in eyes that received 
204 
fairly frequent dosing during the 1st year of treatment (DRCR protocol I), it is yet unknown 
205 
whether or not an earlier but less frequent dosing regimen would result in similar, favorable 
206 
anatomic outcomes, and whether favorable anatomic outcomes subsequently would result in 
207 
favorable visual acuity outcomes.  Indeed, recently available data reveal that in the open label 
208 
extension phase that followed the RIDE/RISE core studies, 28% of eyes that did not receive 
209 
further ranibizumab treatment experienced 2 or more step worsening over the subsequent year, 
210 
suggesting that the beneficial effects on DR severity of anti-VEGF therapy may not be sustained 
211 
in all eyes once that therapy is withheld or given at decreasing frequency.36  
212 
 
213 
The ability of anti-VEGF therapy to prevent DME onset has not been addressed by data from 
214 
large scale clinical studies, since these studies largely have enrolled eyes with CI-DME at 
215 
baseline.  However, given the efficacy of anti-VEGF therapy in ameliorating retinal thickening 
216 
in the RIDE/RISE, VIVID/VISTA, and Protocol I trials, as well as the very low rates of DME 
217 
worsening in patients treated with anti-VEGF in these studies, it is plausible that anti-VEGF 
218 
injections also might be effective in reducing the onset of and worsening to CI-DME in eyes at 
219 
risk for CI-DME development and subsequently result in improved vision outcomes.  In 
220 
addition, ranibizumab reduced the rates development of CI-DME with decreased visual acuity in 
221 
eyes with PDR in DRCR.net Protocol S (10% with ranibizumab vs. 27% with PRP, P < 0.001).   
222 
 
 
223 
1.1.5 Aflibercept 
224 
The anti-VEGF drug to be used in this trial is intravitreous aflibercept injection, also known as 
225 
VEGF Trap-Eye or Aflibercept (Eylea®), which is a soluble decoy receptor fusion protein that 
226 


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has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.  
227 
Aflibercept received approval by the United States Food and Drug Administration (FDA) for the 
228 
treatment of neovascular age-related macular degeneration in 201137, for treatment of macular 
229 
edema due to central retinal vein occlusion in 201238-40, and for treatment of macular edema due 
230 
to branch retinal vein occlusion in 2014.  In 2014, the FDA approved aflibercept for treatment of 
231 
DME based on data from two phase III studies, VISTA and VIVID, which included 872 eyes 
232 
with DME with central involvement that received either intravitreous aﬂibercept every 4 weeks, 
233 
intravitreous aflibercept every 8 weeks after 5 initial monthly doses, or macular laser 
234 
photocoagulation.  The mean change in visual acuity letter score at 1 year compared to baseline 
235 
was 12.5 and 10.7 letters in the aflibercept groups compared with 0.2 letters in the laser group in 
236 
VISTA (P < 0.0001) and 10.5 and 10.7 compared with 1.2 letters in VIVID (P < 0.0001). The 
237 
visual gains in the aflibercept arms as compared with the macular laser arm were sustained 
238 
through 100 weeks. The FDA further approved aflibercept for treatment of diabetic retinopathy 
239 
in patients with diabetic macular edema in March 2015 based on VIVD and VISTA data that 
240 
showed that eyes treated with q4 or q8 week aflibercept had a significantly higher chance of at 
241 
least a 2 step improvement in Diabetic Retinopathy Severity Scale score as compared to eyes 
242 
treated with laser control (VIVID:  29.3% and 32.6% vs. 8.2%, respectively; P < 0.0004 for 
243 
q4wk and P < 0.0001 for q8wk; VISTA:  37.0% and 37.1% vs. 15.6%, P < 0.0001 for both 
244 
aflibercept vs control comparisons).41  With regard to safety, the incidences of ocular and non-
245 
ocular adverse events were similar across treatment groups.  The incidence of APTC-defined 
246 
thromboembolic events was similar across treatment groups.  There were no reported cases of 
247 
endophthalmitis, and intraocular inflammation occurred in less than 1% of injections.42   
248 
 
249 
Although there is no currently available head-to-head data on the available anti-VEGF agents for 
250 
treatment and prevention of PDR, a comparative effectiveness trial in DME reported that 
251 
aflibercept was more effective than ranibizumab and bevacizumab in improving vision in eyes 
252 
starting with CI-DME and worse levels of visual acuity (approximately 20/50 or worse).43  No 
253 
difference in efficacy was identified for eyes with CI-DME and mild visual acuity loss 
254 
(approximately 20/40 or better).     
255 
 
256 
1.1.6 Summary of Study Rationale 
257 
The prevention of PDR or DME in eyes that are high risk for PDR and DME onset might prevent 
258 
vision loss secondary to retinal neovascularization or central retinal thickening and also might 
259 
avoid potential complications and adverse effects on vision associated with more aggressive 
260 
treatments for these diabetic ocular complications once established.  Although anti-VEGF 
261 
therapy given for DME improves PDR-related outcomes and results in regression of 
262 
nonproliferative changes in some eyes with baseline NPDR, these data derive largely from trials 
263 
of frequent, often monthly dosing of intravitreous anti-VEGF.  No study to date has specifically 
264 
evaluated the role of anti-VEGF in prevention of DME.  This study will evaluate the safety and 
265 
efficacy of an anti-VEGF regimen for prevention of PDR or CI-DME or both in eyes that are at 
266 
high risk for worsening to PDR or CI-DME.  Treatment will be deferred in the control 
267 
(observation) arm since there is no clear treatment mandate for these eyes at this time.  This 
268 
protocol will evaluate both anatomic outcomes of development of either PDR within the 7-
269 
modified ETDRS fields or CI-DME on OCT associated with vision loss as well as whether 
270 
favorable anatomic outcomes, if identified, result in longer-term beneficial visual outcomes. 
271 
 
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If this study demonstrates that intravitreous aflibercept treatment is effective and safe for 
273 
reducing the onset of PDR or CI-DME in eyes that are at high risk for these complications, a new 
274 
strategy to prevent vision threatening complications of diabetes will be available for patients.  
275 
The application of intravitreous aflibercept earlier in the course of disease (i.e., at the time when 
276 
an eye has baseline severe NPDR) could help to reduce future potential treatment burden in 
277 
patients, at the same time resulting in similar or better long-term visual outcomes, if PDR and 
278 
DME are prevented. 
279 
 
280 
1.2 
Study Objective 
281 
The objectives of this study are to 1) determine the efficacy and safety of intravitreous 
282 
aflibercept injections versus sham injections (observation) for prevention of PDR or CI-DME in 
283 
eyes at high risk for development of these complications and 2) compare long-term visual 
284 
outcomes in eyes that receive anti-VEGF therapy early in the course of disease with those that 
285 
are observed initially, and treated only if high-risk PDR or CI-DME with vision loss develops. 
286 
 
287 
1.3 
Study Design and Synopsis of Protocol 
288 
A. Study Design 
289 
• Phase III, multi-center randomized clinical trial 
290 
 
291 
B. Major Eligibility Criteria 
292 
• Age >=18 years 
293 
• Type 1 or type 2 diabetes 
294 
• Study eye with  
295 
o Best corrected Electronic-ETDRS (E-ETDRS) visual acuity letter score in the study 
296 
eye ≥79 (approximate Snellen equivalent 20/25 or better) 
297 
o Severe NPDR (based on the 4:2:1 rule) on clinical examination and on digital 
298 
imaging as judged by the investigator  
299 
• Reading Center grading of less than ETDRS level 43 or greater than 53 is 
300 
an exclusion 
301 
o No evidence of neovascularization on fluorescein angiography within the 7-modified 
302 
ETDRS fields, confirmed by Reading Center grading. 
303 
o No clinical exam evidence of neovascularization including active neovascularization 
304 
of the iris (small iris tufts are not an exclusion) or angle neovascularization (if the 
305 
angle is assessed).  
306 
o No prior PRP (defined as ≥ 100 burns placed previously outside of the posterior pole) 
307 
o No CI-DME on clinical exam and OCT central subfield thickness below the 
308 
following gender and OCT-machine specific thresholds: 
309 
• Zeiss Cirrus: 290µm in women and  305µm in men 
310 
• Heidelberg Spectralis: 305µm in women and 320µm in men 
311 
o No history of DME or DR treatment with laser or intraocular injections of medication 
312 
within the prior 12 months and no more than 4 prior intraocular injections at any time 
313 
in the past. 
314 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
1-6 
 
C. Treatment Groups 
315 
Study eyes will be assigned randomly (1:1) to one of the following two groups: 
316 
 
317 
• Sham injections 
318 
• Intravitreous 2 mg aflibercept injections 
319 
 
320 
Study participants may have one or two study eyes.  Study participants with two study eyes will 
321 
receive intravitreous aflibercept in one eye and sham injection in the other eye. Further details on 
322 
randomization are located in section 2.4. 
323 
 
324 
Injections (intravitreous or sham) will be given at baseline, 1 and 2 months in all participants.  
325 
Thereafter, injections will be given at each 4-month visit until 2 years.  At and after the 2-year 
326 
visit, retreatment with injections (intravitreous or sham) will be based on DR level, as assessed 
327 
by the investigator.   
328 
 
329 
Treatment for DME or PDR, if developed, may only be given once protocol-specified criteria are 
330 
met and will follow a protocol-specified regimen (see Section 4.4 and 4.5).   
331 
 
332 
D. Sample Size 
333 
• A minimum of 386 eyes (approximately 322 study participants assuming 20% have two 
334 
study eyes)  
335 
 
336 
E. Duration of Follow-up 
337 
• Primary outcome: 2 years 
338 
• Total follow-up: 4 years 
339 
 
340 
F. Follow-up Schedule 
341 
• All participants will have visits at 1 month, 2 months, and 4 months, followed by visits 
342 
every 4 months thereafter through 4 years. 
343 
• Eyes may be seen more frequently depending on disease progression and treatment 
344 
administered.  Further details on the follow-up visit schedule are described in Section 3.1. 
345 
 
346 
G. Main Efficacy Outcomes 
347 
 
348 
Primary outcome:     
349 
 
350 
 Development of PDR or DME, defined as the first occurrence of any of the following 
351 
(composite time-to-event outcome): 
352 
• NV within the 7-modified ETDRS fields on fundus photography or FA, confirmed by 
353 
a masked grader at the central reading center 
354 
o At non-annual visits, fundus photography and FA will only be submitted to the 
355 
reading center to assess for this component of the primary outcome if the 
356 
investigator thinks treatment is necessary. 
357 
• NV of the iris (at least 2 cumulative clock hours), definitive NV of the angle, or 
358 
neovascular glaucoma on clinical exam (photographic documentation not required) 
359 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
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• Other outcomes presumed to be from PDR and documented: traction retinal 
360 
detachment, vitreous hemorrhage, or pre-retinal hemorrhage greater than ½ disc area 
361 
• Procedures undertaken for the treatment of PDR (when present or presumed to be 
362 
present): PRP, anti-VEGF, or vitrectomy 
363 
• CI-DME on clinical exam with at least 10% increase in central subfield thickness 
364 
from baseline and either (1) at least a 10-letter decrease in visual acuity from baseline 
365 
at a single visit or (2) 5-to-9-letter decrease in visual acuity from baseline at 2 
366 
consecutive visits at least 21 days apart, with vision loss presumed to be from DME  
367 
• Non-topical treatment for DME performed without meeting the above criteria, 
368 
including focal/grid laser or intravitreous injections for DME 
369 
 
370 
The primary outcome analysis will be performed when the last randomized participant reaches 2 
371 
years of follow up, using all available follow up data. The treatment groups will be compared 
372 
using the hazard ratio. 
373 
 
374 
Other Key Outcomes: 
375 
• Development of PDR or DME outcome through 4 years 
376 
• Mean visual acuity change from baseline at 2 years 
377 
• Mean visual acuity change from baseline at 4 years  
378 
 
379 
See section 7.3 for methods of handling multiplicity.   
380 
 
381 
Additional secondary outcomes at 2 and 4 years: 
382 
• Development of PDR or PDR-related outcome (as defined above within the 
383 
composite time-to-event outcome) 
384 
• Development of CI-DME with visual acuity impairment (as defined above within the 
385 
composite time-to-event outcome) 
386 
• Development of PDR or DME based only on the objective components defined in the 
387 
composite outcome, including OCT, visual acuity, and reading center assessment of 
388 
photos and FA (i.e. not including investigator-only assessments) 
389 
• Development of each component of the composite outcome assessed individually 
390 
• Proportion of eyes with at least 10 or at least 15 letter loss from baseline, or gain or 
391 
loss of at least 5 letters at consecutive study visits, consisting of the visits just before 
392 
and the 2- or 4-year visit 
393 
• Visual acuity area under the curve (AUC) between randomization and the 2- and 4-
394 
year visits 
395 
• Mean change in OCT central subfield thickness from baseline 
396 
• Mean change in OCT volume from baseline 
397 
• Development of CI-DME on clinical exam with at least 10% increase in central 
398 
subfield thickness and at least a 25-micron increase from baseline, regardless of 
399 
visual acuity change 
400 
• Proportion of eyes with at least 2-step worsening of DR severity level (scale for 
401 
individual eyes) by central reading center from baseline 
402 
• Proportion of eyes with at least 2-step improvement of DR severity level (scale for 
403 
individual eyes) by central reading center from baseline 
404 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
1-8 
 
• Proportion of eyes with at least 3-step worsening of DR severity level (scale for 
405 
individual eyes) by central reading center from baseline 
406 
• Proportion of eyes with at least 3-step improvement of DR severity level (scale for 
407 
individual eyes) by central reading center from baseline 
408 
• Level of retinopathy on color photos 
409 
• Number of aflibercept injections performed 
410 
• Follow-up costs and patient-centered outcomes from the Workplace Productivity and 
411 
Activity Impairment Questionnaire 
412 
 
413 
H. Main Safety Outcomes 
414 
Ocular: endophthalmitis, inflammation, retinal detachment, traumatic cataract from injection, 
415 
vitreous hemorrhage 
416 
 
417 
Systemic: Antiplatelet Trialists’ Collaboration (APTC) events and hypertension 
418 
 
419 
I. Schedule of Assessment Visits and Examination Procedures 
420 
 
Screening 
Randomization 
Follow-Up 
Visits* 
Annual 
Visits 
Visit Window 
 
within 35 days of 
screening 
(±1to8w) 
(±8w) 
Usual care visual acuitya 
X 
 
 
 
E-ETDRS best corrected visual acuityb 
 
X 
X 
X 
Questionnairesc 
 
X 
 
X 
OCTd 
X 
X 
X 
X 
Eye Exame 
X 
X 
X 
X 
Fundus Photographyf 
X 
 
Xg 
X 
Fluorescein angiographyf 
X 
 
Xg 
X 
Blood pressure 
 
X 
 
X 
HbA1ch 
 
X 
 
X 
OCT angiographyi 
X 
 
Xg 
X 
*= Assessment Visits at 1 month (±1w), 2 months (±1w), 4 months (±8w) and every 4 months  (±8w) thereafter; additional study 
421 
visits may occur for treatment of DME/PDR as needed 
422 
a=study eye only; refraction and/or electronic ETDRS testing may be performed at the discretion of the site for usual care visual 
423 
acuity.  
424 
b=both eyes including protocol refraction in the study eye at each study visit. Protocol refraction in non-study eye is only 
425 
required at baseline and annual visits.  E-ETDRS refers to electronic ETDRS testing using the Electronic Visual Acuity Tester 
426 
that has been validated against 4-meter chart ETDRS testing. 
427 
c= only in participants with one study eye 
428 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
1-9 
 
d= study eye only at randomization and annual visits and at other study visits only if evaluating for DME treatment (see section 
429 
3.2 for more details) or prior to initiating more frequent anti-VEGF treatment for PDR, if the DME outcome was not confirmed 
430 
previously. 
431 
e=both eyes at randomization; study eye only at each additional study visit including slit lamp exam, lens assessment, 
432 
measurement of intraocular pressure, and dilated ophthalmoscopy 
433 
f= study eye only. Fundus photography is 7MF or 4WF and FA is using the widest approach available at the site. 
434 
g= fundus photography,  FA, and OCTA (if available at the site) is also required in the study eye at 4 months AND 1) the first 
435 
time traction retinal detachment, vitreous hemorrhage, or preretinal hemorrhage is identified to confirm the primary outcome has 
436 
been met, or 2) prior to initiating PRP or vitrectomy, if the primary outcome was not confirmed previously or 3) prior to initiating 
437 
more frequent anti-VEGF treatment for either DME or PDR, if the primary outcome was not confirmed previously.  Fundus 
438 
photography is 7MF or 4WF and FA is using the widest approach available at the site. 
439 
h= does not need to be repeated if HbA1c is available from within the prior 3 months.  If not available, can be performed within 3 
440 
weeks after randomization. 
441 
i=study eye only; only at sites with OCT angiography capabilities.    
442 
1.4 
General Considerations 
443 
The study is being conducted in compliance with the policies described in the DRCR.net Policies 
444 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
445 
the protocol described herein, and with the standards of Good Clinical Practice. 
446 
 
447 
The DRCR.net Procedures Manuals (Visual Acuity-Refraction Testing Procedures Manual, OCT 
448 
procedures manuals, photography and FA procedures manuals, and Study Procedures Manual) 
449 
provide details of the examination procedures and intravitreous injection procedure.   
450 
 
451 
Photographers, OCT technicians, and visual acuity testers, including refractionists, will be 
452 
masked to treatment group at the annual visits.  Study participants will be masked to their 
453 
treatment group assignment and will continue to be masked to their original treatment 
454 
assignment even once they initiate treatment for PDR or CI-DME.  Investigators and study 
455 
coordinators are not masked to treatment group. 
456 
   
457 
Data will be directly collected in electronic case report forms, which will be considered the 
458 
source data. 
459 
 
460 
There is no restriction on the number of study participants to be enrolled by a site. 
461 
 
462 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
463 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
464 
2013). 
465 
 
466 
The risk level is considered to be research involving greater than minimal risk.
467 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
2-1 
 
CHAPTER 2. STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 
468 
 
469 
2.1 
Identifying Eligible Subjects and Obtaining Informed Consent 
470 
A minimum of 386 eyes (322 participants assuming 20% have two study eyes) are expected to be 
471 
enrolled into the randomized trial.  As the enrollment goal approaches, sites will be notified of 
472 
the end date for recruitment.  Study participants who have signed an informed consent form can 
473 
be randomized up until the end date, which means the recruitment goal might be exceeded.   
474 
 
475 
Potential eligibility will be assessed as part of a routine-care examination.  Prior to completing 
476 
any procedures or collecting any data that are not part of usual care, written informed consent 
477 
will be obtained.  For patients who are considered potentially eligible for the study based on a 
478 
routine-care exam, the study protocol will be discussed with the potential study participant by a 
479 
study investigator and clinic coordinator.  The potential study participant will be given the 
480 
Informed Consent Form to read.  Potential study participants will be encouraged to discuss the 
481 
study with family members and their personal physician(s) before deciding whether to participate 
482 
in the study.   
483 
 
484 
Consent may be given in two stages (if approved by the IRB).  The initial stage will provide 
485 
consent to complete any of the screening procedures needed to assess eligibility that have not 
486 
already been performed as part of a usual-care exam.  The second stage will be obtained prior to 
487 
randomization and will be for participation in the study.  A single consent form will have two 
488 
signature/date lines for the study participant:  one for a study participant to give consent for the 
489 
completion of the screening procedures and one for the study participant to document consent for 
490 
the randomized trial.  Study participants will be provided with a copy of the signed Informed 
491 
Consent Form. 
492 
 
493 
Once a study participant is randomized, that participant will be counted regardless of whether the 
494 
assigned treatment is received.  Thus, the investigator must not proceed to randomize an 
495 
individual until he/she is convinced that the individual is eligible and will accept assignment to 
496 
either of the two treatment groups. 
497 
 
498 
2.2 
Subject Eligibility Criteria 
499 
2.2.1 Individual-level Criteria 
500 
Inclusion 
501 
To be eligible, the following inclusion criteria must be met: 
502 
1. Age >= 18 years  
503 
• Individuals <18 years old are not being included because DR is so rare in this age group 
504 
that the diagnosis of NPDR may be questionable.  
505 
2. Diagnosis of diabetes mellitus (type 1 or type 2)  
506 
• Any one of the following will be considered to be sufficient evidence that diabetes is 
507 
present:  
508 
 Current regular use of insulin for the treatment of diabetes 
509 
 Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes 
510 
 Documented diabetes by ADA and/or WHO criteria (see Procedures Manual for 
511 
definitions) 
512 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
2-2 
 
3. At least one eye meets the study eye criteria listed in section 2.2.2. 
513 
4. Able and willing to provide informed consent. 
514 
Exclusion 
515 
An individual is not eligible if any of the following exclusion criteria are present:  
516 
5. History of chronic renal failure requiring dialysis or kidney transplant. 
517 
6. A condition that, in the opinion of the investigator, would preclude participation in the study 
518 
(e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic 
519 
control).  
520 
7. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months 
521 
prior to randomization or plans to do so in the next 4 months. 
522 
8. Participation in an investigational trial that involved treatment within 30 days of 
523 
randomization with any drug that has not received regulatory approval for the indication 
524 
being studied. 
525 
• Note: study participants cannot participant in another investigational trial that involves 
526 
treatment with an investigational drug while participating in the study. 
527 
9. Known allergy to any component of the study drug or any drug used in the injection prep 
528 
(including povidone iodine prep).   
529 
10. Known allergy to fluorescein dye. 
530 
11. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). 
531 
• If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual 
532 
can become eligible.  
533 
12. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization. 
534 
• These drugs should not be used during the study. 
535 
13. For women of child-bearing potential: pregnant or lactating or intending to become pregnant 
536 
within the next 2 years. 
537 
• Women who are potential study participants should be questioned about the potential for 
538 
pregnancy.  Investigator judgment is used to determine when a pregnancy test is needed. 
539 
14. Individual is expecting to move out of the area of the clinical center to an area not covered by 
540 
another DRCR.net certified clinical center during the next 2 years. 
541 
 
542 
2.2.2 Study Eye Criteria 
543 
The potential study participant must have at least one eye meeting all of the inclusion criteria and 
544 
none of the exclusion criteria listed below.   
545 
 
546 
A study participant can have two study eyes only if both are eligible at the time of 
547 
randomization.  For study participants with two eligible eyes, the logistical complexities of the 
548 
protocol must be considered for each individual prior to randomizing both eyes.    
549 
 
550 
The eligibility criteria for a study eye are as follows: 
551 
 
552 
 
 
553 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
2-3 
 
Inclusion 
554 
a. Best corrected E-ETDRS visual acuity letter score ≥79 (approximate Snellen equivalent 
555 
20/25 or better) 
556 
b. Severe NPDR (based on the 4:2:1 rule) evident on clinical examination and/or on digital 
557 
imaging as judged by the investigator. Severe NPDR is defined as:  
558 
1. 4 fields show severe hemorrhages or microaneurysms (at least as great as Standard 
559 
photograph 2A), or 
560 
2. At least 2 fields of definite venous beading or at least 1 field at least as severe as 
561 
Standard photograph 6A, or 
562 
3. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA), at 
563 
least as severe as Standard photograph 8A 
564 
c. No evidence of neovascularization on clinical exam including active neovascularization of 
565 
the iris (small iris tufts are not an exclusion) or angle neovascularization (if the angle is 
566 
assessed).  
567 
d. No evidence of neovascularization on fluorescein angiography within the 7-modified ETDRS 
568 
fields, confirmed by the central Reading Center prior to randomization.   
569 
• The widest method of imaging available at the site must be used to document whether 
570 
there is NV present in the periphery; however, presence of NV outside of the 7-modified 
571 
ETDRS fields on ultra-widefield imaging will not be an exclusion provided treatment is 
572 
not planned.   
573 
e. No CI-DME on clinical exam and OCT central subfield thickness must be below the 
574 
following gender and OCT-machine specific thresholds: 
575 
 Zeiss Cirrus: 290µ in women and  305µ in men 
576 
 Heidelberg Spectralis: 305µ in women and 320µ in men 
577 
AND investigator and potential participant are comfortable withholding treatment for DME 
578 
until there is at least a 10% increase in OCT central subfield thickness with confirmed visual 
579 
acuity loss (10 letter loss at a single visit or 5 to 9 at two consecutive visits). 
580 
f. Prompt PRP or anti-VEGF treatment not required AND investigator and potential participant 
581 
are willing to wait for development of high-risk characteristics (defined in Section 4.5.2) to 
582 
treat PDR.   
583 
g. Media clarity, pupillary dilation, and study participant cooperation sufficient to obtain 
584 
adequate fundus photographs, FA, and OCT.  
585 
• Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate 
586 
quality (including segmentation line placement)  
587 
 
588 
Exclusion 
589 
The following exclusions apply to the study eye only (i.e., they may be present for the non-study 
590 
eye): 
591 
 
592 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
2-4 
 
h. Central Reading Center grading of DR severity level on fundus photographs less severe than 
593 
ETDRS level 43 or more severe than level 53. 
594 
• Enrollment will be limited to a maximum of 50% of the planned sample size with DR 
595 
severity level 47A or 43 by RC grading (with a maximum of 25% of the planned 
596 
sample size with DR severity level 43 by RC grading). Once the number of eyes has 
597 
been enrolled for each severity level, RC grading of that level will be an exclusion 
598 
criterion.  
599 
i. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed 
600 
to be from PDR.  
601 
j. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.  
602 
k. History of prior PRP (defined as ≥100 burns outside of the posterior pole). 
603 
l. An ocular condition is present (other than DR) that, in the opinion of the investigator, might 
604 
alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis 
605 
or other ocular inflammatory disease, vitreomacular traction, etc.).  
606 
m. History of DME or DR treatment with laser or intraocular injections of medication within the 
607 
prior 12 months and no more than 4 prior intraocular injections at any time in the past. 
608 
• Enrollment will be limited to a maximum of 25% of the planned sample size with any 
609 
history of treatment for DME/DR. Once this number of eyes has been enrolled, any 
610 
history of treatment for DME/DR will be an exclusion criterion.  
611 
 
612 
n. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular 
613 
surgery, etc.) within prior 4 months or anticipated within the next 6 months following 
614 
randomization.  
615 
o. Any history of vitrectomy. 
616 
p. History of YAG capsulotomy performed within 2 months prior to randomization.  
617 
q. Aphakia. 
618 
r. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or 
619 
substantial blepharitis. 
620 
s. Evidence of uncontrolled glaucoma. 
621 
• Intraocular pressure must be <30, with no more than one topical glaucoma 
622 
medication, and no documented glaucomatous field loss for the eye to be eligible. 
623 
2.2.3 Non-Study Eye Criteria 
624 
If anti-VEGF treatment is indicated for any condition in the non-study eye at any time during the 
625 
study, the investigator must be willing to use the study anti-VEGF drug (2 mg aflibercept) for the 
626 
non-study eye.  If the non-study eye is currently being treated with a different anti-VEGF drug 
627 
for any condition, then the investigator and patient must be willing to switch to aflibercept.  If 
628 
the investigator or patient is unwilling to change anti-VEGF treatment in the non-study eye, the 
629 
patient should not be enrolled.    
630 
 
631 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
2-5 
 
2.3 
Screening Evaluation and Baseline Testing 
632 
2.3.1 Historical Information 
633 
A history will be elicited from the potential study participant and extracted from available 
634 
medical records.  Data to be collected will include:  age, gender, ethnicity and race, diabetes 
635 
history and current management, other medical conditions, medications being used, as well as 
636 
ocular diseases, surgeries, and treatment. 
637 
 
638 
2.3.2 Baseline Testing Procedures 
639 
2.3.2.1 Screening Visit 
640 
The following procedures are needed to assess eligibility at Screening. 
641 
• If a procedure has been performed (using the study technique and by study certified 
642 
personnel) as part of usual care, it does not need to be repeated specifically for the study 
643 
if it was performed within the defined time windows specified below.  
644 
• The testing procedures are detailed in the DRCR.net Procedures Manuals.  Visual acuity 
645 
testing, ocular exam, fundus photography, fluorescein angiography and OCT will be 
646 
performed by DRCR.net certified personnel.  
647 
• The fundus photographs and fluorescein angiograms will be promptly sent to the central 
648 
reading center for grading and a participant cannot be randomized until reading center 
649 
confirmation of eligibility has been received. 
650 
• OCTs meeting DRCR.net criteria for manual grading may be sent to a reading center, but 
651 
study participant eligibility regarding DME status is determined by the site (i.e., 
652 
individuals deemed eligible by the investigator will be randomized without pre-
653 
randomization reading center confirmation of the OCT central subfield thickness). 
654 
 
655 
1. Visual acuity using clinic’s usual care method or Electronic-ETDRS visual acuity to 
656 
confirm vision is 20/25 or better in the study eye (within prior 8 days). 
657 
2. Spectral Domain OCT using Zeiss Cirrus or Heidelberg Spectralis on the study eye (within 
658 
prior 8 days).  
659 
3. Ocular examination on the study eye including slit lamp, measurement of intraocular 
660 
pressure, lens assessment, and dilated ophthalmoscopy (on day of Screening).  
661 
4. Digital fundus photography in the study eye.  (within prior 8 days)  
662 
5. Digital fluorescein angiogram (FA) in the study eye, using the widest approach available at 
663 
the clinical site (e.g. ultra-widefield imaging device, if available). (within prior 8 days) 
664 
6. OCT angiography on the study eye. (within prior 8 days) 
665 
• Only obtained by a subset of sites with OCT angiography capabilities.  If a site has 
666 
OCT angiography systems from more than one manufacturer, the images should be 
667 
obtained on each system available.   
668 
• See procedure manual for more details on acquisition, including which fields to 
669 
collect on a given OCT angiography system. 
670 
 
671 
2.3.2.2 Randomization Visit 
672 
The randomization visit must be completed within 35 days of Screening.  The visit should not be 
673 
completed until Reading Center confirmation of eligibility based on the Screening fundus 
674 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
2-6 
 
photographs and FA has been received.  The following procedures are needed to confirm 
675 
eligibility and to serve as baseline measures for the study:   
676 
 
677 
1. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 
678 
(including protocol refraction) in each eye. (on day of randomization) 
679 
2. Spectral Domain OCT using Zeiss Cirrus or Heidelberg Spectralis on study eye (on day of 
680 
randomization) 
681 
• The same OCT machine type as Screening should be used. 
682 
3. Ocular examination on each eye including slit lamp, measurement of intraocular pressure, 
683 
lens assessment, and dilated ophthalmoscopy.  (on day of  randomization) 
684 
4. Workplace Productivity and Activity Impairment (WPAI) Questionnaire (only in participants 
685 
with one study eye, on day of randomization).  
686 
5. Measurement of blood pressure.  
687 
6. Laboratory testing of Hemoglobin A1c. 
688 
• HbA1c does not need to be repeated if available in the prior 3 months.  If not 
689 
available at the time of randomization, the potential study participant may be 
690 
enrolled but the test must be obtained within 3 weeks after randomization.  
691 
2.4 
Randomization of Eligible Study Participants  
692 
1. Prior to randomization, the study participant’s understanding of the trial, willingness to 
693 
accept the assigned treatment group, and commitment to the follow-up schedule should be 
694 
reconfirmed. 
695 
2. The initial injection must be given on the day of randomization. A study participant should 
696 
not be enrolled until this is possible 
697 
3. Randomization is completed on the DRCR.net website.  
698 
• Study participants with one study eye will be randomly assigned (stratified by  
699 
Reading Center grading of DR severity level [43, 47A, 47B-D, 53 with no NV in the 
700 
periphery, or 53 with NV in the periphery]) with equal probability to one of the 
701 
treatment groups:  
702 
o Group A: Sham injections  
703 
o Group B: Intravitreous 2 mg aflibercept injections 
704 
 
705 
• For study participants with two study eyes (both eyes eligible at the time of 
706 
randomization), the study participant will be randomly assigned with equal 
707 
probability to receive either: 
708 
o Group A in the eye with greater DR severity and Group B in the eye with 
709 
lower DR severity 
710 
o Group B in the eye with greater DR severity and Group A in the eye with 
711 
lower DR severity 
712 
 
713 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
2-7 
 
Note: if both eyes have the same DR severity, the right eye will be considered the eye 
714 
with the greater DR severity. 
715 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
3-1 
 
CHAPTER 3. FOLLOW-UP VISITS AND TESTING 
716 
 
717 
3.1 
Visit Schedule 
718 
3.1.1 Assessment Visits 
719 
The schedule of protocol-specified Assessment Visits for all participants is as follows: 
720 
 
721 
• Visits at 1 and 2 months (± 1 week) 
722 
 Study injections for prevention of PDR and DME must be at least 21 days 
723 
apart; therefore, follow-up visits should be scheduled accordingly so that 
724 
the eye is eligible for retreatment. 
725 
• Visits at 4 months and then every 4 months at 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 
726 
months (±8 weeks) 
727 
 The every 4-month study visits/injections for prevention of PDR and DME 
728 
must be no closer than 8 weeks apart. 
729 
3.1.2 Additional Study Visits 
730 
 
731 
1. DME Outcome Visits 
732 
• If the eye has not already met the primary outcome and visual acuity has decreased 5 
733 
to 9 letters from baseline and the loss is attributable to DME, the participant will 
734 
return in 4 weeks (± 1 week) to assess whether the eye has met the primary outcome 
735 
for DME progression and is eligible for treatment. 
736 
 
737 
2. DME Treatment Visits 
738 
• Once DME treatment has been initiated, follow-up visits for DME treatment occur 
739 
every 4 weeks for the first 6 months from initial aflibercept treatment for DME. After 
740 
6 months, if the injection is deferred at the current and previous 2 visits (see section 
741 
4.4 for retreatment criteria), the next study follow-up visit is in twice the time since 
742 
the last visit up to a maximum of 16 weeks between visits.  Otherwise, the next study 
743 
follow-up visit is in 4 weeks. 
744 
 
745 
3. PDR Treatment Visits 
746 
• Once NV is present, the participant may return sooner than the next scheduled 
747 
Assessment Visit to evaluate for progression to high-risk, at the discretion of the 
748 
investigator. 
749 
• Once PDR treatment has been initiated, follow-up visits for PDR treatment occur 
750 
every 4 weeks for the first 6 months from initial aflibercept treatment for PDR. After 
751 
6 months, if the injection is deferred at the current and previous 2 visits (see section 
752 
4.5.4 for retreatment criteria), the next study follow-up visit is in twice the time since 
753 
the last visit up to a maximum of 16 weeks between visits.  Otherwise, the next study 
754 
follow-up visit is in 4 weeks. 
755 
 
756 
Note: Regardless of the timing of additional visits for DME/PDR treatment, the participant will 
757 
return for the protocol-specified Assessment Visits listed above in Section 3.1.1. 
758 
 
759 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
3-2 
 
3.2 
Testing Procedures  
760 
The following procedures will be performed at each study visit (listed in 3.1.1 and 3.1.2) on the 
761 
study eye only unless otherwise specified. A grid in section 1.3 summarizes the testing 
762 
performed at each visit. Photographers, OCT technicians, and visual acuity testers, including 
763 
refractionists, will be masked to treatment group at annual visits. 
764 
 
765 
1. E-ETDRS visual acuity testing in each eye (best corrected). 
766 
• A protocol refraction in the study eye is required at all study visits.  Refraction in the 
767 
non-study eye is only required at annual visits.  When a refraction is not performed, 
768 
the most-recently performed refraction is used for the testing. 
769 
2. Workplace Productivity and Activity Impairment (WPAI) Questionnaire (only in participants 
770 
with one study eye) at annual visits.  
771 
3. OCT on the study eye at annual visits and if any of the following are met: 
772 
• If visual acuity has decreased by at least 5 letters (equivalent to approximately 1 or 
773 
more line) since baseline in an eye that has not previously met the DME outcome and 
774 
there is no other apparent cause (e.g. cataract), an OCT must be performed to 
775 
determine if DME is the cause of vision loss.   
776 
• If DME treatment is being considered, an OCT must be done to confirm the eye has 
777 
met the primary outcome before proceeding with treatment.   
778 
• Once DME treatment has been initiated, an OCT must be done at each subsequent 
779 
DME Treatment Visit. 
780 
• Prior to initiating more frequent anti-VEGF treatment for PDR, if DME outcome was 
781 
not met previously. 
782 
 The same OCT machine type as Randomization should be used. 
783 
4. Ocular exam on the study eye, including slit lamp examination, lens assessment, 
784 
measurement of intraocular pressure and dilated ophthalmoscopy 
785 
• Undilated exam of the iris and examination of the angle is at investigator discretion. 
786 
5. Digital fundus photographs on the study eye at the 4-month visit and annual visits. 
787 
• Digital fundus photography must also be performed 1) the first time traction retinal 
788 
detachment, vitreous hemorrhage, or preretinal hemorrhage is identified to confirm 
789 
the primary outcome has been met, or 2) prior to initiating PRP or vitrectomy, if the 
790 
primary outcome was not confirmed previously or 3) prior to initiating more frequent 
791 
anti-VEGF treatment for either DME or PDR, if the primary outcome was not 
792 
confirmed previously.   
793 
6. Digital FA using the widest approach available (e.g. ultra-widefield imaging device, if 
794 
available) on the study eye at the 4-month visit and annual visits.  
795 
• Digital FA must also be performed 1) the first time traction retinal detachment, 
796 
vitreous hemorrhage, or preretinal hemorrhage is identified to confirm the primary 
797 
outcome has been met, or 2) prior to initiating PRP or vitrectomy, if the primary 
798 
outcome was not confirmed previously or 3) prior to initiating more frequent anti-
799 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
3-3 
 
VEGF treatment for either DME or PDR, if the primary outcome was not confirmed 
800 
previously.   
801 
 If a site obtains a new ultra-widefield imaging device during the course of the study, 
802 
the widest approach available should be used for all study visits going forward. 
803 
 For participants with two study eyes, the transit eye at follow-up should be consistent 
804 
with the transit eye selected at baseline. 
805 
7. OCT angiography on the study eye at the 4-month visit and annual visits, as well as the time 
806 
points above when fundus photographs and FA are obtained for primary outcome 
807 
documentation. 
808 
• Only obtained by a subset of sites with OCT angiography capabilities.  If a site has 
809 
OCT angiography systems from more than one manufacturer, the images should be 
810 
obtained on each system available.   
811 
 See procedure manual for more details on acquisition, including which fields to 
812 
collect on a given OCT angiography system. 
813 
8. Measurement of blood pressure at annual visits only.  
814 
9. Laboratory testing of Hemoglobin A1c at annual visits only. 
815 
 HbA1c does not need to be repeated at annual visits if available in the prior 3 
816 
months.  
817 
All of the testing procedures do not need to be performed on the same day, provided that they are 
818 
completed within the time window of a visit and prior to initiating any treatment. 
819 
Testing procedures at unspecified visits are at investigator discretion.  However, it is 
820 
recommended that procedures that are performed should follow the standard DRCR.net protocol 
821 
for each procedure.  If a primary outcome criterion is identified at an unspecified visit, the 
822 
imaging requirements above apply and best-corrected visual acuity testing should be performed 
823 
whenever possible.   
824 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
4-1 
 
CHAPTER 4. TREATMENT REGIMEN 
825 
 
826 
4.1 
Treatment Groups 
827 
The treatment groups are as follows: 
828 
A: Sham injections  
829 
B: Intravitreous 2 mg aflibercept injections 
830 
 
831 
For both groups, the baseline injection (sham or intravitreous) must be given on the day of 
832 
randomization.   
833 
 
834 
4.2 
Injection Procedure 
835 
4.2.1  Intravitreous Aflibercept Injection (Eylea®) 
836 
Eylea® (intravitreal aflibercept injection) is made by Regeneron Pharmaceuticals, Inc. and is 
837 
approved by the FDA for the treatment of neovascular age-related macular degeneration, 
838 
macular edema due to central retinal vein occlusion, macular edema due to branch retinal vein 
839 
occlusion, diabetic macular edema, and diabetic retinopathy in eyes with diabetic macular 
840 
edema.   
841 
 
842 
Study eyes that receive anti-VEGF will receive a dose of 2 mg aflibercept in 0.05 cc each time a 
843 
study injection is performed.  The physical, chemical and pharmaceutical properties and 
844 
formulation are provided in the Clinical Investigator Brochure. Aflibercept for the study and 
845 
non-study eye will be distributed by the Network. 
846 
 
847 
4.2.2  Intravitreous Injection Technique 
848 
The injection is preceded by a povidone iodine prep of the conjunctiva.  In general, topical 
849 
antibiotics in the pre-, peri-, or post-injection period should not be used.  
850 
 
851 
The injection will be performed using sterile technique.  The full injection procedure is described 
852 
in the protocol-specific study procedures manual. 
853 
 
854 
4.2.3 Sham Injection Technique 
855 
The prep will be performed as for an intravitreous injection.  A syringe without a needle will be 
856 
used, with the hub pressed against the conjunctival surface to simulate the force of an actual 
857 
injection. 
858 
 
859 
4.2.4 Deferral of Injections Due to Pregnancy 
860 
Female study participants of child-bearing age must be questioned regarding the possibility of 
861 
pregnancy prior to each injection. In the event of pregnancy, study injections must be 
862 
discontinued during the pregnancy and any post-partum period of breastfeeding.   
863 
 
864 
4.2.5 Non-Study Eye Injections 
865 
If the non-study eye is going to be treated for any condition which requires treatment with an 
866 
anti-VEGF agent, study provided aflibercept must be used.  However, if intravitreous treatment 
867 
is planned on the same day as an intravitreous injection in the study eye, the study eye will be 
868 
injected first, followed by the non-study eye (see Procedures Manual for additional details).  If a 
869 
non-study anti-VEGF medication is desired to be administered by intravitreous injection in the 
870 
non-study eye, a discussion with the Protocol Chair is required first. 
871 
 
872 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
4-2 
 
4.3 
Follow-Up Treatment Protocol for Prevention of PDR/DME 
873 
Injections for prevention of PDR/DME will be given according to the criteria below at each 
874 
Assessment Visit (listed in 3.1.1).  Additional injections must not be given in-between the 
875 
Assessment Visits, unless criteria are met for PDR or DME treatment (see Sections 4.4 and 4.5). 
876 
 
877 
If an eye experienced adverse effects from a prior intravitreous injection, retreatment is at the 
878 
discretion of the investigator.   
879 
 
880 
4.3.1 Injections at 4 and 8 Weeks and Each 4-Month Interval Visit until 2 Years 
881 
During Years 1 and 2, study eyes receive an injection (sham or intravitreous) at each Assessment 
882 
Visit (listed in 3.1.1). Group A receives a sham injection and group B receives a 2 mg aflibercept 
883 
injection.   
884 
 
885 
4.3.2 Injections at and After the 2-Year Visit 
886 
At and after the 2-year visit, the study eye is evaluated for intravitreous (sham) injection 
887 
retreatment at each Assessment Visit. Group A receives a sham injection and group B receives a 
888 
2 mg aflibercept injection.   
889 
 
890 
• If the DR level is mild NPDR or better (≤ Level 35) based on the investigator’s 
891 
assessment, the injection should be deferred. 
892 
o Level 35 can be clinically defined as microaneurysms plus venous loops, hard 
893 
exudates, cotton wool spots and/or mild retinal hemorrhages (less than present in 
894 
ETDRS Standard photograph 2a). 
895 
• If the DR level is worse than mild NPDR (> Level 35, defined above), the injection (or 
896 
sham) is given. 
897 
 
898 
4.4 
Treatment for CI-DME 
899 
Treatment for CI-DME must not be given until the following criteria have been met: 
900 
• CI-DME on clinical exam with ≥10% increase in central subfield thickness from baseline 
901 
and either: 
902 
o 1) at least 10 letter decrease in visual acuity presumed to be from DME at a single 
903 
visit or  
904 
o 2) 5 to 9 letter decrease in visual acuity presumed to be from DME at two-
905 
consecutive visits at least 21 days apart. 
906 
Once the above criteria have been met, an injection of 2 mg aflibercept will be given.  
907 
Thereafter, the eye will be evaluated at each visit for retreatment. In general, an eye will continue 
908 
to receive an injection if the eye is improving or worsening on OCT or visual acuity. The first 
909 
time an eye has not improved or worsened, the eye will receive an injection.  If the eye has not 
910 
improved or worsened for at least 2 consecutive 4-week injections and the OCT CSF thickness is 
911 
less than the gender specific spectral domain OCT threshold (see below) and visual acuity is 
912 
20/20 or better, then injection will be deferred.  If the eye has not improved or worsened for at 
913 
least 2 consecutive 4-week visits and the OCT CSF thickness is ≥ the gender specific spectral 
914 
domain OCT threshold or visual acuity is worse than 20/20, the following will be done: 
915 
• If less than 24 weeks from the initial injection for DME, an injection will be given. 
916 
• At and after 24 weeks, the injection will be deferred. 
917 
 
918 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
4-3 
 
The protocol chair or designee must be contacted prior to deviation from the injection protocol.  
919 
See the DRCR.net Procedure Manual for additional details. 
920 
 
921 
Spectral domain OCT central subfield gender-specific threshold: 
922 
 Zeiss Cirrus: 290 microns in women, and 305 microns in men 
923 
 Heidelberg Spectralis: 305 microns in women, and 320 microns in men 
924 
 
925 
4.4.1 Initiation of Focal/Grid Photocoagulation While Receiving Anti-VEGF Injections 
926 
In general, focal/grid laser will be initiated at or after the 24 week visit if 1) the OCT central 
927 
subfield thickness is greater than the OCT central subfield gender-specific threshold (above) or 
928 
there is edema that is threatening the fovea and 2) the eye has not improved on OCT or visual 
929 
acuity from the last two consecutive injections.  Once focal/grid laser has been initiated, 
930 
retreatment with focal/grid laser will be given unless one of the following is present: 1) 
931 
focal/grid laser has been given in the previous 13 weeks, 2) complete focal/grid laser has already 
932 
been given in the investigator’s judgment, 3) the OCT central subfield thickness is less than the 
933 
OCT central subfield gender-specific threshold (above) and there is no edema threatening the 
934 
fovea, 4) the eye has improved since the last laser treatment. The protocol chair or designee must 
935 
be contacted prior to deviating from the focal/grid laser protocol.  See the DRCR.net Procedure 
936 
Manual for additional details. 
937 
 
938 
4.4.2 Continuation of Prevention Treatment Protocol 
939 
Eyes for which the above anti-VEGF treatment regimen is initiated for DME will continue 
940 
injections as part of the prevention protocol.  At each Assessment Visit, if an injection has not 
941 
been given within the prior 21 days, the eye will be treated per protocol (years 1 and 2) or 
942 
evaluated for a prevention injection (sham or intravitreous) following section 4.3.2 in years 3 and 
943 
4, regardless of DME status. 
944 
   
945 
4.5 
Treatment for PDR 
946 
4.5.1 Primary Outcome for PDR 
947 
An eye will be considered to have met the primary outcome for PDR if any of the following are 
948 
met: 
949 
• Development of NV within the 7-modified ETDRS fields on fundus photography or 
950 
FA, confirmed by a masked grader at the central reading center 
951 
o At non-annual visits, fundus photography and FA will only be submitted to the 
952 
reading center to assess for this component of the primary outcome if the 
953 
investigator thinks treatment is necessary. 
954 
• NV of the iris (at least 2 cumulative clock hours), definitive NV of the angle, or 
955 
neovascular glaucoma development on clinical exam (photographic documentation 
956 
not required) 
957 
• Other outcomes presumed to be from PDR and documented: traction retinal 
958 
detachment, vitreous hemorrhage, pre-retinal hemorrhage greater than ½ disc area 
959 
• Procedures undertaken for the treatment of PDR (when present or presumed to be 
960 
present): PRP, anti-VEGF, or vitrectomy 
961 
 
962 
Once NV develops, the participant may return sooner than the next scheduled Assessment Visit 
963 
to evaluate for initiation of treatment (see below), at the discretion of the investigator. 
964 
 
965 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
4-4 
 
4.5.2 Initiating Treatment for PDR 
966 
If at any point NV of the angle develops, treatment with anti-VEGF and/or PRP is at investigator 
967 
discretion; otherwise, treatment for PDR must not be given until one of the following criteria has 
968 
been met: 
969 
 
970 
1. The eye has PDR with high-risk characteristics, defined as:  
971 
o NVD greater than Standard photograph 10A (1/4 to 1/3 disc area), or  
972 
o Any NVD with pre-retinal or vitreous hemorrhage, or  
973 
o NVE greater than ½ disc area with pre-retinal or vitreous hemorrhage 
974 
2. The eye has vitreous hemorrhage requiring treatment that is presumed to be from 
975 
PDR (either NV identified on FA or unable to assess NV due to density of the 
976 
hemorrhage but there is no other attributable cause) 
977 
3. The reading center has confirmed NV is present within the 7-modified fields and 
978 
protocol chair approval has been received to initiate treatment prior to high-risk 
979 
characteristics being present. 
980 
o Treatment for NVE outside of the 7-modified fields without the presence of pre-
981 
retinal or vitreous hemorrhage is discouraged.  If the investigator believes 
982 
treatment for peripheral NV is necessary, protocol chair approval is required. 
983 
 
984 
If at least 4 study injections have been given in the prior 4 months (for DME) and the eye has 
985 
developed high-risk PDR as defined above, PRP may be performed at the discretion of the 
986 
investigator. 
987 
 
988 
Otherwise, once one of the above criteria for treatment has been met, an injection of 2 mg 
989 
aflibercept will be given.  Thereafter, the eye will be evaluated at each visit for retreatment using 
990 
the criteria below (Sections 4.5.3 to 4.5.4).  If an anti-VEGF injection was already given in the 
991 
prior 5 weeks for prevention, it will be considered the baseline injection, and retreatment will 
992 
begin with section 4.5.3. 
993 
 
994 
4.5.3 Intravitreous Injection for PDR at 4 weeks, 8 weeks and 12 weeks  
995 
All eyes that initiate treatment for PDR will receive injections at 4, 8, and 12 weeks following 
996 
the initial injection.  If an eye experienced adverse effects from a prior intravitreous injection, 
997 
retreatment with intravitreous aflibercept is at the discretion of the investigator.   
998 
 
999 
4.5.4 Intravitreous Injection for PDR at and after 16 weeks 
1000 
Starting at 16 weeks, the eye will be evaluated for retreatment with intravitreous injection for 
1001 
PDR based on appearance of neovascularization. 
1002 
 
1003 
If an eye has experienced adverse effects from prior intravitreous injection treatment, retreatment 
1004 
with intravitreous aflibercept is at the discretion of the investigator.  In addition, if any future 
1005 
treatment with aflibercept is contraindicated based on a previous adverse reaction, treatment with 
1006 
PRP for PDR is at investigator discretion after discussion with and approval from the Protocol 
1007 
Chair or Coordinating Center designee.  Each eye with no contraindication to additional 
1008 
injections will be categorized into one of the following 5 categories based on neovascularization 
1009 
(NV) status: 
1010 
 
1011 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
4-5 
 
* Note: examination of the angle is at investigator discretion; however, if the angle is 
1012 
examined, then the results from this examination should be factored into the 
1013 
subsequent treatment decision. 
1014 
 
1015 
• Resolved 
1016 
o NV (of the retina, disc, AND iris/angle*) is absent and visualization of the entire 
1017 
retina is adequate to completely assess for NV.  Decision to re-inject is at 
1018 
investigator discretion.  In general, if NV is completely regressed the injection 
1019 
should be deferred.  PRP should not be given.   
1020 
 
1021 
• Improved 
1022 
NV (of the retina, disc OR iris/angle*) still persists, but there is evidence of 
1023 
improvement (improvement defined as a decrease in the size of NV or diminished 
1024 
density of NV) since the last visit and visualization of the entire retina is adequate to 
1025 
completely assess for NV.  An injection is given.  PRP should not be given.   
1026 
 
1027 
• Stable 
1028 
o NV (of the retina, disc AND iris/angle*) is clinically unchanged since the last 
1029 
visit and visualization of the entire retina is adequate to completely assess for NV.  
1030 
Once the eye meets criteria for stability, at least 2 more injections must be given, 
1031 
each one month apart (one at the visit at which stability criteria are met and the 
1032 
second at the following study visit one month later if still stable).  Further 
1033 
reinjection is then at investigator discretion as long as the eye remains 
1034 
stable.  PRP should not be given.   
1035 
 
1036 
• Not fully treated 
1037 
o Failure/futility criteria not met and recurrent or worsening NV (of the retina, disc 
1038 
OR iris) is present since the last visit in an eye that has had fewer than 4 injections 
1039 
over the previous 4 months or there is vitreous or preretinal hemorrhage 
1040 
preventing adequate visualization of the fundus to assess NV status.  An injection 
1041 
is given.  PRP should not be given.   
1042 
 
1043 
• Failed/futile 
1044 
o Failure/futility criteria met.  Decision to re-inject is at investigator 
1045 
discretion.  PRP may be given at this time (see below for cases that first require 
1046 
discussion with the Protocol Chair or Coordinating Center designee).  
1047 
 
1048 
 Failure criteria are defined as  
1049 
1. growth of NV or new NV of the retina, disc OR iris since the last 
1050 
visit such that the NV, including fibrosis, is greater in extent than 
1051 
when treatment for NV was initiated and at least 4 study injections 
1052 
have been given over the previous 4 months.  The investigator may 
1053 
perform PRP.   
1054 
 
1055 
OR 
1056 
 
1057 
2. New or worsened NV of the angle* has developed since the last 
1058 
visit. The investigator may perform PRP.   
1059 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
4-6 
 
 
1060 
OR  
1061 
 
1062 
3. definite worsening of NV or fibrous proliferation of the retina, disc 
1063 
OR iris at least 1 day after the last injection that the investigator 
1064 
believes is likely to lead to substantial vision loss if PRP is not 
1065 
performed within 1 week.  PRP may only be performed after 
1066 
discussion with and approval from the Protocol Chair or 
1067 
Coordinating Center designee. 
1068 
 
1069 
 Futility criteria are defined as continued persistence or recurrence of NV 
1070 
at least 1.5 years from initial study aflibercept injection that is equal to or 
1071 
greater than the extent of the NV when treatment for NV was initiated and 
1072 
at least 5 study injections performed over the preceding 6 months.  PRP 
1073 
may only be performed after discussion with and approval from the 
1074 
Protocol Chair or Coordinating Center designee. 
1075 
 
1076 
4.5.5 Continuation of Prevention Treatment Protocol 
1077 
Eyes for which the above anti-VEGF treatment regimen is initiated for PDR will continue 
1078 
injections as part of the prevention protocol.  At each Assessment Visit, if an injection has not 
1079 
been given within the prior 21 days, the eye will treated per protocol (years 1 and 2) or be 
1080 
evaluated for a prevention injection (sham or intravitreous) following section 4.3.2 in years 3 and 
1081 
4, regardless of whether the injection can be deferred according to the PDR treatment criteria. 
1082 
   
1083 
4.6 
Panretinal Photocoagulation Technique  
1084 
An eye may receive PRP only if failure/futility criteria for intravitreous injection for PDR above 
1085 
are met.  Study eyes that receive panretinal photocoagulation should have 1200 to1600 burns 
1086 
with a spot size on the retina of approximately 500 microns (or the equivalent area treated with a 
1087 
PASCAL) given over 1 to 3 sittings and completed within 8 weeks (56) days of initiation.   
1088 
 
1089 
The burn characteristics for non-automated photocoagulation will be as follows: 
1090 
 
1091 
Size (on retina) 
500 microns [e.g. argon laser using 200 micron spot size with 
Rodenstock lens (or equivalent) or 500 micron spot size with 3 
mirror contact lens] 
Exposure 
0.1 seconds recommended, 0.05 to 0.2 allowed 
Intensity 
mild white (i.e. 2+ to 3+ burns) 
Distribution 
edges 1 burn width apart 
No. of Sessions/Sittings 
1 to 3 
Nasal proximity to disk 
No closer than 500 microns 
Temp. proximity to 
center 
No closer than 3000 microns 
Superior/inferior limit 
No further posterior than 1 burn within the temporal arcades 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
4-7 
 
Extent 
Arcades (~3000 microns from the macular center) to at least the 
equator 
Total # of burns 
1200 to 1600: There may be instances where 1200 burns are not 
possible such as development of vitreous hemorrhage or study 
participant inability to complete a sitting precluding completion 
of the PRP session.  Similarly, there may be clinical situations in 
which more than 1600 burns are needed such as initial difficulty 
with laser uptake due to media opacity. 
Wavelength 
Green or yellow (red can be used if vitreous hemorrhage is 
present precluding use of green or yellow) 
 
1092 
An anesthetic injection (retrobulbar, peribulbar or sub-Tenon’s) can be used at investigator 
1093 
discretion.   
1094 
 
1095 
An indirect laser approach can be used at investigator discretion. 
1096 
  
1097 
If a laser is used that has the capability of producing an automated pattern (e.g. the PASCAL), 
1098 
the automated pattern producing mode is permissible.  Guidelines for use of the automated 
1099 
pattern are included in the study procedure manual. 
1100 
 
1101 
4.7 
Surgery for Vitreous Hemorrhage, Traction Detachment, and Other Complications 
1102 
of DR 
1103 
A study eye could develop a vitreous hemorrhage or traction detachment that may cause visual 
1104 
impairment.  In these cases, vitrectomy may be performed at the discretion of the investigator; 
1105 
however, vitrectomy for hemorrhage alone should not be performed without first confirming 
1106 
presence of neovascularization on color photographs and/or FA.  If NV has not been confirmed 
1107 
by the investigator in the setting of vitreous hemorrhage alone, review with the Protocol Chair or 
1108 
Coordinating Center designee must occur prior to proceeding with vitrectomy.    
1109 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
5-1 
 
 
1110 
CHAPTER 5.                                                                                          
1111 
MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
1112 
 
1113 
5.1 
Endophthalmitis  
1114 
Diagnosis and treatment of endophthalmitis is based on investigator’s judgment.  Obtaining 
1115 
cultures of vitreous and aqueous fluid is highly recommended prior to initiating antibiotic 
1116 
treatment for presumed endophthalmitis.  
1117 
  
1118 
5.2 
Treatment in Non-study Eye 
1119 
Treatment of PDR or DME in the non-study eye is at investigator discretion. However, if anti-
1120 
VEGF treatment will be given in the non-study eye, study aflibercept must be used. 
1121 
  
1122 
5.3 
Diabetes Management 
1123 
Diabetes management is left to the study participant’s medical care provider. 
1124 
 
1125 
5.4 
Study Participant Withdrawal and Losses to Follow-up 
1126 
A study participant has the right to withdraw from the study at any time.  If s/he is considering 
1127 
withdrawal from the study, the principal investigator should personally speak to the individual 
1128 
about the reasons, and every effort should be made to accommodate the study participant to 
1129 
allow continued participation if possible.   
1130 
 
1131 
The goal for the study is to have as few losses to follow-up as possible.  The Coordinating Center 
1132 
will assist in the tracking of study participants who cannot be contacted by the site.  The 
1133 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 
1134 
 
1135 
Study participants who withdraw will be asked to have a final closeout visit at which the testing 
1136 
described for the annual study visits will be performed.  Study participants who have an adverse 
1137 
effect attributable to a study treatment or procedure will be asked to continue in follow-up until 
1138 
the adverse event has resolved or stabilized. 
1139 
 
1140 
Study participants who withdraw or are determined to have been ineligible post-randomization 
1141 
will not be replaced. 
1142 
 
1143 
5.5 
Discontinuation of Study 
1144 
The study may be discontinued by the Executive Committee (with approval of the Data and 
1145 
Safety Monitoring Committee) prior to the preplanned completion of follow-up for all study 
1146 
participants. 
1147 
 
1148 
5.6 
Contact Information Provided to the Coordinating Center 
1149 
The Coordinating Center will be provided with contact information for each study participant.  
1150 
Permission to obtain such information will be included in the Informed Consent Form.  The 
1151 
contact information may be maintained in a secure database and will be maintained separately 
1152 
from the study data. 
1153 
 
1154 
Phone contact from the Coordinating Center will be made with each study participant in the first 
1155 
month after enrollment, and approximately every six months thereafter.  Additional phone 
1156 
contacts from the Coordinating Center will be made if necessary to facilitate the scheduling of 
1157 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
5-2 
 
the study participant for follow-up visits.  A study participant-oriented newsletter will be sent at 
1158 
least twice a year.  A study logo item may be sent once a year.  
1159 
 
1160 
Study participants will be provided with a summary of the study results in a newsletter format 
1161 
after completion of the study by all study participants.  
1162 
  
1163 
5.7 
Study Participant Reimbursement 
1164 
The study will be providing the study participant with a $25 merchandise or money card per 
1165 
completed non-annual study visit and $100 in merchandise or money cards per annual visit.  
1166 
Additional travel expenses will be paid in select cases for study participants with higher 
1167 
expenses.  
1168 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
6-1 
 
CHAPTER 6.                                                                                          
1169 
ADVERSE EVENTS 
1170 
 
1171 
6.1 
Definition 
1172 
An adverse event is any untoward medical occurrence in a study participant, irrespective of 
1173 
whether or not the event is considered treatment-related.  An adverse event can therefore be any 
1174 
unfavorable and unintended sign (including an abnormal lab finding), symptom or disease 
1175 
temporally associated with the use of the treatment, whether or not related to the treatment.   This 
1176 
includes preexisting medical conditions (other than the condition being studied) judged by the 
1177 
investigator to have worsened in severity or frequency or changed in character. 
1178 
 
1179 
6.2 
Recording of Adverse Events 
1180 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
1181 
events or untoward findings.  The first concern will be the safety of the study participant, and 
1182 
appropriate medical intervention will be made. 
1183 
 
1184 
All adverse events whether volunteered by the subject, discovered by study personnel during 
1185 
questioning, or detected through physical examination, laboratory test, or other means will be 
1186 
reported on an adverse event form online.  Each adverse event form is reviewed by the Medical 
1187 
Monitor to verify the coding and the reporting that is required.      
1188 
 
1189 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1190 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1191 
by the treatment. 
1192 
 
1193 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1194 
following general guideline when determining whether an adverse event is related: 
1195 
 
1196 
Yes 
1197 
There is a plausible temporal relationship between the onset of the adverse event and 
1198 
administration of the study treatment, and the adverse event cannot be readily explained by the 
1199 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event 
1200 
follows a known pattern of response to the study treatment; and/or the adverse event abates or 
1201 
resolves upon discontinuation of the study treatment or dose reduction and, if applicable, 
1202 
reappears upon re-challenge. 
1203 
 
1204 
No 
1205 
Evidence exists that the adverse event has an etiology other than the study treatment (e.g., 
1206 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1207 
medication); and/or the adverse event has no plausible temporal relationship to study treatment 
1208 
administration (e.g., cancer diagnosed 2 days after first dose of study drug).    
1209 
 
1210 
The intensity of adverse events will be rated on a three-point scale:  (1) mild, (2) moderate, or (3) 
1211 
severe.  It is emphasized that the term severe is a measure of intensity:  thus, a severe adverse 
1212 
event is not necessarily serious.  For example, itching for several days may be rated as severe, 
1213 
but may not be clinically serious. 
1214 
 
1215 
Adverse events will be coded using the MedDRA dictionary.  
1216 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
6-2 
 
 
1217 
Definitions of relationship and intensity are listed on the DRCRnet website data entry form.   
1218 
 
1219 
Adverse events that continue after the study participant’s discontinuation or completion of the 
1220 
study will be followed until their medical outcome is determined or until no further change in the 
1221 
condition is expected.   
1222 
 
1223 
6.3 
Reporting Serious or Unexpected Adverse Events 
1224 
A serious adverse event is any untoward occurrence that: 
1225 
• Results in death 
1226 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
1227 
become life-threatening, is not necessarily considered a serious adverse event) 
1228 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
1229 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
1230 
to conduct normal life functions (sight threatening)  
1231 
• Is a congenital anomaly/birth defect 
1232 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
1233 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
1234 
the outcomes listed above) 
1235 
 
1236 
Unexpected adverse events are those that are not identified in nature, severity, or frequency in 
1237 
the current Eylea® Clinical Investigator’s Brochure, protocol, or informed consent form. 
1238 
 
1239 
Serious or unexpected adverse events must be reported to the Coordinating Center immediately 
1240 
via completion of the online serious adverse event form. 
1241 
 
1242 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1243 
both serious and unexpected.  Notification will be made within 10 days after the Coordinating 
1244 
Center becomes aware of the event.   
1245 
 
1246 
Each principal investigator is responsible for informing his/her IRB of serious study-related 
1247 
adverse events and abiding by any other reporting requirements specific to their IRB.  
1248 
 
1249 
6.4 
Data and Safety Monitoring Committee Review of Adverse Events 
1250 
A Data and Safety Monitoring Committee (DSMC) will advise the Coordinating Center 
1251 
regarding the protocol, template informed consent form, and substantive amendments and will 
1252 
provide independent monitoring of adverse events. Cumulative adverse event data are semi-
1253 
annually tabulated for review by the DSMC.  Following each DSMC data review, a summary 
1254 
will be provided to institutional review boards.  A list of specific adverse events to be reported to 
1255 
the DSMC expeditiously, if applicable, will be compiled and included as part of the DSMC 
1256 
Standard Operating Procedures document. 
1257 
 
1258 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
6-3 
 
6.5 
Risks 
1259 
6.5.1 Potential Adverse Effects of Aflibercept 
1260 
The most common adverse reactions (≥ 5%) reported in patients receiving aflibercept were 
1261 
conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and 
1262 
vitreous detachment.   
1263 
 
1264 
Serious adverse reactions related to the injection procedure have occurred in <0.1% of 
1265 
intravitreal injections with aflibercept including endophthalmitis and retinal detachment. 
1266 
 
1267 
The DA VINCI study, a phase II study evaluating aflibercept for treatment of DME, reported 
1268 
common adverse events that were consistent with those previously seen with intravitreal 
1269 
injections.  Over one year of follow-up, two cases of endophthalmitis and one case of uveitis 
1270 
occurred (all in aflibercept treatment groups).  Seven deaths (4.0%) occurred in the groups 
1271 
randomized to aflibercept treatment as compared with 1 (2.3%) in the group treated with laser.  
1272 
Myocardial infarction or cerebrovascular accident occurred in 6 (3.4%) participants treated with 
1273 
aflibercept as compared with 1 (2.3%) participant treated with laser alone.44  Percentages of 
1274 
study participants that experienced events meeting APTC criteria were 5.1% (N = 9) in the 
1275 
combined aflibercept groups and 4.5% (N = 2) in the laser group.45  
1276 
  
1277 
The DRCR.net Protocol T study assessed ocular and systemic adverse events in eyes with 
1278 
central-involved DME treated with aflibercept over 1 year.43  In the aflibercept-treated study 
1279 
eyes, there were no cases of endophthalmitis and 2 cases of ocular inflammation. Non-study eyes 
1280 
treated with aflibercept had 1 case of endophthalmitis and 3 cases of ocular inflammation. 
1281 
Systemic adverse events were infrequent with only 6 APTC events (4 nonfatal myocardial 
1282 
infarctions, 2 deaths from a potential vascular cause or unknown cause, 6% of participants) over 
1283 
the 1 year period in the aflibercept group. 
1284 
 
1285 
Additional safety data were published from phase III studies VISTA and VIVID, which included 
1286 
872 eyes with DME with central involvement that received either intravitreal aﬂibercept every 4 
1287 
weeks, intravitreal aflibercept every 8 weeks after 5 initial monthly doses, or macular laser 
1288 
photocoagulation.  Overall, the incidences of ocular and non-ocular adverse events were similar 
1289 
across treatment groups at 52 weeks.42  The incidence of APTC-defined thromboembolic events 
1290 
was similar across treatment groups.  There were no reported cases of endophthalmitis, and 
1291 
intraocular inflammation occurred in less than 1% of injections.  Through 100 weeks, an 
1292 
integrated safety analysis found that the most frequent serious ocular adverse event was cataract 
1293 
(2.4% and 1.0% in the aflibercept groups compared with 0.3% in the laser group).41   
1294 
 
1295 
There may be side effects and discomforts that are not yet known.   
1296 
 
1297 
6.5.2 Potential Adverse Effects of Intravitreous Injection 
1298 
Rarely, the drugs used to anesthetize the eye before the study drug injections (proparacaine, 
1299 
tetracaine, or xylocaine) can cause an allergic reaction, seizures, and an irregular heartbeat.   
1300 
 
1301 
Subconjunctival hemorrhage or floaters will commonly occur as a result of the intravitreous 
1302 
injection.  Discomfort, redness, or itching lasting for a few days is also likely. 
1303 
 
1304 
Immediately following the injection, there may be elevation of intraocular pressure. It usually 
1305 
returns to normal spontaneously, but may need to be treated with topical drugs or a 
1306 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
6-4 
 
paracentesis to lower the pressure.  The likelihood of permanent loss of vision from elevated 
1307 
intraocular pressure is less than 1%. 
1308 
 
1309 
As a result of the injection, endophthalmitis (infection in the eye) could develop.  If this occurs, it is 
1310 
treated by intravitreous injection of antibiotics, but there is a risk of permanent loss of vision including 
1311 
blindness.  The risk of endophthalmitis is less than 1%. 
1312 
 
1313 
As a result of the injection, a retinal detachment could occur.  If this occurs, surgery may be 
1314 
needed to repair the retina.  The surgery is usually successful at reattaching the retina.  
1315 
However, a retinal detachment can produce permanent loss of vision and even blindness.  The 
1316 
risk of retinal detachment is less than 1%. 
1317 
 
1318 
The injection could cause a vitreous hemorrhage.  Usually the blood will resolve 
1319 
spontaneously, but if not, surgery may be needed to remove the blood.  Although the surgery 
1320 
usually successfully removes the blood, there is a small risk of permanent loss of vision and 
1321 
even blindness.  The risk of having a vitreous hemorrhage due to the injection is less than 1%. 
1322 
 
1323 
6.5.3 Risks of Eye Examination and Tests 
1324 
There is a rare risk of an allergic response to the topical medications used to anesthetize the eye 
1325 
or dilate the pupil. Dilating drops rarely could cause an acute angle closure glaucoma attack, but 
1326 
this is highly unlikely since the study participants in the study will have had their pupils dilated 
1327 
many times previously.   
1328 
 
1329 
There are no known risks associated with OCT or fundus photographs.  The bright flashes used 
1330 
to take the photographs may be annoying, but are not painful and cause no damage. 
1331 
 
1332 
For fluorescein angiography, both the skin and urine are expected to turn yellow/orange for up to 
1333 
24 hours after the injection of fluorescein dye.  There is a small risk of discomfort or phlebitis at 
1334 
the site of the injection.  Patients occasionally experience lightheadedness or nausea after dye 
1335 
injection which are usually transient and resolve after a few minutes without further intervention.  
1336 
An allergic reaction to the dye used to do the fluorescein angiography imaging is rare.  A rash or 
1337 
pruritus (itching) can develop, but true anaphylactic reactions are very rare.   
1338 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-1 
 
CHAPTER 7. 
1339 
STATISTICAL METHODS 
1340 
 
1341 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1342 
analysis plan will be written and finalized prior to the first assessment of 2-year outcome data.  
1343 
The analysis plan synopsis in this chapter contains the framework of the anticipated final 
1344 
analysis plan. 
1345 
 
1346 
7.1 
Primary Objectives and Key Outcomes 
1347 
This study has two objectives. First, to determine the efficacy and safety of intravitreous 
1348 
aflibercept injections versus sham injections (observation) for prevention of PDR and CI-DME 
1349 
in eyes at high risk for development of these complications. Second, to compare long-term vision 
1350 
outcomes in eyes that receive anti-VEGF therapy early in the course of disease with those that 
1351 
are initially observed and treated only if high-risk PDR or CI-DME with vision loss develops. 
1352 
 
1353 
Primary outcome: development of PDR or DME defined as the first occurrence of any of the 
1354 
following (composite time-to-event outcome): 
1355 
• NV within the 7-modified ETDRS fields on fundus photography or FA, confirmed by 
1356 
a masked grader at the central reading center 
1357 
o At non-annual visits, fundus photography and FA will only be submitted to the 
1358 
reading center to assess for this component of the primary outcome if the 
1359 
investigator thinks treatment is necessary. 
1360 
• NV of the iris (at least 2 cumulative clock hours), definitive NV of the angle, or 
1361 
neovascular glaucoma on clinical exam (photographic documentation not required) 
1362 
• Other outcomes presumed to be from PDR and documented: traction retinal 
1363 
detachment, vitreous hemorrhage, or pre-retinal hemorrhage greater than ½ disc area 
1364 
• Procedures undertaken for the treatment of PDR (when present or presumed to be 
1365 
present): PRP, anti-VEGF, or vitrectomy 
1366 
• CI-DME on clinical exam with at least 10% increase in central subfield thickness 
1367 
from baseline and either (1) at least a 10-letter decrease in visual acuity from baseline 
1368 
at a single visit or (2) a 5-to-9-letter decrease in visual acuity from baseline at 2 
1369 
consecutive visits at least 21 days apart, with vision loss presumed to be from DME  
1370 
• Non-topical treatment for DME performed without meeting the above criteria, 
1371 
including focal/grid laser or intravitreous injections for DME 
1372 
 
1373 
The primary outcome analysis will be performed when the last enrolled participant reaches 2 
1374 
years of follow up, using all available follow up data. The treatment groups will be compared 
1375 
using the hazard ratio.  
1376 
 
1377 
Other Key Outcomes:  
1378 
• Development of PDR or DME outcome through 4 years 
1379 
• Mean visual acuity change from baseline at 2 years 
1380 
• Mean visual acuity change from baseline at 4 years  
1381 
 
1382 
The overall type 1 error for the primary outcome and all key outcomes will be controlled at 5%.  
1383 
To control the type 1 error for each time point, 2.5% type I error will be allocated to the 2-year 
1384 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-2 
 
analysis, and 2.5% will be allocated to the 4-year analysis.  To control the type 1 error for the 
1385 
multiple key outcomes, a hierarchical approach will be used. The visual acuity outcome will be 
1386 
formally compared (i.e., with a P value) only if there is a significant treatment group difference 
1387 
in the anatomic outcome at the same time point (P ≤ .025). If not, only point estimates and 
1388 
confidence intervals for within and between group changes in visual acuity from baseline will be 
1389 
computed. 
1390 
 
1391 
See Section 7.4 for secondary outcomes to be evaluated at 2 and 4 years. 
1392 
 
1393 
7.2 
Sample Size 
1394 
The sample size has been computed for the primary outcome at 2 years. The primary analysis 
1395 
will consist of a treatment group comparison based on the hazard ratio for the composite time-to-
1396 
event outcome, as defined in Section 7.1, estimated using the marginal Cox proportional hazards 
1397 
model (see Section 7.3). 
1398 
 
1399 
7.2.1 Projected Control Group Proportion 
1400 
Data from the ETDRS, the Protein Kinase C β Inhibitor Diabetic Retinopathy Study (PKC-
1401 
DRS), Diabetic Retinopathy Study (DRS)-2, prior DRCR.net studies, and RIDE/RISE were used 
1402 
to estimate progression rates in the control group.  Estimates for this study are based largely on 
1403 
PDR development, although approximately 4% of eyes in ETDRS developed CI-DME prior to 
1404 
PDR, which would increase the expected progression rate.   
1405 
 
1406 
It should be noted that eligibility for this study is based primarily on investigator assessment of 
1407 
DR severity as severe NPDR (level 53).  The data below are presented by DR severity level as 
1408 
assessed by central reading center grading of fundus photographs; however, it is unknown 
1409 
whether features of severe NPDR were evident on clinical exam or FA in these cohorts    
1410 
 
1411 
Fifty-nine percent (N=249), 43% (N=461), and 23% (N=499) of eyes in the ETDRS assigned to 
1412 
observation with DR Severity levels graded on fundus photography of 53, 47, and 43, 
1413 
respectively, with no DME on fundus photography at baseline, progressed to PDR on fundus 
1414 
photography at 2 years (personal communication, Adam Glassman). 
1415 
 
1416 
More recent data for longer-term progression rates are available from 2 separate phase 3 trials of 
1417 
the protein kinase C inhibitor, ruboxistaurin, which demonstrated rates of PDR progression of 
1418 
approximately 40% and 60% in the 2 trials, respectively, over 3 years with lower levels of DR 
1419 
(47A) being included in the first trial.7, 8    
1420 
 
1421 
Data from DRCR.net Protocol A and Protocol B include eyes with baseline DME treated with 
1422 
laser alone and having DR severity levels 43 to 53 at baseline (Table 1, personal communication, 
1423 
Adam Glassman). Data from RIDE/RISE include eyes with DME and diabetic retinopathy less 
1424 
severe than active PDR on clinical exam that were treated with sham (Table 2).34 
1425 
 
1426 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-3 
 
Table 1. Proportion of Eyes with PDR* at 2 years by Baseline Level of Retinopathy (Laser 
1427 
group only; DME at Baseline) 
1428 
Protocol A – A Pilot Study of Laser Photocoagulation for Diabetic Macular Edema 
DR Severity 
N 
Proportion of eyes with PDR at 2 years 
Level 43 
27 
7% 
Level 47A 
62 
13% 
Level 47B-47D 
22 
32% 
Level 53 
26 
58% 
Protocol B – A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and 
Laser Photocoagulation for Diabetic Macular Edema 
DR Severity 
N 
Proportion of eyes with PDR at 2 years 
Level 43 
41 
10% 
Level 47A 
59 
15% 
Level 47B-47D 
23 
13% 
Level 53 
27 
55% 
* Defined as ETDRS DR Severity Score ≥ 60 (i.e. includes eyes with PRP prior to 2 years) 
1429 
 
1430 
Table 2.  RIDE/RISE Cumulative Proportion with PDR Events in Sham Eyes (includes 
1431 
eyes with DME) 
1432 
RIDE/RISE 
N 
1 Year 
N 
2 Year 
Sham 
135 
18% 
116 
30% 
 
1433 
Based on these data and the expected proportion of eyes enrolled in each DR severity level, we 
1434 
estimate the overall outcome proportion in the control group to be 30%. This estimate includes 
1435 
approximately 5% that are expected to meet the outcome by development of CI-DME prior to 
1436 
PDR.  
1437 
 
1438 
7.2.2 Projected Treatment Group Rate 
1439 
Pooled data from the RIDE/RISE Open-Label Extension include only eyes with DME and 
1440 
diabetic retinopathy less severe than active PDR on clinical exam (Table 3).34 
1441 
 
1442 
Table 3.  RIDE/RISE Cumulative Proportion with PDR Events in the Anti-VEGF Treated 
1443 
Groups 
1444 
RIDE/RISE 
N 
1 Year 
N 
2 Year 
0.3 mg Ranibizumab 
164 
5% 
152 
12% 
0.5 mg Ranibizumab 
154 
6% 
147 
10% 
 
1445 
The cumulative proportions of eyes with progression from RIDE/RISE are supported by 
1446 
unpublished data of PDR progression in eyes with DR severity levels of 43 to 53 treated with 
1447 
anti-VEGF from DRCR.net Protocol T (personal communication, Adam Glassman).  Based on 
1448 
these data, the projected cumulative outcome proportion for the treatment group is estimated to 
1449 
be no more than one-half the rate in the control group (10-15%).   
1450 
 
1451 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-4 
 
7.2.3 Sample Size Estimates 
1452 
Table 4 shows sample size estimates under varying assumptions for primary outcome 
1453 
proportions in the treatment and control groups at 2 years. These calculations assume a type I 
1454 
error rate of 5% with 90% power, and a null hypothesis of no difference between groups.   
1455 
 
1456 
Table 4: Total Sample Size for Various Outcome Rates of PDR/DME Development 
1457 
 
Control Group Rate 
Treatment Group 
Rate 
20% 
30% 
40% 
10% 
564 
180 
94 
15% 
2496 
346 
144 
20% 
-- 
822 
236 
 
1458 
For true outcome rates of 30% vs. 15%, a sample of N=346 (173 per group) gives 90% power to 
1459 
reject the null hypothesis of no difference for a 2-sided test with a type I error rate of 5%.  
1460 
Sample size is increased by 10% for possible dropouts giving N=386 (193 per group).  Sample 
1461 
size was selected based on the original study design, which included the parameters above.  
1462 
Considering that the study is sufficiently powered for the current design (see below), no change 
1463 
to sample size will be made.    
1464 
 
1465 
Given the approach to control type 1 errors, the alpha allocation at 2 years will be 2.5%.  Using 
1466 
the assumptions above, with a sample size of 386 and an alpha level of 2.5%, the study will have 
1467 
89% power to reject the null hypothesis of no difference.  As this power calculation does not 
1468 
include estimates for person-time beyond 2 years, which will be included in the primary analysis, 
1469 
and is not adjusted for the correlation between eyes of participants with two study eyes, power is 
1470 
expected to be greater than this projection. 
1471 
 
1472 
7.2.4 Power for the Visual Acuity Outcome 
1473 
Table 5 shows the expected statistical power to detect a difference in the mean change in visual 
1474 
acuity from baseline if the true difference between the groups is 3, 4, or 5 letters under varying 
1475 
assumptions for standard deviation, using the estimated sample size for 2 and 4 years.  
1476 
Table 5. Expected Statistical Power for Mean Change in Visual Acuity Outcome Adjusted 
1477 
for Baseline Visual Acuity  
1478 
Standard 
Deviation* 
N† 
Difference in Letter Score 
3 
4 
5 
6 
346 
>99% 
>99% 
>99% 
306 
98% 
>99% 
>99% 
8 
346 
89% 
>99% 
>99% 
306 
85% 
98% 
>99% 
10 
346 
71% 
93% 
>99% 
306 
65% 
89% 
98% 
Alpha = 0.025 for a 2-sided hypothesis test. 
1479 
* For reference, the adjusted standard deviation from the DRCR.net Protocol T aflibercept group 
1480 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-5 
 
(baseline visual acuity 20/32 to 20/40) of change in visual acuity from baseline at 2 years, adjusted for 
1481 
baseline visual acuity, was 7.7 (personal communication, Adam Glassman) 
1482 
† Based on 5% annual lost to follow-up 
1483 
 
1484 
7.3 
Primary Analysis Plan 
1485 
7.3.1 Principles for Analysis 
1486 
The primary analysis consists of a treatment group comparison based on the hazard ratio for the 
1487 
PDR/DME composite time-to-event outcome when the last participant reaches 2 years.  
1488 
 
1489 
Other key analyses include a treatment group comparison of (1) the development of PDR/DME 
1490 
composite time-to-event outcome when the last participant reaches 4 years, (2) the difference in 
1491 
the mean change in visual acuity from baseline at 2 years, and (3) the difference in the mean 
1492 
change in visual acuity from baseline at 4 years. Note that (2) and (3), the comparisons of mean 
1493 
change in visual acuity, will only be conducted if there is a significant difference (P ≤ .025) in 
1494 
the PDR/DME composite outcome at the corresponding time point.  The 2-year analysis will be 
1495 
conducted when the last enrolled participant reaches 2 years of follow up and include all of the 
1496 
data collected through that point. The 4-year analysis will be conducted at the end of the study.   
1497 
 
1498 
PDR/DME Outcome 
1499 
The comparison of the PDR/DME composite time-to-event outcome will be based on the hazard 
1500 
ratio from a marginal Cox regression model that accounts for the correlation within study 
1501 
participants having two study eyes, and adjusts for randomization stratification factors.46  The 
1502 
primary analysis is an intention-to-treat analysis.  Data from participants not observed to meet 
1503 
outcome criteria who are lost to follow up will be censored at the time of the last completed visit.  
1504 
If there is evidence that assumptions are not reasonably satisfied, an alternative analysis method 
1505 
will be considered. 
1506 
 
1507 
Visual Acuity Outcome 
1508 
If there is a significant difference (P ≤ .025) in the PDR/DME composite outcome, a treatment 
1509 
group comparison of the difference in the mean change in visual acuity from baseline to the 
1510 
outcome visit will be conducted. A linear mixed effects model will be used to estimate the 
1511 
treatment group difference.  The analysis will adjust for baseline visual acuity and randomization 
1512 
stratification factors. This will also be an intention-to-treat analysis that includes all randomized 
1513 
eyes. Multiple imputation will be used to impute missing data.  The correlation between eyes of 
1514 
participants having two study eyes will be modeled using random intercepts.  If model 
1515 
assumptions are not reasonably satisfied, a transformation or non-parametric analysis will be 
1516 
considered.  
1517 
 
1518 
Imbalances between groups in important covariates are not expected to be of sufficient 
1519 
magnitude to produce confounding.  However, the presence of confounding will be evaluated in 
1520 
a sensitivity analysis by including factors potentially associated with the outcome for which there 
1521 
is an imbalance between groups as covariates in the mixed effects model.  
1522 
 
1523 
Pre-planned subgroup analyses will be described in the detailed Statistical Analysis Plan.  There 
1524 
are no data to suggest that the treatment effect will vary by gender or race/ethnicity.  However, 
1525 
both of these factors will be evaluated in exploratory subgroup analyses. 
1526 
 
1527 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-6 
 
7.3.2 Per-protocol Analysis 
1528 
A per-protocol analysis for the 2- and 4-year outcomes will be performed including only eyes 
1529 
that received at least 80% of injections (sham or intravitreous) according to protocol and no other 
1530 
treatment for DR or DME. If the intention-to-treat and per-protocol analyses yield similar results, 
1531 
the per-protocol analyses will be used to provide supportive evidence of the magnitude of 
1532 
treatment effect among subjects who received the treatment.  If the results of the methods differ, 
1533 
exploratory analyses will be performed to evaluate the factors that may have contributed to the 
1534 
differences. 
1535 
 
1536 
7.3.3 Interim Analysis Plan  
1537 
The DSMC will review tabulated safety and efficacy data at semi-annual meetings to assess the 
1538 
risk-benefit ratio of adverse events against benefits, if any, of anti-VEGF as compared with 
1539 
sham.  No formal statistical analysis is planned during these reviews. 
1540 
 
1541 
It is not expected that the trial will be stopped early for efficacy, based on the following reasons: 
1542 
• Even if there is a significant difference in the primary outcome at 2 years, this may not 
1543 
translate to a long-term visual acuity difference. 
1544 
• Even if there is a significant difference in mean visual acuity change from baseline at 2 
1545 
years, it is important to know whether in the long term, treatment when progression 
1546 
occurs results in worse, equal, or better visual acuity outcome compared with treatment to 
1547 
prevent progression, and the relative differences in amount of treatment required with the 
1548 
two approaches to DR management. 
1549 
 
1550 
7.4 
Secondary Outcomes for Treatment Group Comparison 
1551 
The treatment groups will be compared on the following outcomes of interest at the time of the 
1552 
2- and 4-year analyses of the primary outcome: 
1553 
• Development of PDR or PDR-related outcome (as defined above within the 
1554 
composite time-to-event outcome) 
1555 
• Development of CI-DME with visual acuity impairment (as defined above within the 
1556 
composite time-to-event outcome) 
1557 
• Development of PDR or DME based only on the objective components defined in the 
1558 
composite outcome, including OCT, visual acuity, and reading center assessment of 
1559 
photos and FA (i.e. not including investigator-only assessments)* 
1560 
• Development of each component of the composite outcome assessed individually*  
1561 
• Proportion of eyes with at least 10 or at least 15 letter loss from baseline, or gain or 
1562 
loss of at least 5 letters at consecutive study visits, consisting of the visits just before 
1563 
and the 2- or 4-year visit† 
1564 
• Visual acuity area under the curve (AUC) between randomization and the 2- and 4-
1565 
year visits† 
1566 
• Mean change in OCT central subfield thickness from baseline 
1567 
• Mean change in OCT volume from baseline 
1568 
• Development of CI-DME on clinical exam with at least 10% increase in central 
1569 
subfield thickness and at least a 25-micron increase from baseline, regardless of 
1570 
visual acuity change* 
1571 
• Proportion of eyes with at least 2-step worsening of DR severity level (scale for 
1572 
individual eyes) by central reading center from baseline 
1573 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-7 
 
• Proportion of eyes with at least 2-step improvement of DR severity level (scale for 
1574 
individual eyes) by central reading center from baseline 
1575 
• Proportion of eyes with at least 3-step worsening of DR severity level (scale for 
1576 
individual eyes) by central reading center from baseline*  
1577 
• Proportion of eyes with at least 3-step improvement of DR severity level (scale for 
1578 
individual eyes) by central reading center from baseline*  
1579 
• Level of retinopathy on color photos* 
1580 
• Number of aflibercept injections performed* 
1581 
 
1582 
* Outcomes will include descriptive statistics only with no statistical comparisons of treatment 
1583 
groups. 
1584 
† If the statistical comparison of the mean change in visual acuity is not performed because the 
1585 
anatomic outcome comparison is not statistically significant, any analysis on visual acuity 
1586 
outcomes will be considered exploratory. 
1587 
 
1588 
Descriptive statistics for the outcomes listed above will also be presented for the 1- and 3-year 
1589 
visits, with no statistical analyses conducted.  
1590 
 
1591 
Binary outcomes will be analyzed using logistic regression with generalized estimating equations 
1592 
(GEE).  Continuous outcomes will be analyzed using a linear mixed model. Time-to-event 
1593 
outcomes will be analyzed using the marginal Cox regression model. Analyses will be adjusted 
1594 
for baseline measure, correlation within study participants having two study eyes, and 
1595 
randomization stratification factors, where appropriate.  If model assumptions are not reasonably 
1596 
satisfied, a transformation, nonparametric approach, or alternative method will be considered.  
1597 
Methods for handling missing secondary outcome data will be included in the detailed Statistical 
1598 
Analysis Plan. 
1599 
 
1600 
7.5 
Economic Analysis 
1601 
The purpose of the economic analysis is to compare the treatment groups with respect to cost and 
1602 
workplace productivity loss. Data from the clinical trial on number of clinic visits completed, 
1603 
number of procedures performed (e.g., OCT, fundus photographs), and number of aflibercept 
1604 
injections will be used to estimate an average cost per patient for each treatment arm, using the 
1605 
Medicare Fee Schedule to estimate medical costs.  The cost estimates, in combination with the 
1606 
percentage of productivity loss for each treatment arm, will be incorporated into the analysis.  
1607 
The following will be analyzed by treatment group: 
1608 
• Mean change from baseline in the percentage of work time missed due to vision problems 
1609 
over the past week (Absenteeism score) 
1610 
o Tabulated without statistical comparison 
1611 
• Mean change from baseline in the percentage of impairment while working due to vision 
1612 
problems over the past week (Presenteeism score) 
1613 
o Tabulated without statistical comparison 
1614 
• Mean change from baseline in the percentage of overall work impairment due to vision 
1615 
problems over the past week (Work Productivity Loss score) 
1616 
• Mean change from baseline in the percentage of activity impairment due to vision 
1617 
problems over the past week (Activity Impairment score) 
1618 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-8 
 
 
1619 
For functional outcomes measured at the participant level, bilateral participants are non-
1620 
informative with respect to the treatment comparison and will not be included in the analyses.   
1621 
 
1622 
7.6 
OCT Angiography Ancillary Study 
1623 
At a subset of sites with OCT angiography capabilities, images will be taken at baseline and at 
1624 
least one annual visit.  Features evident on OCT angiography alone will not be used for the 
1625 
primary outcome determination.  Exploratory analyses of OCT angiography may include, but are 
1626 
not limited to, the following: 
1627 
1. Comparison with current imaging modalities for detection of diabetic retinopathy 
1628 
pathology. 
1629 
2. Identification of biomarkers at baseline that are associated with retinopathy 
1630 
progression. 
1631 
3. Comparison of different OCT angiography systems at sites with more than one 
1632 
available.   
1633 
 
1634 
7.7 
Safety Analysis Plan 
1635 
7.7.1 Ocular Adverse Events 
1636 
The following ocular adverse events are of primary interest:  
1637 
o Endophthalmitis 
1638 
o Retinal detachment  
1639 
o Traumatic cataract 
1640 
o Vitreous hemorrhage  
1641 
o Inflammation  
1642 
o Neovascular glaucoma  
1643 
o Iris neovascularization  
1644 
 
1645 
The ocular adverse events of primary interest will be tabulated by treatment group. In addition, a 
1646 
tabulation will be made for non-study eyes receiving study aflibercept. The frequency of the 
1647 
event occurring at least once per eye will be calculated.  Eye-level outcomes will be compared 
1648 
between treatment groups using logistic regression with GEE to account for the potential 
1649 
correlation within participants having two study eyes. 
1650 
 
1651 
7.7.2 Systemic Adverse Events 
1652 
Systemic adverse events will be reported in three groups: (1) unilateral participants randomized 
1653 
to sham, (2) unilateral participants randomized to aflibercept, and (3) bilateral study participants.  
1654 
The frequency of the event occurring at least once per participant will be calculated.  However, 
1655 
statistical comparisons for systemic adverse events will only include unilateral participants 
1656 
randomized to sham and unilateral participants randomized to aflibercept.  Analysis of 
1657 
participant-level adverse events will be conducted with Barnard’s Unconditional Exact Test. 
1658 
 
1659 
o Primary systemic adverse events of interest: 
1660 
 Death 
1661 
 Serious adverse event (proportion of participants with at least one) 
1662 
 Hospitalization (proportion of participants with at least one) 
1663 
 Cardiovascular and cerebrovascular events according to Antiplatelet Trialists’ 
1664 
Collaboration (excerpted from BMJ Jan 8, 1994): 
1665 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
7-9 
 
• Non-fatal myocardial infarction 
1666 
• Non-fatal stroke (counted only if symptoms lasted at least 24 hours) 
1667 
• Death of unknown cause 
1668 
• Death attributed to cardiac, cerebral, hemorrhagic, embolic, or other 
1669 
vascular cause (does not need to be ischemic in origin) 
1670 
 
1671 
Note that transient ischemic attack, angina, possible myocardial infarction, and possible stroke 
1672 
are not counted. Non-fatal myocardial infarction and non-fatal stroke require that the participant 
1673 
is alive at the end of the study.  If not, then only the death is counted. 
1674 
 
1675 
o Secondary systemic adverse events of interest to be tabulated without statistical 
1676 
comparison: 
1677 
 Hypertension  
1678 
 Frequency of at least one event per participant in each Medical Dictionary for 
1679 
Regulatory Activities (MedDRA) system organ class 
1680 
 
1681 
Sensitivity analyses will replicate the analyses above within two groups: (1) participants who 
1682 
received study aflibercept in either eye and (2) participants who did not receive study aflibercept 
1683 
in either eye. 
1684 
 
1685 
A tabulation of all study eye ocular, non-study eye ocular, and systemic adverse events by 
1686 
primary treatment groups will be created.  
1687 
 
1688 
7.8 
Additional Tabulations and Analyses 
1689 
The following will be tabulated according to treatment group: 
1690 
1) Baseline demographic and clinical characteristics 
1691 
2) Visit completion rate 
1692 
3) Treatment adherence 
1693 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
8-1 
 
CHAPTER 8. REFERENCES 
1694 
 
1695 
1. 
Centers for Disease Control and Prevention. State-specific incidence of diabetes among 
1696 
adults--participating states, 1995-1997 and 2005-2007. MMWR Morb Mortal Wkly Rep. 
1697 
2008;57(43):1169-73. 
1698 
2. 
International Diabetes Federation: Facts and figures.  
1699 
http://www.idf.org/worlddiabetesday/toolkit/gp/facts-figures Accessed Accessed June 19, 
1700 
2014. 
1701 
3. 
Varma R, Bressler NM, Doan QV, et al. Prevalence of and risk factors for diabetic 
1702 
macular edema in the United States. JAMA Ophthalmol. 2014;132(11):1334-40. 
1703 
4. 
Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 
1704 
2012;366(13):1227-39. 
1705 
5. 
Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J Med. 2005;353:839-
1706 
41. 
1707 
6. 
Klein R, Klein BE, Moss SE. A population-based study of diabetic retinopathy in insulin-
1708 
using patients diagnosed before 30 years of age. Diabetes Care. 1985;8 Suppl 1:71-6. 
1709 
7. 
The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with 
1710 
moderately severe to very severe nonproliferative diabetic retinopathy: initial results of 
1711 
the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter 
1712 
randomized clinical trial. Diabetes. 2005;54(7):2188-97. 
1713 
8. 
The PKC-DRS2 Group. Effect of ruboxistaurin on visual loss in patients with diabetic 
1714 
retinopathy. Ophthalmology. 2006;113(12):2221-30. 
1715 
9. 
The Diabetic Retinopathy Study Research Group. Preliminary report on effects of 
1716 
photocoagulation therapy. Am J Ophthalmol. 1976;81(4):383-96. 
1717 
10. 
Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for 
1718 
diabetic retinopathy.  ETDRS report number 9. Ophthalmology. 1991;98(5 suppl):766-
1719 
85. 
1720 
11. 
The Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating short-
1721 
term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema 
1722 
following focal/grid laser for diabetic macular edema in eyes also receiving panretinal 
1723 
photocoagulation. Retina. 2011;31(6):1009-27. 
1724 
12. 
Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans 
1725 
Am Ophthalmol Soc. 1996;94:505-37. 
1726 
13. 
AAO Preferred Practice Patterns: Diabetic retinopathy <http://one.aao.org/preferred-
1727 
practice-pattern/diabetic-retinopathy-ppp--september-2008-4th-print>. Accessed 
1728 
Accessed: 27 February 2014. 
1729 
14. 
Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating 
1730 
ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic 
1731 
macular edema. Ophthalmology. 2010;117(6):1064-77 e35. 
1732 
15. 
Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema 
1733 
with prompt versus deferred laser treatment: three-year randomized trial results. 
1734 
Ophthalmology. 2012;119(11):2312-8. 
1735 
16. 
Gross JG, Glassman AR, Jampol LM, et al. Diabetic Retinopathy Clinical Research 
1736 
Network. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative 
1737 
Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2015;Submitted. 
1738 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
8-2 
 
17. 
International Diabetes Federation: Diabetes and blindness due to DME Q&A.  
1739 
http://www.idf.org/sites/default/files/Toolkit%2520Q%2526A_FINAL.pdf. Accessed 
1740 
Accessed June 19, 2014. 
1741 
18. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
1742 
diabetic macular edema: ETDRS report number 4. Int Ophthalmol Clin. 1987;27(4):265-
1743 
72. 
1744 
19. 
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for Diabetic Macular Edema: 
1745 
Results from 2 Phase III Randomized Trials: RISE and RIDE. Ophthalmology. 
1746 
2012;119(4):789-801. 
1747 
20. 
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic 
1748 
macular edema. Ophthalmology. 2014;121(11):2247-54. 
1749 
21. 
Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study ranibizumab 
1750 
monotherapy or combined with laser versus laser monotherapy for diabetic macular 
1751 
edema. Ophthalmology. 2011;118(4):615-25. 
1752 
22. 
Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic 
1753 
Study of Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema 
1754 
in persons with type 1 diabetes. Ophthalmology. 2009;116(3):497-503. 
1755 
23. 
Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor 
1756 
levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 
1757 
1994;118(4):445-50. 
1758 
24. 
Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth 
1759 
factor prevents retinal ischemia-associated iris neovascularization in a nonhuman 
1760 
primate. Arch Ophthalmol. 1996;114(1):66-71. 
1761 
25. 
Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid 
1762 
of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 
1763 
1994;331(22):1480-7. 
1764 
26. 
Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo 
1765 
by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor 
1766 
chimeric proteins. Proc Natl Acad Sci USA. 1995;92(23):10457-61. 
1767 
27. 
Amano S, Rohan R, Kuroki M, Tolentino M, Adamis AP. Requirement for vascular 
1768 
endothelial growth factor in wound- and inflammation-related corneal 
1769 
neovascularization. Invest Ophthalmol Vis Sci. 1998;39(1):18-22. 
1770 
28. 
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-
1771 
6. 
1772 
29. 
Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal 
1773 
neovascularization with intravitreal anti-vascular endothelial growth factor antibody 
1774 
fragment. Arch Ophthalmol. 2002;120(3):338-46. 
1775 
30. 
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial 
1776 
growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306-9. 
1777 
31. 
Malecaze F, Clamens S, Simorre-Pinatel V, et al. Detection of vascular endothelial 
1778 
growth factor messenger RNA and vascular endothelial growth factor-like activity in 
1779 
proliferative diabetic retinopathy. Arch Ophthalmol. 1994;112(11):1476-82. 
1780 
32. 
Schwesinger C, Yee C, Rohan RM, et al. Intrachoroidal neovascularization in transgenic 
1781 
mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. 
1782 
Am J Pathol. 2001;158(3):1161-72. 
1783 


Anti-VEGF Treatment for Prevention of PDR-DME v6.0 12-9-19 
 
 
 
8-3 
 
33. 
Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP. 
1784 
Vascular endothelial growth factor is sufficient to produce iris neovascularization and 
1785 
neovascular glaucoma in a nonhuman primate. Arch Ophthalmol. 1996;114(8):964-70. 
1786 
34. 
Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of 
1787 
ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 
1788 
2012;130(9):1145-52. 
1789 
35. 
Bressler SB, Qin H, Melia M, et al. Exploratory analysis of the effect of intravitreal 
1790 
ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized 
1791 
clinical trial. JAMA Ophthalmol. 2013;131(8):1033-40. 
1792 
36. 
Sun JK, P W, A F. Impact of treatment delayand durability of diabetic retinopathy 
1793 
improvement with PRN ranibizumab during the RIDE/RISE open-label extension (OLE). 
1794 
Presented at: 38th Annual Macula Society Meeting; 2015 Feb 25-28; Scottsdale, AZ. 
1795 
37. 
US FDA approves EYLEA (aflibercept) injection for the treatment of we age-related 
1796 
macular degeneration.  
1797 
http://www.press.bayer.com/baynews/baynews.nsf/0/EB1AAB6D8405A0BDC125794A0
1798 
056C856. Accessed accessed January 1, 2012. 
1799 
38. 
Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to 
1800 
central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J 
1801 
Ophthalmol. 2013;97(3):278-84. 
1802 
39. 
Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular 
1803 
edema secondary to central retinal vein occlusion: 1-year results from the phase 3 
1804 
COPERNICUS study edema secondary to central retinal vein occlusion: 1-year results 
1805 
from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429-37. 
1806 
40. 
Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for 
1807 
macular edema secondary to central retinal vein occlusion: six-month results of the phase 
1808 
3 COPERNICUS study. Ophthalmology. 2012;119(5):1024-32. 
1809 
41. 
Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal Aflibercept for Diabetic 
1810 
Macular Edema: 100-Week Results From the VISTA and VIVID Studies. 
1811 
Ophthalmology. 2015. 
1812 
42. 
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic 
1813 
macular edema. Ophthalmology. 2014;121(6):2247-54. 
1814 
43. 
Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for 
1815 
diabetic macular edema. N Engl J Med. 2015;372(13):1193-203. 
1816 
44. 
Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the DA VINCI Study of 
1817 
VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 
1818 
2012;119(8):1658-65. 
1819 
45. 
Regeneron Pharmaceuticals Inc. Investigator's brochure: VEGF Trap-Eye Intravitreal 
1820 
aflibercept injection (IAI) intravitreal administration. Tarrytown, NY; 2012. 
1821 
46. 
Lee EW, Wei LJ, Amato DA. Cox-type regression analysis for large numbers of small 
1822 
groups of correlated failure time observations Dordrecht: Kluwer Academic; 1992. 
1823 

SAP_001.pdf: 
Diabetic Retinopathy Clinical Research Network 
Intravitreous Anti-VEGF Treatment for Prevention of Vision 
Threating Diabetic Retinopathy in Eyes at High Risk  
Statistical Analysis Plan 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0 
Danni Liu 
Michele Melia 
17 October 2017 
Initial version for Protocol version 4.0 
2.0 
Wesley T. Beaulieu 
Michele Melia 
10 January 2019 
Revisions for Protocol version 5.0 and 
consistency with other DRCR.net SAPs 
following DSMC review. Key changes include 
the following. (1) No interim analysis is 
planned. (2) Four key outcomes defined with a 
hierarchical approach to controlling Type I 
error. (3) Changed the minimum sample size 
for subgroup analyses to 20 per treatment per 
level of subgroup covariate. (4) Will impute 
missing data for secondary analyses of visual 
acuity and OCT data. 
3.0 
Kristin Josic 
Michele Melia 
04 Mar 2021 
Revised to extend the 48-month visit analysis 
close window from 3 to 6 months due to 
concerns about delayed visits during COVID.  
Note: revision implemented after the primary 
2-year manuscript was submitted for 
publication and did not affect the 2-year 
publication. 
 
 


Protocol W Statistical Analysis Plan 
 
Page 2 of 15 
1.0 
Introduction 
1 
This document specifies the statistical analyses to be performed for the Diabetic Retinopathy 
2 
Clinical Research Network (DRCR.net) study evaluating anti-vascular endothelial growth factor 
3 
(anti-VEGF) treatment for prevention of vision-threatening diabetic retinopathy in high-risk eyes 
4 
(Protocol W). Technical details of the analyses reported in the primary manuscript will be 
5 
documented separately in a technical analysis plan. 
6 
This study has two primary objectives. First, to determine the efficacy and safety of intravitreous 
7 
aflibercept injections versus sham injections (observation) for prevention of proliferative diabetic 
8 
retinopathy (PDR) and central-involved diabetic macular edema (CI-DME) with vision loss in 
9 
high-risk eyes. Second, to compare long-term vision outcomes in eyes that receive anti-VEGF 
10 
therapy early in the course of disease with those that are observed initially and treated only if 
11 
PDR or CI-DME with vision loss develop. 
12 
Study eyes are randomly assigned to one of two treatment groups: sham injections or 
13 
intravitreous 2-mg aflibercept injections. Study participants may have one or two study eyes. 
14 
Participants with two study eyes receive sham injections in one eye and intravitreous aflibercept 
15 
injections in the other eye.  
16 
Randomization is stratified as follows: 
17 
• Study participants with one study eye are randomly assigned with equal probability to 
18 
one of two treatment groups: sham injections or intravitreous aflibercept injections. 
19 
o Randomization for participants with one study eye is stratified by reading 
20 
center grading of diabetic retinopathy (DR) severity level (43, 47A, 47B-D, 53 
21 
with no neovascularization in the periphery, or 53 with neovascularization in 
22 
the periphery). 
23 
• Study participants with two study eyes (both eyes must be eligible at the time of 
24 
randomization) are randomized with equal probability to one of the following: 
25 
o Sham injections in the eye with greater DR severity and intravitreous 
26 
aflibercept injections in the eye with lower DR severity. 
27 
o Intravitreous aflibercept injections in the eye with greater DR severity and 
28 
sham injections in the eye with lower DR severity. 
29 
 If both eyes have the same DR severity, then the right eye is 
30 
considered the eye with the greater DR severity. 
31 
For the purpose of analysis, the randomization stratification variables will be modeled as two 
32 
categorical variables, defined as laterality (one or two eyes randomized) and DR severity level 
33 
based on reading center assessment of digital fundus photographs (43, 47A, 47B-D, 53 with no 
34 
neovascularization in the periphery, or 53 with neovascularization in the periphery). If there are 
35 
not at least 20 eyes per treatment group in each of the DR severity levels specified above, then 
36 


Protocol W Statistical Analysis Plan 
 
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adjacent categories may be combined (e.g., 47A and 47B-D; 53 without peripheral 
37 
neovascularization and 53 with peripheral neovascularization). 
38 
2.0  
Efficacy Analysis Plan  
39 
Primary outcome: development of PDR or DME defined as the first occurrence of any of the 
40 
following (composite time-to-event outcome): 
41 
• PDR Outcomes: 
42 
o Neovascularization within the 7-modified Early Treatment Diabetic Retinopathy 
43 
Study (ETDRS) fields on fundus photography or fluorescein angiography, 
44 
confirmed by a masked grader at the central reading center 
45 
 At non-annual visits, fundus photography and fluorescein angiography 
46 
will only be submitted to the reading center to assess for this component 
47 
of the primary outcome if the investigator thinks treatment is necessary. 
48 
o Neovascularization of the iris (at least 2 cumulative clock hours), definitive 
49 
neovascularization of the angle, or neovascular glaucoma on clinical exam 
50 
(photographic documentation not required) 
51 
o Other outcomes presumed to be from PDR and documented: traction retinal 
52 
detachment, vitreous hemorrhage, or pre-retinal hemorrhage greater than ½ disc 
53 
area 
54 
o Procedures undertaken for the treatment of PDR (when present or presumed to be 
55 
present): PRP, anti-VEGF, or vitrectomy 
56 
• DME Outcomes: 
57 
o CI-DME on clinical exam with at least 10% increase in central subfield thickness 
58 
from baseline and either (1) at least a 10-letter decrease in visual acuity from 
59 
baseline at a single visit or (2) a 5-to-9-letter decrease in visual acuity from 
60 
baseline at 2 consecutive study (i.e., not unspecified) visits at least 21 days apart, 
61 
with vision loss presumed to be from DME  
62 
o Non-topical treatment for DME performed without meeting the above criteria, 
63 
including focal/grid laser or intravitreous injections for DME 
64 
The primary outcome analysis will be performed when the last enrolled participant reaches 2 
65 
years of follow up and will include all available follow-up data. The treatment groups will be 
66 
compared using the hazard ratio.  
67 
Other Key Outcomes:  
68 
• Development of PDR or DME outcome through 4 years 
69 
• Mean visual acuity change from baseline at 2 years 
70 
• Mean visual acuity change from baseline at 4 years  
71 


Protocol W Statistical Analysis Plan 
 
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Type I Error Rate Control 
72 
The overall Type I error rate for the primary outcome and all key outcomes will be controlled at 
73 
5%. To control the Type I error rate for each time point, 2.5% Type I error will be allocated to 
74 
the 2-year analysis, and 2.5% will be allocated to the 4-year analysis. To control the Type I error 
75 
rate for the multiple key outcomes, a hierarchical approach will be used. The visual acuity 
76 
outcome will be formally compared (i.e., with a P value) only if there is a significant treatment 
77 
group difference in the anatomic outcome at the same time point. If the visual acuity outcome is 
78 
not compared because the PDR/DME outcome is not significant, then only point estimates and 
79 
97.5% confidence intervals for within and between group changes in visual acuity from baseline 
80 
will be computed at the time point. 
81 
2.1 
Primary Outcome Analyses 
82 
PDR/DME Outcome 
83 
Comparison of the PDR/DME composite time-to-event outcome will be based on the hazard 
84 
ratio from a marginal Cox regression model. The analysis will adjust for laterality and 
85 
retinopathy severity. The correlation between eyes of participants having two study eyes will be 
86 
modeled with a robust sandwich estimate of the covariance matrix (Lee, Wei, and Amato 1992). 
87 
The primary analysis is an intention-to-treat analysis. Data from participants not observed to 
88 
meet outcome criteria who are lost to follow up will be censored at the time of the last completed 
89 
visit. The hazard ratio and 97.5% confidence interval for the treatment effect will be presented. 
90 
Visual Acuity Outcome 
91 
If there is a significant difference in the PDR/DME composite outcome at 2 or 4 years (P ≤ 
92 
.025), a treatment group comparison of the difference in the mean change in visual acuity from 
93 
baseline to the outcome visit will be conducted at the same time point with alpha of .025. A 
94 
linear mixed model will be used to estimate the mean treatment group difference and 97.5% 
95 
confidence interval. The analysis will adjust for baseline visual acuity, laterality, and retinopathy 
96 
severity. The correlation between eyes of participants having two study eyes will be modeled 
97 
using random intercepts. This will be an intention-to-treat analysis that includes all randomized 
98 
eyes. Multiple imputation will be used to impute missing data. The imputation model will 
99 
include laterality, retinopathy severity, baseline visual acuity, and change in visual acuity from 
100 
baseline at each protocol assessment visit up to and including the analysis time point. For the 2-
101 
year analysis, visual acuity measured beyond 2 years, if available, will not be included in the 
102 
analysis or imputation. If the PDR/DME outcome is not significant at the same time point, then 
103 
the P value will not be reported, but the 97.5% confidence interval will be reported. 
104 
2.1.1 Sensitivity Analyses 
105 
A sensitivity analysis of the key visual acuity outcomes including only observed data from 
106 
participants completing the visit (2 or 4 years) will be conducted (i.e., complete-case analysis). If 
107 
the analyses of imputed and observed data differ substantially, then exploratory analyses will be 
108 


Protocol W Statistical Analysis Plan 
 
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performed to evaluate factors that may have contributed to the difference. The sensitivity 
109 
analysis of completers will only be performed if more than 10% of randomized participants 
110 
would be excluded by these criteria.  
111 
Multiple imputation assumes that data are missing at random (MAR). In the present study, this 
112 
means that whether change in visual acuity is missing may be a function of observed 
113 
characteristics included in the imputation model, but not a function of the unobserved data being 
114 
imputed. This assumption cannot be tested directly since these data are unknown. However, a 
115 
tipping point analysis for the key visual acuity outcomes will be conducted to adjust the imputed 
116 
values using a shift parameter and thereby determine how severe the departure from MAR must 
117 
be to change the outcome of the analysis with respect to rejecting or failing to reject the null 
118 
hypothesis. The tipping point analysis will only be conducted if more than 10% of randomized 
119 
participants would be excluded by these criteria. 
120 
A shift parameter will be applied to the imputed values in the aflibercept group to determine the 
121 
tipping point at which the results of the primary analysis are nullified. That is, if one group is 
122 
found to be superior, the tipping point will identify the shift parameter necessary to negate the 
123 
superiority. Conversely, if the null hypothesis is not rejected, two tipping points will be 
124 
identified – one that would make aflibercept superior and one that would make sham superior. In 
125 
either case, this tipping point will be evaluated to determine if it is plausible. If not, then the 
126 
MAR assumption is likely reasonable. For example, if the tipping point were 100 letters, then 
127 
this would be evidence that the MAR assumption is reasonable. 
128 
2.1.2 Per-protocol Analysis 
129 
Per-protocol analyses for the PDR/DME composite and visual acuity outcomes will be 
130 
performed including only eyes that received at least 80% of injections (sham or intravitreous) 
131 
according to protocol and no other treatment for DR or DME. The limited cohort for the per-
132 
protocol analysis will be described in the technical plan. Missing data will not be imputed. The 
133 
per-protocol analysis will be conducted only if at least 10% of randomized participants would be 
134 
excluded by these criteria. 
135 
The intention-to-treat analyses are considered the primary analyses. If the intention-to-treat and 
136 
per-protocol analyses yield similar conclusions, then the per-protocol analyses will be used to 
137 
provide supportive evidence of the magnitude of the treatment effect among participants who 
138 
had good adherence to the treatment. If the results of the two methods differ, then exploratory 
139 
analyses will be performed to evaluate factors that could have contributed to the differences. 
140 
2.1.3 Confounding 
141 
Imbalances between groups in important covariates are not expected to be of sufficient 
142 
magnitude to produce confounding in the primary analysis and other key analyses. However, the 
143 
presence of confounding in the primary and other key analyses will be evaluated in additional 
144 
regression models by adding baseline covariates that are potentially associated with the outcome. 
145 
These include but are not limited to the following:  
146 


Protocol W Statistical Analysis Plan 
 
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• Age 
147 
• Duration of diabetes 
148 
• HbA1c 
149 
• Mean arterial blood pressure 
150 
• Visual acuity 
151 
• Prior treatment for DME 
152 
o Note that eyes with prior DME treatment within 12 months of randomization or 
153 
more than 4 prior intraocular injections were ineligible 
154 
• OCT central subfield thickness 
155 
• Each of the following within 500 µm of the center of the macula on OCT as graded by 
156 
the reading center (minimum 20 eyes in the cohort with the characteristic): 
157 
o Epiretinal membrane 
158 
o Vitreomacular traction 
159 
o Cystoid abnormalities 
160 
o Subretinal fluid 
161 
• Hard exudates within 1800 µm of the center of the macula on fundus photography as 
162 
graded by the reading center (minimum 20 eyes in the cohort with the characteristic) 
163 
Additional variables associated with the outcome will be included if there is an imbalance in the 
164 
variables between groups. Imbalance by treatment group will not be judged using statistical 
165 
testing, but will be based on judgment regarding whether the size of the imbalance is clinically 
166 
important, i.e., whether it is large enough that it could have a clinically important effect on visual 
167 
acuity or worsening to PDR or DME. 
168 
2.1.4 Subgroup Analyses 
169 
The treatment effect will be assessed at the 2- and 4-year visits in subgroups determined by 
170 
baseline factors in pre-planned subgroup analyses. These analyses will repeat the primary and 
171 
other key analyses, with the exception that multiple imputation for missing outcome data will not 
172 
be performed for the visual acuity outcome. Unless the imputation process is done separately for 
173 
each treatment group and the subgroup factor is included in the imputation model, the analysis is 
174 
biased towards the null hypothesis of no interaction when an interaction is present (Sullivan et 
175 
al., 2016). It is recognized that analyzing only observed data also might be biased if data are not 
176 
missing at random; however, the imputed analysis is unavoidably biased in the presence of 
177 
interaction. 
178 
A term for the main effect of the baseline subgroup factor and an interaction term for baseline 
179 
subgroup factor by treatment will be added to the models used for the primary outcome and all 
180 
other key outcomes. If the interaction P value is less than .025, the estimated treatment effect and 
181 
97.5% confidence interval will be obtained from the interaction model for each subgroup. 
182 
Summary statistics will be presented for each outcome by subgroup, regardless of significance. 
183 
Baseline factors to be evaluated for possible subgroup effects include the following: 
184 


Protocol W Statistical Analysis Plan 
 
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• Prior anti-VEGF treatment: yes vs. no 
185 
• Prior DME treatment: yes vs. no 
186 
• Diabetic retinopathy severity (as graded by the photograph reading center): less than 
187 
53 vs. 53 with no neovascularization in the periphery vs. 53 with neovascularization 
188 
in the periphery  
189 
• Non-central DME: yes vs. no 
190 
To increase statistical power and reduce the risk of spurious results, which are more likely in a 
191 
small sample size, subgroups will only be analyzed if there are at least 20 eyes in each treatment 
192 
group for each subgroup. Interaction p-values will be calculated using continuous and ordinal 
193 
variables, where possible, in addition to the categorizations described above.  
194 
Subgroup analyses will be conducted to determine whether the overall treatment effect is similar 
195 
to the treatment effects seen in these subgroups. For each subgroup, the hypothesized direction of 
196 
effect is for a larger treatment difference among eyes with more severe characteristics (i.e., prior 
197 
anti-VEGF treatment, prior DME treatment, more severe DR level, or non-central DME). 
198 
It is recognized that the study is not powered to detect subgroup effects and that lack of 
199 
significance is not necessarily an indication that subgroup effects do not exist. In the absence of a 
200 
significant treatment effect in the primary or other key analyses, assessment of subgroups will be 
201 
interpreted with caution. 
202 
There are no data to suggest that the treatment effect will vary by gender or race/ethnicity. 
203 
However, both factors will be evaluated in exploratory subgroup analyses. 
204 
2.1.5 Center Effects 
205 
The number of study participants per center is expected to be small for many centers. Therefore, 
206 
center effects will not be included in the statistical model. However, for centers with a large 
207 
number of study participants (N ≥ 20 in either treatment group), heterogeneity across centers will 
208 
be explored using random center effects by estimating empirical best linear unbiased predictors 
209 
with 95% confidence intervals. 
210 
2.2 
Secondary Outcome Analyses 
211 
The treatment groups will be compared on secondary outcomes of interest at 2 and 4 years. In 
212 
general, analyses will be adjusted for the baseline measure of the outcome, where appropriate, 
213 
and laterality and retinopathy severity. For each secondary outcome, the hypothesis test of no 
214 
difference between treatment groups will be conducted and the estimated treatment effect with a 
215 
97.5% confidence interval will be calculated. Descriptive statistics will be presented at 1 and 3 
216 
years without formal statistical testing.  
217 
Binary outcomes will be analyzed using logistic regression and robust variance estimation. 
218 
Potential correlations between two study eyes of the same participant will be modeled using 
219 


Protocol W Statistical Analysis Plan 
 
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generalized estimating equations (GEE) with an exchangeable correlation structure. The number 
220 
and percentage of eyes meeting the outcome at the visit (observed data only) will be reported. 
221 
The treatment effect will be estimated as an odds ratio. 
222 
Continuous outcomes will be analyzed using a linear mixed model with robust variance 
223 
estimation. Potential correlations between two study eyes of the same participant will be 
224 
modeled using a random intercepts. Means and standard deviations will be reported (observed 
225 
data only). The treatment effect will be estimated as a mean difference. 
226 
Time-to-event outcomes will be analyzed using a marginal Cox proportional hazards regression 
227 
model. Potential correlations between two study eyes of the same participant will be modeled 
228 
using a robust sandwich estimate of the covariance matrix. The number and percentage of eyes 
229 
meeting the outcome at or before the visit (observed data only) will be reported. The treatment 
230 
effect will be estimated as a hazard ratio. 
231 
For each outcome, a plot showing the proportion, mean, or cumulative survival by treatment 
232 
group over time will be constructed without imputation of missing data.  
233 
2.2.1 Visual Acuity 
234 
Additional analyses will be conducted on the visual acuity data (Table 1). The primary purpose 
235 
will be to aid in interpretation of the key visual acuity outcome. If the statistical comparison of 
236 
the mean change in visual acuity is not performed at a given time point because the anatomic 
237 
outcome comparison is not statistically significant, then all analyses of visual acuity will be 
238 
considered exploratory at that time point. Analyses will use the imputed data sets created for the 
239 
mean change analysis. 
240 
Table 1. Secondary Visual Acuity Outcomes 
241 
Outcome 
Analysis Method 
Failure proportion: visual acuity loss ≥ 10 letters 
Logistic regression with GEE 
Failure proportion: visual acuity loss ≥ 15 letters 
Tabulation only 
Success proportion: visual acuity gain ≥ 5 letters at both 
the time point and the previous study visit 
Tabulation only 
Failure proportion: visual acuity loss ≥ 5 letters at both 
the time point and the previous study visit 
Tabulation only 
Success proportion: visual acuity letter score  ≥ 84 
(approximate Snellen equivalent 20/20 or better) 
Tabulation only 
Success proportion: visual acuity letter score  ≥ 69 
(approximate Snellen equivalent 20/40 or better) 
Tabulation only 
Failure proportion: visual acuity letter score ≤ 38 
(approximate Snellen equivalent 20/200 or worse) 
Tabulation only 
Change in VA from baseline AUC 
Linear mixed model 
Abbreviations: AUC, area under the curve. 
242 


Protocol W Statistical Analysis Plan 
 
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Change in visual acuity from baseline area under the curve will be calculated using the 
243 
trapezoidal method:  
244 
𝐴𝐴𝐴𝐴𝐴𝐴= ෍൬𝑉𝑉𝑖𝑖+ 𝑉𝑉𝑖𝑖+1
2
× 𝑑𝑑൰
𝑛𝑛
𝑖𝑖=1
  
245 
Where Vi is the truncated (see Section 7.4) change in visual acuity from baseline measured at the 
246 
ith visit, d is the number of days between visits i and i+1, and n is the number of common visits 
247 
included in the analysis. For example, the 2-year outcome has n = 9 as the analysis will include 
248 
visits at baseline, 1, 2, 4, 8, 12, 16, 20, and 24 months. For presentation, AUC will be divided by 
249 
the number of days between baseline and the 2-year (or 4-year) visit so that the value shown will 
250 
have units of letters rather than letter⋅days (e.g., 730 days at 2 years). This statistic can then be 
251 
interpreted as the average change in visual acuity over the time between baseline and the 2-year 
252 
(or 4-year) visit. 
253 
2.2.2 Development of PDR or DME 
254 
Additional analyses will be conducted on the components of the composite PDR/DME outcome 
255 
to aid in interpretation. 
256 
Table 2. Secondary PDR and DME Outcomes. 
257 
Outcome 
Analysis Method 
Development of PDR or PDR-related outcome (as 
defined within the composite time-to-event outcome) 
Marginal Cox proportional hazards regression 
Development of DME or DME-related outcome (as 
defined within the composite time-to-event outcome) 
Marginal Cox proportional hazards regression 
Mean change in OCT central subfield thickness from 
baseline* 
Linear mixed model 
Mean change in OCT volume from baseline* 
Linear mixed model 
Proportion of eyes with at least 2-step worsening of 
DR severity level (scale for individual eyes) by central 
reading center from baseline 
Logistic regression with GEE 
Proportion of eyes with at least 2-step improvement of 
DR severity level (scale for individual eyes) by central 
reading center from baseline 
Logistic regression with GEE 
*Analyses will use multiply imputed data sets created similarly as for visual acuity, but substituting central subfield 
258 
thickness or retinal volume for visual acuity. 
259 


Protocol W Statistical Analysis Plan 
 
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The following outcomes will include descriptive statistics without statistical comparison of 
260 
treatment groups: 
261 
• Development of PDR or DME based only on the objective components defined in the 
262 
composite outcome, including OCT, visual acuity, and reading center assessment of 
263 
photos and FA (i.e. not including investigator-only assessments) 
264 
• Development of each component of the composite outcome assessed individually 
265 
• Development of CI-DME on clinical exam with at least 10% increase in central subfield 
266 
thickness and at least a 25 µm increase from baseline, regardless of visual acuity change 
267 
• Proportion of eyes with at least 3-step worsening of DR severity level (scale for 
268 
individual eyes) by central reading center from baseline 
269 
• Proportion of eyes with at least 3-step improvement of DR severity level (scale for 
270 
individual eyes) by central reading center from baseline 
271 
• Level of retinopathy on color photos 
272 
The definitions for at least 2-step and 3-step improvement and worsening of diabetic retinopathy 
273 
for individual eyes on photographs, graded by central reading center, are shown in Tables 3 and 
274 
4, respectively. Note that only levels 43 to 53 are enrolled in Protocol W following reading 
275 
center grading. If an eye outside of this range were to be enrolled, it will be excluded from the 
276 
analyses of improvement and worsening. 
277 
Table 3. Definitions for 2-Step Improvement and Worsening of Diabetic Retinopathy on 
278 
Photographs for Individual Eyes. 
279 
Baseline 
Worsening 
(if FU ≥) 
Improvement 
(if FU ≤) 
NPDR 
43 
53 
14/15/20 
47 
60 
35 
53 
60 
43 
Abbreviations: FU, follow up. 
280 
Table 4. Definitions for 3-Step Improvement and Worsening of Diabetic Retinopathy on 
281 
Photographs for Individual Eyes. 
282 
Baseline 
Worsening 
(if FU ≥) 
Improvement 
(if FU ≤) 
NPDR 
43 
60 
10/12 
47 
65 
14/15/20 
53 
71 
35 
Abbreviations: FU, follow up.  
283 


Protocol W Statistical Analysis Plan 
 
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2.2.3 Workplace Productivity and Activity Impairment Questionnaire 
284 
Outcomes from the Workplace Productivity and Activity Impairment Questionnaire will be 
285 
compared between treatment groups at 2 and 4 years. For functional outcomes measured at the 
286 
participant level, bilateral participants are non-informative with respect to the treatment 
287 
comparison and will not be included in the analyses. Analyses will be conducted with a general 
288 
linear model and robust variance estimation. Baseline level of the score being analyzed, 
289 
laterality, and retinopathy severity will be included as adjustments. Only participants completing 
290 
the corresponding visit will be included in the analysis, and there will be no imputation of 
291 
missing data. The adjusted treatment effect will be presented along with a 95% confidence 
292 
interval and P value. The following outcomes will be evaluated: 
293 
• Mean change from baseline in the percentage of work time missed due to vision problems 
294 
over the past week (Absenteeism score) 
295 
o Tabulated without statistical comparison 
296 
• Mean change from baseline in the percentage of impairment while working due to vision 
297 
problems over the past week (Presenteeism score) 
298 
o Tabulated without statistical comparison 
299 
• Mean change from baseline in the percentage of overall work impairment (Absenteeism 
300 
and Presenteeism scores combined) due to vision problems over the past week (Work 
301 
Productivity Loss score) 
302 
• Mean change from baseline in the percentage of activity impairment due to vision 
303 
problems over the past week (Activity Impairment score) 
304 
3.0 Outcomes within Treatment Groups 
305 
Within each treatment group, the following outcomes will be tabulated without formal statistical 
306 
comparison. 
307 
• Distribution and median (inter-quartile range) number of intravitreous injections 
308 
performed up to 12, 24, 36, and 48 months as well as the intervening periods for eyes 
309 
completing any visit at or beyond the upper limit (e.g., for injections through 36 months, 
310 
eyes must have completed the 36-, 40-, 44-, or 48-month visit). 
311 
o Intervals will be closed on the left and open on the right (e.g., for injections 
312 
through 12 months, an injection given at 12 months will not be counted towards 
313 
the total; however, an injection given at 12 months will count for the interval of 
314 
12 to 24 months). 
315 
4.0  
Economic Analysis 
316 
The purpose of the economic analysis is to compare the treatment groups with respect to cost and 
317 
workplace productivity loss. Data from the clinical trial on number of clinic visits completed, 
318 
number of procedures performed (e.g., OCT, fundus photography), and number of aflibercept 
319 


Protocol W Statistical Analysis Plan 
 
Page 12 of 15 
injections will be used to estimate an average cost per patient for each treatment arm, using the 
320 
Medicare Fee Schedule to estimate medical costs. The cost estimates, in combination with the 
321 
percentage of productivity loss for each treatment arm (estimated from the WPAIQ), will be 
322 
incorporated into the analysis.  
323 
5.0  
Safety Analysis Plan 
324 
Adverse events will be categorized as study eye, non-study eye, and systemic. All randomized 
325 
eyes will be included in the safety analysis and analyzed according to treatment group 
326 
assignment at randomization. A tabulation of all study eye ocular, non-study eye ocular, and 
327 
systemic adverse events by treatment group as defined above will be created. An additional 
328 
tabulation will be made for adverse events possibly related to study treatment. For all analyses, 
329 
the null hypothesis of no difference between treatment groups will be evaluated. 
330 
5.1  
Ocular adverse events 
331 
The ocular adverse events below will be tabulated by treatment group for study eyes. A separate 
332 
tabulation will be made for non-study eyes receiving study aflibercept. The frequency of the 
333 
event occurring at least once per eye will be calculated. Ocular adverse events will be compared 
334 
between treatment groups using logistic regression with GEE to account for the potential 
335 
correlation between study eyes of bilateral participants. If there are convergence issues with the 
336 
GEE model due to low event rates for one or more outcomes, then Barnard’s Unconditional 
337 
Exact Test may be used for analysis of all ocular adverse events. 
338 
The following ocular adverse events are of primary interest:  
339 
• Endophthalmitis 
340 
• Any retinal detachment (rhegmatogenous, traction, combined rhegmatogenous and 
341 
traction, or not otherwise specified) 
342 
o Rhegmatogenous retinal detachment (tabulated without formal analysis) 
343 
o Traction retinal detachment (tabulated without formal analysis) 
344 
• Traumatic cataract due to intravitreal injection (limit to eyes that are phakic at baseline) 
345 
• Vitreous hemorrhage 
346 
• Ocular inflammation 
347 
• Intraocular pressure (IOP) elevation (any of the following) 
348 
o Increase of IOP ≥ 10 mmHg from baseline (at a follow-up visit) 
349 
o IOP ≥ 30 mmHg (at a follow-up visit) 
350 
o Initiation of glaucoma medications 
351 
o Glaucoma procedure 
352 
• Neovascularization of the iris 
353 


Protocol W Statistical Analysis Plan 
 
Page 13 of 15 
• Neovascular glaucoma 
354 
5.2  
Systemic adverse events 
355 
Systemic adverse events will be reported in three groups: (1) unilateral participants randomized 
356 
to sham, (2) unilateral participants randomized to aflibercept, and (3) bilateral participants. The 
357 
frequency of the event occurring at least once per participant will be calculated. Statistical 
358 
comparisons for systemic adverse events will include only unilateral participants. Analysis of 
359 
systemic adverse events will be conducted with Barnard’s Unconditional Exact Test. 
360 
Primary: 
361 
• Death 
362 
• Serious adverse event (at least one) 
363 
• Hospitalization (at least one) 
364 
• Cardiovascular and cerebrovascular events according to the Antiplatelet Trialists’ 
365 
Collaboration (excerpted from BMJ Jan 8, 1994): 
366 
o Nonfatal myocardial infarction 
367 
o Nonfatal stroke (counted only if symptoms lasted at least 24 hours) 
368 
o Death attributed to cardiac, cerebral, hemorrhagic, embolic, other vascular (does 
369 
not need to be ischemic in origin), or unknown cause 
370 
o At least one event (nonfatal myocardial infarction, nonfatal stroke, or death 
371 
attributed to potential vascular or unknown cause) 
372 
Note that transient ischemic attack, angina, possible myocardial infarction, and possible stroke 
373 
are not counted. Nonfatal myocardial infarction and nonfatal stroke require that the patient is 
374 
alive at the end of the study. If not, then only the death is counted. 
375 
Secondary (for tabulation without formal statistical comparison): 
376 
• Hypertension 
377 
• Frequency of at least one event per participant in each Medical Dictionary for Regulatory 
378 
Activities (MedDRA) system organ class 
379 
Sensitivity analyses will replicate the systemic analyses above by whether a participant was 
380 
randomized to receive aflibercept (in either eye) or not. The formal comparison groups will be 
381 
unilateral participants randomized to aflibercept and bilateral study participants versus unilateral 
382 
participants randomized to sham.  
383 
6.0  
Additional Tabulations 
384 
The following will be tabulated according to treatment group: 
385 
• Baseline demographic and clinical characteristics 
386 


Protocol W Statistical Analysis Plan 
 
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• Annual visit completion rate (excluding deaths) 
387 
• Treatment adherence  
388 
7.0  
General Principles for Analysis 
389 
7.1 
Analysis Cohort 
390 
Unless otherwise specified, treatment group comparisons will follow the intention-to-treat 
391 
principle with all randomized eyes included and each eye analyzed according to the treatment 
392 
assignment at randomization, regardless of the actual treatment received. 
393 
7.2 
Visit Windows for Analysis 
394 
All participants are required by protocol to have assessment visits at baseline, 1, 2, and 4 months. 
395 
After the 4-month visit, protocol assessment visits will be every 4 months at 8, 12, 16, 20, 24, 28, 
396 
32, 36, 40, 44, and 48 months (Table 5).  
397 
Table 5. Analysis Windows 
398 
Visit 
(Protocol Window) 
Target 
Analysis Window 
1 month ± 1 week 
30 days 
16 – 44 days           (1 month ± 2 week) 
2 months ± 1 week 
61 days 
54 – 68 days           (2 months ± 1 week) 
4 months ± 8 weeks 
122 days 
66 – 178 days         (4 months ± 8 weeks) 
8 months ± 8 weeks 
244 days 
188 – 300 days       (8 months ± 8 weeks) 
12 months ± 8 weeks 
365 days 
281 – 449 days       (12 months ± 12 weeks) 
16 months ± 8 weeks 
487 days 
431 – 543 days       (16 months ± 8 weeks) 
20 months ± 8 weeks 
609 days 
553 – 665 days       (20 months ± 8 weeks) 
24 months ± 8 weeks 
731 days 
647 – 815 days       (24 months ± 12 weeks) 
28 months ± 8 weeks 
852 days 
796 – 908 days       (28 months ± 8 weeks) 
32 months ± 8 weeks 
974 days 
918 – 1030 days     (32 months ± 8 weeks) 
36 months ± 8 weeks 
1096 days 
1012 – 1180 days   (36 months ± 12 weeks) 
40 months ± 8 weeks 
1218 days 
1162 – 1274 days   (40 months ± 8 weeks) 
44 months ± 8 weeks 
1339 days 
1283 – 1395 days   (44 months ± 8 weeks) 
48 months ± 8 weeks 
1461 days 
1377 – 1629 days    
(48 months - 12 weeks, + 24 weeks) 
If multiple visits fall within the same analysis window, then protocol assessment visits will be 
399 
prioritized. If there is no protocol assessment visit in the analysis window, then priority will be 
400 
given as follows: (1) a DME outcome assessment visit, (2) a treatment assessment visit, and (3) 
401 
an unspecified visit. If there are multiple visits of the same type in the analysis window, then 
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Protocol W Statistical Analysis Plan 
 
Page 15 of 15 
whichever is closest to the target will be used. The DME outcome assessment visits take priority 
403 
after treatment assessment visits because they occur prior to the primary outcome. Unspecified 
404 
visits have the lowest priority because not all study procedures are required at these visits. To 
405 
account for overlapping analysis windows, annual visits will be assigned before non-annual 
406 
visits. 
407 
7.3 
Missing Data 
408 
The strategy for handling missing data generally is included with the description of each 
409 
analysis. If not otherwise specified, only participants with non-missing data will be included in 
410 
the analysis (i.e., complete-case analysis). 
411 
7.4 
Outliers 
412 
To help ensure that statistical outliers do not have undue impact on analyses of continuous visual 
413 
acuity and optical coherence tomography (OCT) data, outcomes will be truncated to ± 3 standard 
414 
deviations based on the mean and standard deviation at 2 years for 2-year completers, 
415 
irrespective of treatment group. Change in visual acuity from baseline, change in OCT central 
416 
subfield thickness from baseline, and change in OCT retinal volume baseline will be truncated. 
417 
Truncation will be performed after imputation of missing data, where applicable (i.e., raw data 
418 
will be used for imputation). 
419 
7.5 
Model Assumptions 
420 
All model assumptions will be verified including linearity, normality of residuals, and 
421 
homoscedasticity. The proportional hazards assumption for the marginal Cox regression model 
422 
will be verified by testing the interaction between treatment and time. If model assumptions are 
423 
not reasonably satisfied, then covariates may be categorized or excluded, and a nonparametric 
424 
approach, transformation, or robust method may be considered.  
425 
7.6 
Type I Error 
426 
For the primary outcome and other key outcomes, strict control of the Type I error rate is 
427 
described in Section 2.0. There is no formal adjustment for multiplicity among secondary or 
428 
safety outcomes to compensate for the number of outcomes being compared. All comparisons 
429 
are conducted at alpha level .05 unless otherwise noted. 
430 
References  
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Lee EW, Wei LJ, Amato DA. Cox-type regression analysis for large numbers of small groups of 
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correlated failure time observations. Dordrecht: Kluwer Academic; 1992. 
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Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the method of 
434 
choice for handling missing data in randomized trials? Stat Methods Med Res. 2016. DOI: 
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https://doi.org/10.1177/0962280216683570. 
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