Randomized Trial of Intravitreous Aflibercept Versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema
Phase: PHASE3
Conditions: Diabetic Macular Edema
Sponsor: Jaeb Center for Health Research

 
Aflibercept Switch Protocol 4.0 6-28-21  
 
 
 
 
Diabetic Retinopathy Clinical Research 
Network 
 
 
Randomized Trial of 
Intravitreous Aflibercept versus 
Intravitreous Bevacizumab + 
Deferred Aflibercept for 
Treatment of Central-Involved 
Diabetic Macular Edema 
 
 
Version 4.0 
 
June 28, 2021 

 
Aflibercept Switch Protocol 4.0 6-28-21  
 
 
Contact Information 
 
 
Coordinating Center 
Director: Adam R. Glassman, M.S. 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL  33647 
Phone:  813-975-8690 
Fax:  800-816-7601 
Email:  aglassman@jaeb.org 
 
 
 
Protocol Co-Chairs 
 
Chirag Jhaveri, MD 
Retina Research Center 
3705 Medical Parkway Suite 420 
Austin, TX 78705 
Phone: 512-454-5851 
Email: cjhaveri@e-retina.net 
 
Frederick L. Ferris III, MD 
National Eye Institute 
BG 10-CRC RM 3-2531 
10 CENTER DR 
BETHESDA MD 20814 
Phone: 301-496-5248 
Email: frederick.ferris@nih.gov 
 
 
 
 

 
 
Aflibercept Switch Protocol 4.0 6-28-21  
 
 
 
 
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 
DME and Its Treatment ......................................................................................... 1-1 
6 
1.1.3 
Rationale for Comparing Aflibercept to Bevacizumab + Deferred Aflibercept .... 1-1 
7 
1.1.4 
Summary of Previous Research of Switching Anti-VEGF Agents ....................... 1-2 
8 
1.2 
Study Objectives ........................................................................................................... 1-2 
9 
1.3 
Study Design and Synopsis of Protocol ........................................................................ 1-2 
10 
1.4 
General Considerations ................................................................................................. 1-5 
11 
Chapter 2 Study Participant eligibility and enrollment ......................................................... 2-1 
12 
2.1 
Identifying Eligible Subjects and Obtaining Informed Consent ................................... 2-1 
13 
2.2 
Study Participant Eligibility Criteria ............................................................................. 2-1 
14 
2.2.1 
Participant-level Criteria ........................................................................................ 2-1 
15 
2.2.2 
Study Eye Criteria .................................................................................................. 2-2 
16 
2.3 
Screening Evaluation and Baseline Testing .................................................................. 2-4 
17 
2.3.1 
Historical Information ............................................................................................ 2-4 
18 
2.3.2 
Baseline Testing Procedures .................................................................................. 2-4 
19 
2.4 
Enrollment/Randomization of Eligible Study Participants ........................................... 2-5 
20 
Chapter 3 Treatment Regimens ............................................................................................... 3-1 
21 
3.1 
Introduction ................................................................................................................... 3-1 
22 
3.2 
Intravitreous Injections .................................................................................................. 3-1 
23 
3.2.1 
Intravitreous Aflibercept Injection (Eylea) ............................................................ 3-1 
24 
3.2.2 
Bevacizumab (Avastin) .......................................................................................... 3-1 
25 
3.2.3 
Intravitreous Injection Technique .......................................................................... 3-1 
26 
3.2.4 
Deferral of Injections Due to Pregnancy ............................................................... 3-2 
27 
3.2.5 
Delay in Giving Injections ..................................................................................... 3-2 
28 
Chapter 4 Follow-up visits and treatment ............................................................................... 4-1 
29 
4.1 
Visit Schedule ............................................................................................................... 4-1 
30 
4.2 
Testing Procedures ........................................................................................................ 4-1 
31 
4.3 
Treatment During Follow Up ........................................................................................ 4-2 
32 
4.3.1 
Intravitreous Injection Re-Treatment ..................................................................... 4-2 
33 
4.3.2 
Switch Criteria (Bevacizumab + Deferred Aflibercept group) .............................. 4-2 
34 
4.3.3 
Failure Criteria ....................................................................................................... 4-3 
35 

 
 
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4.3.4 
Laser for DME ....................................................................................................... 4-4 
36 
Chapter 5 Miscellaneous Considerations in Follow-up .......................................................... 5-1 
37 
5.1 
Endophthalmitis ............................................................................................................ 5-1 
38 
5.2 
Use of Intravitreous Anti-VEGF for Conditions Other than DME in the Study Eye ... 5-1 
39 
5.3 
Treatment in Non-study Eye ......................................................................................... 5-1 
40 
5.4 
Diabetes Management ................................................................................................... 5-1 
41 
5.5 
Study Participant Withdrawal and Losses to Follow-up ............................................... 5-1 
42 
5.6 
Discontinuation of Study ............................................................................................... 5-1 
43 
5.7 
Contact Information Provided to the Coordinating Center ........................................... 5-1 
44 
5.8 
Study Participant Reimbursement ................................................................................. 5-2 
45 
Chapter 6 Adverse Events ......................................................................................................... 6-1 
46 
6.1 
Definition ...................................................................................................................... 6-1 
47 
6.2 
Recording of Adverse Events ........................................................................................ 6-1 
48 
6.3 
Reporting Serious or Unexpected Adverse Events ....................................................... 6-2 
49 
6.4 
Data and Safety Monitoring Committee Review of Adverse Events ............................ 6-2 
50 
6.5 
Risks .............................................................................................................................. 6-3 
51 
6.5.1 
Potential Adverse Effects of Study Drugs ............................................................. 6-3 
52 
6.5.2 
Potential Adverse Effects of Intravitreous Injection .............................................. 6-5 
53 
6.5.3 
Risks of Eye Examination and Tests ..................................................................... 6-6 
54 
Chapter 7 Statistical Methods................................................................................................... 7-1 
55 
7.1 
Primary Outcome .......................................................................................................... 7-1 
56 
7.2 
Sample Size ................................................................................................................... 7-1 
57 
7.2.1 
Outcome Projections .............................................................................................. 7-1 
58 
7.2.2 
Sample Size Estimates ........................................................................................... 7-2 
59 
7.3 
Primary Analysis Plan ................................................................................................... 7-2 
60 
7.3.1 
Principles for Analysis ........................................................................................... 7-2 
61 
7.3.2 
Sensitivity Analyses ............................................................................................... 7-3 
62 
7.3.3 
Subgroup Analyses ................................................................................................ 7-3 
63 
7.3.4 
Interim Analysis Plan ............................................................................................. 7-4 
64 
7.4 
Secondary Outcomes for Treatment Group Comparison .............................................. 7-4 
65 
7.5 
Economic Analysis ........................................................................................................ 7-4 
66 
7.6 
Safety Analysis Plan...................................................................................................... 7-5 
67 
7.7 
Additional Tabulations and Analyses ........................................................................... 7-6 
68 
7.8 
Multiple Testing ............................................................................................................ 7-6 
69 
Chapter 8 References ................................................................................................................. 8-1 
70 
71 

 
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1-1 
CHAPTER 1                                                                                            
72 
BACKGROUND INFORMATION AND STUDY SYNOPSIS 
73 
 
74 
1.1 Background Information 
75 
1.1.1 Diabetic Retinopathy Complications and Public Health Impact 
76 
The age-adjusted incidence of diabetes mellitus in the United States has reportedly doubled in 
77 
recent history.1 Estimates suggest that by the year 2035, approximately 592 million individuals 
78 
worldwide will be affected by this chronic disease.2 The increasing global epidemic of diabetes 
79 
implies an increase in rates of associated vascular complications from diabetes. At present at 
80 
least 5 million people over the age of 40 in the United States are estimated to have diabetic 
81 
retinopathy (DR) in the absence of diabetic macular edema (DME), and an additional 800,000 
82 
have DME, according to data from the Centers for Disease Control.3 Despite advances in 
83 
diagnosis and management of ocular disease in patients with diabetes, eye complications from 
84 
diabetes mellitus continue to be a leading cause of vision loss and new onset blindness in 
85 
working-age individuals throughout the United States.4, 5 
86 
 
87 
1.1.2 DME and Its Treatment 
88 
DME is manifestation of diabetic retinopathy that produces loss of central vision.  DME is 
89 
currently a leading cause of moderate vision loss in patients with diabetes.6  Without 
90 
intervention, 33% of 221 eyes in the Early Treatment Diabetic Retinopathy Study (ETDRS) with 
91 
center-involved DME (CI-DME) experienced “moderate visual loss” (defined as a 15 or more 
92 
letter score decrease in visual acuity) over a 3 year period.7  The Diabetic Retinopathy Clinical 
93 
Research Network (DRCR.net) study “Intravitreal Ranibizumab or Triamcinolone Acetonide in 
94 
Combination with Laser Photocoagulation for Diabetic Macular Edema” (Protocol I) indicated 
95 
that treatment for DME with intravitreous anti-VEGF therapy (0.5 mg ranibizumab) with prompt 
96 
or deferred focal/grid laser provides visual acuity outcomes at 1 year and 2 years that are 
97 
superior to focal/grid laser alone or focal/grid laser combined with intravitreous corticosteroids.8  
98 
Results of that study provided definitive confirmation of the important role of vascular 
99 
endothelial growth factor (VEGF) in DME and the superiority of anti-VEGF agents in the 
100 
treatment of DME.  Additional phase 3 studies have since confirmed the superiority of anti-
101 
VEGF agents to manage DME.9-11 
102 
 
103 
1.1.3 Rationale for Comparing Aflibercept to Bevacizumab + Deferred Aflibercept 
104 
Three anti-VEGF agents, aflibercept, bevacizumab, and ranibizumab, have been shown to be 
105 
effective for treatment of diabetic macular edema.  Based on results from DRCR.net Protocol T, 
106 
when visual acuity loss is relatively mild, there are not meaningful differences in visual acuity 
107 
outcomes, on average, among the three agents.  However, at worse levels of visual acuity, 
108 
aflibercept is more effective at improving vision than the other 2 agents at 1 year and more 
109 
effective at improving vision than bevacizumab at 2 years. There are considerable cost 
110 
differences among aflibercept ($1961/dose), bevacizumab (current Medicare allowable charge: 
111 
$67/dose), and 0.3-mg ranibizumab ($1189/dose).   
112 
 
113 
In Protocol T, although aflibercept treatment in Protocol T resulted in better visual acuity 
114 
outcomes for eyes with worse levels of visual acuity, bevacizumab was effective for many eyes 
115 
and a cost-effectiveness analysis showed that bevacizumab was more cost effective than 
116 
aflibercept.12  The cost difference between aflibercept and bevacizumab might limit availability 
117 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
1-2 
of aflibercept for some patients.  According to the 2016 ASRS PAT Survey, approximately 50% 
118 
of United States retinal specialist indicated that insurance requires use of bevacizumab as the 
119 
first line treatment for at least some of their patients.  In the subgroup of Protocol T eyes with 
120 
baseline visual acuity of 20/50 or worse, 60% of bevacizumab treated eyes had a 10 or more 
121 
letter improvement and 41% had a 15 or more letter improvement at 1 year. At 2 years, 66% of 
122 
eyes with worse baseline visual acuity had a 10 or more letter improvement and 52% had a 15 or 
123 
more letter improvement.13 Thus, many eyes initially treated with bevacizumab for DME might 
124 
gain enough vision with bevacizumab therapy that they might not derive greater benefit if given 
125 
another anti-VEGF agent such as aflibercept.  Many clinicians initiate treatment with 
126 
bevacizumab for patients with decreased visual acuity from DME (61% of PAT Survey 
127 
respondents start with bevacizumab for decreased visual acuity from DME).  However, there is 
128 
no scientific evidence that this treatment strategy of switching treatment from bevacizumab to 
129 
aflibercept among eyes not improving is as effective at improving vision as initiating treatment 
130 
with aflibercept.  It is unknown if this approach ultimately has deleterious effects on visual 
131 
acuity compared with starting with aflibercept.   
132 
 
133 
Given this, a study assessing a switch from bevacizumab to aflibercept only in cases in which 
134 
bevacizumab was not judged to be successful is perceived to be of great public health interest.   
135 
   
136 
1.1.4 Summary of Previous Research of Switching Anti-VEGF Agents  
137 
Both aflibercept and bevacizumab have been shown to improve vision in eyes with DME.  In 
138 
eyes with DME and at least moderate vision loss, both aflibercept and bevacizumab were also 
139 
shown to be successful in many eyes.  However, aflibercept was shown to be more effective at 
140 
improving vision, on average, at 1 year and at 2 years.  Due to the large cost difference between 
141 
the two drugs, many clinicians and patients are choosing to initiate treatment with bevacizumab 
142 
and then switch to aflibercept depending on the eye’s response to bevacizumab treatment.  
143 
However, there is no scientific evidence that this treatment strategy is as effective at improving 
144 
vision as initiating treatment with aflibercept.  Patients and clinicians do not know if this 
145 
approach ultimately has deleterious effects on visual acuity. If starting with aflibercept is not 
146 
better than starting with bevacizumab and switching to aflibercept if needed, the potential cost 
147 
savings to future patients and the health care system would be substantial.  However, if starting 
148 
with aflibercept is better, then patients, clinicians, and health care providers can make informed 
149 
decisions for how to best treat patients with DME and at least moderate vision loss.    
150 
 
151 
1.2 Study Objectives 
152 
To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab + deferred 
153 
aflibercept if needed in eyes with CI DME and moderate vision loss.   
154 
 
155 
1.3 Study Design and Synopsis of Protocol 
156 
 
157 
A. Study Design 
158 
 
159 
• Randomized, multi-center clinical trial. 
160 
 
161 
B. Major Eligibility Criteria 
162 
 
163 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
1-3 
• Age ≥18 years. 
164 
• Type 1 or type 2 diabetes 
165 
• The study eye must meet the following criteria: 
166 
o Visual acuity (VA) letter score in the study eye < 69 and ≥ 24 (approximate 
167 
Snellen equivalent 20/50 to 20/320) 
168 
o Ophthalmoscopic evidence of center-involved DME (i.e., involving the center of 
169 
the macula) 
170 
o Center-involved macular thickening on optical coherence tomography (OCT) 
171 
 Zeiss Cirrus central subfield (CSF): ≥290µm in women or ≥ 305µm in men 
172 
 Heidelberg Spectralis central subfield: ≥ 305µm in women or ≥320µm in 
173 
men 
174 
o No history of anti-VEGF treatment for DME in the past 12 months in the study 
175 
eye and no history of any other treatment for DME in the study eye in the past 4 
176 
months (such as focal/grid macular photocoagulation, intravitreous or peribulbar 
177 
corticosteroids) 
178 
 Enrollment will be limited to a maximum of 25% of the planned sample 
179 
size with any history of anti-VEGF treatment for DME in the study eye. 
180 
Once this number of eyes has been enrolled, any history of anti-VEGF 
181 
treatment for DME in the study eye will be an exclusion criterion. 
182 
o No history of major ocular surgery in the study eye within prior 4 months or 
183 
anticipated within the next 6 months following randomization 
184 
 
185 
C. Treatment Groups 
186 
Subjects will be assigned randomly (1:1) to one of the following two groups: 
187 
 
188 
• 2.0 mg intravitreous aflibercept 
189 
• 1.25 mg intravitreous bevacizumab + deferred intravitreous 2.0 mg aflibercept if eye 
190 
meets switch criteria  
191 
 
192 
Study participants may have one or two study eyes, if both eyes are eligible at the time of 
193 
randomization.  Study participants with two study eyes will be randomized to receive aflibercept 
194 
in one eye and bevacizumab + deferred aflibercept (if switch criteria is met) in the other eye.  
195 
Further details on randomization are located in section 2.4. 
196 
 
 
197 
D. Sample Size 
198 
A minimum of 312 eyes (260 participants assuming 20% have two study eyes) are expected to be 
199 
enrolled into the randomized trial.   
200 
 
201 
E. Duration of Follow-up: 2 years 
202 
 
203 
F. Follow-up and Treatment Schedule 
204 
• Follow-up visits occur every 4 weeks up to the 1 year visit 
205 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
1-4 
• Study eyes in both groups will be evaluated for an injection at each study visit according 
206 
to the same retreatment protocol (DRCR.net anti-VEGF retreatment algorithm).   
207 
• At 12, 16, and 20 weeks, study eyes in the bevacizumab treatment group that meet all of 
208 
the following switch criteria will be switched to treatment with aflibercept 
209 
o OCT CSF thickness ≥ machine and gender specific thresholds 
210 
 Zeiss Cirrus: ≥290µm in women or ≥ 305µm in men 
211 
 Heidelberg Spectralis: ≥ 305µm in women or ≥320µm in men 
212 
o VA not improved at least 5 letters from the prior two visits    
213 
o OCT CSF not improved at least 10% from the prior two visits  
214 
o VA is 20/50 or worse  
215 
• At and after 24 weeks, study eyes in the bevacizumab treatment group (that have not 
216 
already switched to aflibercept) that meet all of the following switch criteria will switch 
217 
to aflibercept 
218 
o OCT CSF thickness ≥ machine and gender specific thresholds 
219 
 Zeiss Cirrus: ≥290µm in women or ≥ 305µm in men 
220 
 Heidelberg Spectralis: ≥ 305µm in women or ≥320µm in men 
221 
o VA not improved at least 5 letters from the prior two visits    
222 
o OCT CSF not improved at least 10% from the prior two visits  
223 
o VA is 20/32 or worse  
224 
• After 1 year, visits occur every 4 to 16 weeks depending on disease progression and 
225 
treatment administered 
226 
• All participants will have follow-up visits at 1 and 2 years 
227 
 
228 
G. Primary Efficacy Outcomes 
229 
• The primary analysis is a treatment group comparison of mean change in visual acuity 
230 
over 2 years, area under the curve (AUC) adjusted for baseline visual acuity.   
231 
 
232 
I. Main Safety Outcomes 
233 
Ocular: endophthalmitis, retinal detachment, traumatic cataract due to injection, vitreous 
234 
hemorrhage, inflammation, neovascular glaucoma, iris neovascularization 
235 
Systemic: death, serious adverse event, hospitalization, Antiplatelet Trialists’ Collaboration 
236 
(APTC) events 
237 
 
238 
J. Schedule of Study Visits and Examination Procedures 
239 
Visit 
0 
4w-48w 
Visits 
Every 4 w 
52w 
Between 
52w-104w 
Visits Every  
4-16w* 
 
104w 
E-ETDRS Best Corrected Visual 
Acuitya  
X 
X 
X 
X 
X 
OCTb 
X 
X 
X 
X 
X 
Eye Examc 
X 
X 
X 
X 
X 
Fundus Photographyd  
X 
 
X 
 
X 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
1-5 
Blood pressure 
X 
 
X 
 
X 
Hemoglobin A1ce 
X 
 
X 
 
X 
E-ETDRS, Electronic Early Treatment Diabetic Retinopathy Study; OCT, optical coherence tomography 
240 
A medical history will be elicited at baseline and an updated history at each visit.  Concomitant medications will be 
241 
recorded at baseline and updated at each visit.  Adverse events will be recorded at each visit. 
242 
aBoth eyes at each visit; includes protocol refraction in study eye at each visit. Protocol refraction in nonstudy eye is 
243 
only required at baseline, 52 week and 104 week visits.  E-ETDRS refers to electronic ETDRS testing using the 
244 
Electronic Visual Acuity Tester that has been validated against 4-meter chart ETDRS testing. 
245 
bStudy eye only.  
246 
cBoth eyes at baseline, 52 weeks and 104 weeks; study eye only at all other follow-up visits.  Includes slit lamp 
247 
exam (including assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy. 
248 
dDigital 7-fields, 4WF or UWF; study eye only.   
249 
 
eDoes not need to be repeated if Hemoglobin A1c is available from within the prior 3 months.  If not available, can 
250 
be performed within 3 weeks after randomization. 
251 
 
252 
1.4 General Considerations 
253 
The study is being conducted in compliance with the policies described in the DRCR.net Policies 
254 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
255 
the protocol described herein, and with the standards of Good Clinical Practice. 
256 
 
257 
The DRCR.net Procedures Manuals (Visual Acuity-Refraction Testing, OCT, photography, and 
258 
Study procedures manuals) provide details of the examination procedures and intravitreous 
259 
injection procedures.   
260 
 
261 
Photographers, OCT technicians, and visual acuity testers, including refractionists, will be 
262 
masked to treatment group at the annual visits.  Study participants will be initially masked to 
263 
their treatment group assignment, but may find out the identity of the drug from billing 
264 
documents.  Investigators and study coordinators are not masked to treatment group. 
265 
   
266 
Data will be directly collected in electronic case report forms, which will be considered the 
267 
source data. 
268 
 
269 
There is no restriction on the number of study participants to be enrolled by a site. 
270 
 
271 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
272 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
273 
2013). 
274 
 
275 
The risk level is considered to be research involving greater than minimal risk.
276 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
2-1 
CHAPTER 2                                                                                            
277 
STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 
278 
 
279 
2.1 Identifying Eligible Subjects and Obtaining Informed Consent 
280 
A minimum of 312 eyes (260 participants assuming 20% have two study eyes) are expected to be 
281 
enrolled into the randomized trial.  As the enrollment goal approaches, sites will be notified of 
282 
the end date for recruitment.  Study participants who have signed an informed consent form can 
283 
be randomized up until the end date, which means the recruitment goal might be exceeded.   
284 
 
285 
Potential eligibility will be assessed as part of a routine-care examination.  Prior to completing 
286 
any procedures or collecting any data that are not part of usual care, written informed consent 
287 
will be obtained.  For patients who are considered potentially eligible for the study based on a 
288 
routine-care exam, the study protocol will be discussed with the potential study participant by a 
289 
study investigator and clinic coordinator. The potential study participant will be given the 
290 
Informed Consent Form to read.  In addition, participants will be required to watch a short 
291 
informational video about the trial and answer a few short questions to confirm understanding of 
292 
the study.  Potential study participants will be encouraged to discuss the study with family 
293 
members and their personal physician(s) before deciding whether to participate in the study.   
294 
 
295 
Consent may be given in two stages (if approved by the IRB).  The initial stage will provide 
296 
consent to complete any of the screening procedures needed to assess eligibility that have not 
297 
already been performed as part of a usual-care exam.  The second stage will be obtained prior to 
298 
randomization and will be for participation in the study.  Study participants will be provided with 
299 
a copy of the signed Informed Consent Form. 
300 
 
301 
Once a study participant is randomized, that participant will be counted regardless of whether the 
302 
assigned treatment is received.  Thus, the investigator must not proceed to randomize an 
303 
individual until he/she is convinced that the individual is eligible and will accept assignment to 
304 
either of the two treatment groups. 
305 
 
306 
2.2 Study Participant Eligibility Criteria 
307 
2.2.1 Participant-level Criteria 
308 
Inclusion 
309 
To be eligible, the following inclusion criteria must be met: 
310 
1. Age ≥ 18 years  
311 
• Individuals <18 years old are not being included because DME is so rare in this age 
312 
group that the diagnosis of DME may be questionable.  
313 
2. Diagnosis of diabetes mellitus (type 1 or type 2)  
314 
• Any one of the following will be considered to be sufficient evidence that diabetes is 
315 
present:  
316 
 Current regular use of insulin for the treatment of diabetes 
317 
 Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes 
318 
 Documented diabetes by ADA and/or WHO criteria (see Procedures Manual for 
319 
definitions) 
320 
3. At least one eye meets the study eye criteria listed in section 2.2.2. 
321 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
2-2 
4. Able and willing to provide informed consent. 
322 
 
323 
Exclusion 
324 
An individual is not eligible if any of the following exclusion criteria are present:  
325 
5. Significant renal disease, defined as a history of chronic renal failure requiring dialysis or 
326 
kidney transplant. 
327 
6. A condition that, in the opinion of the investigator, would preclude participation in the study 
328 
(e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic 
329 
control).  
330 
• Individuals in poor glycemic control who, within the last four months, initiated intensive 
331 
insulin treatment (a pump or multiple daily injections) or plan to do so in the next four 
332 
months should not be enrolled. 
333 
7. Participation in an investigational trial within 30 days of randomization that involved 
334 
treatment with any drug that has not received regulatory approval for the indication being 
335 
studied at the time of study entry. 
336 
• Note: study participants cannot receive another investigational drug while participating 
337 
in the study. 
338 
8. Known allergy to any component of the study drug or any drug used in the injection prep 
339 
(including povidone iodine prep).  
340 
9. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110). 
341 
• If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual 
342 
can become eligible.  
343 
10. Systemic anti-VEGF or pro-VEGF treatment within four months prior to randomization or 
344 
anticipated use during the study. 
345 
• These drugs cannot be used during the study. 
346 
11. For women of child-bearing potential: pregnant or lactating or intending to become pregnant 
347 
within the next 24 months. 
348 
• Women who are potential study participants should be questioned about the potential for 
349 
pregnancy.  Investigator judgment is used to determine when a pregnancy test is needed. 
350 
12. Individual is expecting to move out of the area of the clinical center to an area not covered by 
351 
another clinical center during the next two years. 
352 
 
353 
2.2.2 Study Eye Criteria 
354 
The study participant must have at least one eye meeting all of the inclusion criteria and none of 
355 
the exclusion criteria listed below.   
356 
 
357 
Study participants can have two study eyes only if both eyes are eligible at the time of 
358 
randomization.  For study participants with two eligible eyes, the logistical complexities of the 
359 
protocol must be considered for each individual prior to randomizing both eyes.   
360 
  
361 
The eligibility criteria for a study eye are as follows: 
 
362 
 
363 
Inclusion 
364 

 
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2-3 
a. Best corrected E-ETDRS visual acuity letter score < 69 (i.e., 20/50 or worse) and ≥ 24 (i.e., 
365 
20/320 or better) within eight days of randomization.  
366 
b. On clinical exam, definite retinal thickening due to diabetic macular edema involving the 
367 
center of the macula. 
368 
c. Diabetic macular edema present on OCT within eight days of randomization 
369 
• Zeiss Cirrus central subfield: ≥290µm in women or ≥ 305µm in men 
370 
• Heidelberg Spectralis central subfield: ≥ 305µm in women or ≥320µm in men 
371 
• Investigator must verify accuracy of OCT scan by ensuring it is centered and of 
372 
adequate quality 
373 
d. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate fundus 
374 
photographs. 
375 
 
376 
Exclusions 
377 
The following exclusions apply to the study eye only (i.e., they may be present for the nonstudy 
378 
eye): 
379 
e. Macular edema is considered to be due to a cause other than diabetic macular edema.  
380 
• An eye should not be considered eligible if: (1) the macular edema is considered to be 
381 
related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT 
382 
suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or 
383 
epiretinal membrane) are the primary cause of the macular edema. 
384 
f. An ocular condition is present such that, in the opinion of the investigator, visual acuity loss 
385 
would not improve from resolution of macular edema (e.g., foveal atrophy, pigment 
386 
abnormalities, dense subfoveal hard exudates, nonretinal condition).  
387 
g. An ocular condition is present (other than diabetes) that, in the opinion of the investigator, 
388 
might affect macular edema or alter visual acuity during the course of the study (e.g., vein 
389 
occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).  
390 
h. Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual 
391 
acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye 
392 
was otherwise normal).  
393 
i. History of an anti-VEGF treatment for DME in the past 12 months or history of any other 
394 
treatment for DME at any time in the past four months (such as focal/grid macular 
395 
photocoagulation, intravitreous or peribulbar corticosteroids).  
396 
• Enrollment will be limited to a maximum of 25% of the planned sample size with any 
397 
history of anti-VEGF treatment for DME. Once this number of eyes has been enrolled, 
398 
any history of anti-VEGF treatment for DME will be an exclusion criterion.  
399 
j. History of pan-retinal photocoagulation within four months prior to randomization or 
400 
anticipated need for pan-retinal photocoagulation in the six months following randomization. 
401 
k. History of anti-VEGF treatment for a disease other than DME in the past 12 months. 
402 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
2-4 
l. History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any 
403 
intraocular surgery, etc.) within prior four months or anticipated within the next six months 
404 
following randomization.  
405 
m. History of YAG capsulotomy performed within two months prior to randomization. 
406 
n. Aphakia. 
407 
o. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant 
408 
blepharitis. 
409 
p. Evidence of uncontrolled glaucoma. 
410 
• Intraocular pressure must be <30, with no more than one topical glaucoma 
411 
medication, and no documented glaucomatous field loss for the eye to be eligible 
412 
 
Note – combination therapies are considered more than one medication 
413 
 
414 
2.3 Screening Evaluation and Baseline Testing 
415 
2.3.1 Historical Information 
416 
A history will be elicited from the potential study participant and extracted from available 
417 
medical records.  Data to be collected will include: age, gender, ethnicity and race, diabetes 
418 
history and current management, other medical conditions, medications being used, as well as 
419 
ocular diseases, surgeries, and treatment. 
420 
 
421 
2.3.2 Baseline Testing Procedures 
422 
The following procedures are needed to assess eligibility and/or to serve as baseline measures for 
423 
the study.   
424 
• If a procedure has been performed (using the study technique and by study certified 
425 
personnel) as part of usual care, it does not need to be repeated specifically for the 
426 
study if it was performed within the defined time windows specified below.  
427 
• The testing procedures are detailed in the DRCR.net Visual Acuity-Refraction 
428 
Testing Procedures Manual, OCT Procedures Manuals, Photography Testing 
429 
Procedures Manual, and Study Procedures Manual. Visual acuity testing, ocular 
430 
exam, fundus photography, and OCT will be performed by DRCR.net certified 
431 
personnel.  
432 
 
433 
1. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity 
434 
Tester (including protocol refraction) in each eye. (within eight days prior to randomization) 
435 
• This testing procedure has been validated against 4-meter ETDRS chart testing.14 
436 
2. OCT on study eye (within eight days prior to randomization) 
437 
• For a given study participant, the same machine type should be used for the duration 
438 
of the study, unless circumstances do not permit (e.g., replacement of damaged 
439 
machine).  If a switch is necessary, the same machine type should be used for the 
440 
remainder of the study. 
441 
3. Ocular examination on each eye including slit lamp, measurement of intraocular pressure, 
442 
lens assessment, and dilated ophthalmoscopy  (within 21 days prior to randomization) 
443 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
2-5 
4. Digital fundus photography in the study eye.  (within 21 days prior to randomization)  
444 
5. Measurement of blood pressure (see study procedures manual for collection procedure.) 
445 
6. Laboratory Testing- Hemoglobin A1c 
446 
• Hemoglobin A1c does not need to be repeated if available in the prior three months.  
447 
If not available at the time of randomization, the individual may be enrolled but the 
448 
test must be obtained within three weeks after randomization.  
449 
 
450 
2.4 Enrollment/Randomization of Eligible Study Participants 
451 
Study participants can have two study eyes.   
452 
1. Prior to randomization, the study participant’s understanding of the trial, willingness to 
453 
accept the assigned treatment group, and commitment to the follow-up schedule should be 
454 
reconfirmed. 
455 
2. The baseline injection must be given on the day of randomization; therefore, a study 
456 
participant should not be randomized until this is possible.  For study participants with two 
457 
study eyes, it is strongly recommended that both eyes are treated on the day of 
458 
randomization.  If the investigator is not willing to perform bilateral injections on the same 
459 
day, the second study eye must receive the injection within 7 days. 
460 
3. Randomization is completed on the DRCR.net website.   
461 
• Study participants with one study eye will be randomly assigned  with equal probability 
462 
stratified by site to receive either:  
463 
 Group A: 2.0 mg intravitreous aflibercept 
464 
 Group B: 1.25 mg intravitreous bevacizumab + deferred intravitreous 2.0 mg 
465 
aflibercept if the eye meets switch criteria  
466 
 
467 
• Study participants with two study eyes (both eyes eligible at time of randomization) will 
468 
be randomized with equal probability to receive either: 
469 
 Group A in the eye with greater visual acuity and Group B in the  eye with lower 
470 
visual acuity 
471 
 Group B in the eye with greater visual acuity and Group A in the eye with lower 
472 
visual acuity 
473 
 
474 
Note: if both eyes have the same visual acuity, the right eye will be considered the eye 
475 
with greater visual acuity. 
476 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
3-1 
CHAPTER 3                                                                                            
477 
TREATMENT REGIMENS 
478 
3.1 Introduction 
479 
The study eye is assigned to one of the two treatment groups. 
480 
 
481 
The treatment groups are as follows: 
482 
• 2.0 mg intravitreous aflibercept 
483 
• 1.25 mg intravitreous bevacizumab + deferred intravitreous 2.0 mg aflibercept if the eye 
484 
meets switch criteria  
485 
 
486 
The initial injection will be given on the day of randomization.  For study participants with two 
487 
study eyes, it is strongly recommended that both eyes are treated on the day of randomization.  If 
488 
the investigator is not willing to perform bilateral injections on the same day, the second study 
489 
eye must receive the injection within 7 days.  
490 
 
491 
Treatment procedures are described below.  The timing and criteria for retreatment are outlined 
492 
in chapter 4. 
493 
 
494 
3.2 Intravitreous Injections 
495 
3.2.1 Intravitreous Aflibercept Injection (Eylea) 
496 
Eylea® (intravitreous aflibercept injection) is made by Regeneron Pharmaceuticals, Inc. and is 
497 
approved by the FDA for the treatment of neovascular age-related macular degeneration, 
498 
macular edema due to central retinal vein occlusion, macular edema due to branch retinal vein 
499 
occlusion, diabetic macular edema, and diabetic retinopathy in eyes with diabetic macular 
500 
edema.   
501 
 
502 
Study eyes assigned to receive aflibercept will receive a dose of 2.0 mg in 0.05 cc.  Aflibercept 
503 
will be obtained commercially by the clinical site.  The physical, chemical, and pharmaceutical 
504 
properties and formulation of aflibercept are provided in the Package Insert.   
505 
 
506 
3.2.2 Bevacizumab (Avastin) 
507 
Bevacizumab (Avastin) is made by Genentech, Inc. and is approved by the FDA for the 
508 
treatment of metastatic colorectal cancer as well as the treatment of non-squamous non-small cell 
509 
lung cancer, glioblastoma, and metastatic renal cell carcinoma.    
510 
 
511 
Study eyes assigned to receive bevacizumab will receive a dose of 1.25 mg either obtained by 
512 
the clinical site or provided by a single compounding pharmacy identified by the Network and 
513 
distributed by the Network.  The volume of the injection will be 0.05 cc.  The physical, chemical, 
514 
and pharmaceutical properties and formulation of bevacizumab are provided in the Clinical 
515 
Investigator’s Brochure.     
516 
 
517 
3.2.3 Intravitreous Injection Technique 
518 
The injection is preceded by a povidone iodine prep of the conjunctiva.  In general, topical 
519 
antibiotics in the pre-, peri-, or post-injection period should not be used.  
520 
 
521 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
3-2 
The injection will be performed using sterile technique.  The full injection procedure is described 
522 
in the protocol-specific study procedures manual. 
523 
 
524 
3.2.4 Deferral of Injections Due to Pregnancy 
525 
Female study participants of child-bearing age must be questioned regarding the possibility of 
526 
pregnancy prior to each injection. In the event of pregnancy, study injections must be 
527 
discontinued during the pregnancy and any post-partum period of breastfeeding.   
528 
 
529 
3.2.5 Delay in Giving Injections 
530 
If a scheduled injection is not given by the end of the visit window, it can still be given up to one 
531 
week prior to the next visit window opening.  If it is not given by that time, it will be considered 
532 
missed. 
533 
 
534 
If an injection is given late, the next scheduled injection should occur no sooner than three weeks 
535 
after the previous injection. 
536 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
4-1 
CHAPTER 4                                                                                            
537 
FOLLOW-UP VISITS AND TREATMENT 
538 
 
539 
4.1 Visit Schedule 
540 
The schedule of protocol-specified follow-up visits is as follows: 
541 
 
542 
First Year 
543 
• Visits every 4±1 weeks (with a minimum of 21 days between visits) through 1 year 
544 
 
545 
Year 2 
546 
• Visits every 4±1 weeks (with a minimum of 21 days between visits) as long as 
547 
intravitreous injections are given 
548 
• Otherwise, visits every 4 to 16 weeks (±1 week windows)  
549 
 The first two times an injection is deferred, the subject will return in 4 
550 
weeks for re-evaluation. If deferral continues, the subject will return in 8 weeks for 
551 
re-evaluation before beginning the every 16 week schedule. 
552 
 
553 
Additional visits may occur as required for usual care of the study participant.  
554 
 
555 
4.2 Testing Procedures 
556 
The following procedures will be performed at each protocol visit unless otherwise specified. A 
557 
grid in section 1.3 summarizes the testing performed at each visit.   
558 
 
559 
Visual acuity testers and OCT technicians will be masked to treatment group at the annual visits.  
560 
Study participants will be initially masked to their treatment group assignment, but may find out 
561 
the identity of the drug from billing documents.  The investigators and the study coordinators 
562 
will not be masked to the treatment group assignment.        
563 
 
564 
1. E- ETDRS visual acuity testing in each eye (best corrected). 
565 
• A protocol refraction in the study eye is required at all protocol visits.  Refraction in the 
566 
non-study eye is only required at the 1 and 2 year visits.  When a refraction is not 
567 
performed, the most-recently performed refraction is used for the testing. 
568 
2. OCT on the study eye   
569 
• For a given study participant, the same machine type should be used for the duration of 
570 
the study, unless circumstances do not permit (e.g., replacement of damaged machine).  If 
571 
a switch is necessary, the same machine type should be used for the remainder of the 
572 
study.  
573 
3. Ocular exam on both eyes at the annual visits and study eye only at all other follow-up visits, 
574 
including slit lamp examination, lens assessment, measurement of intraocular pressure and 
575 
dilated ophthalmoscopy.   
576 
4. Digital fundus photography on the study eye only. 
577 
5. A blood pressure measurement will be collected at the annual visits. 
578 
6. Laboratory testing of Hemoglobin A1c at annual visits only. 
579 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
4-2 
• HbA1c does not need to be repeated at annual visits if available in the prior 3 
580 
months.  
581 
All of the testing procedures do not need to be performed on the same day, provided that they are 
582 
completed within the time window of a visit and prior to initiating any retreatment.  
583 
 
584 
Testing procedures at unscheduled visits are at investigator discretion.  However, it is 
585 
recommended that procedures that are performed should follow the standard DRCR.net protocol 
586 
for each procedure. 
587 
 
588 
4.3 Treatment During Follow Up 
589 
The treatment groups are as follows: 
590 
• 2.0 mg intravitreous aflibercept 
591 
• 1.25 mg intravitreous bevacizumab with deferred intravitreous 2.0 mg aflibercept if the 
592 
eye meets switch criteria  
593 
 
594 
4.3.1 Intravitreous Injection Re-Treatment 
595 
At the baseline visit all treatment groups will receive an intravitreous injection according to their 
596 
assigned treatment group.  After the initial injection each eye will be treated according to 
597 
retreatment protocol.  In general, an eye will continue to receive an injection if the eye is 
598 
improving or worsening on OCT or visual acuity.  The first time an eye has not improved or 
599 
worsened, the eye will receive an injection.  If the eye has not improved or worsened for at least 
600 
2 consecutive injections and OCT CSF thickness is less than the gender-specific spectral domain 
601 
OCT threshold (see below) and visual acuity is 20/20 or better, the injection will be deferred.  If 
602 
the eye has not improved or worsened for at least 2 consecutive visits and OCT CSF thickness is 
603 
≥ the gender-specific spectral domain OCT threshold or visual acuity is worse than 20/20, the 
604 
following will be done: 
605 
• Prior to the 24-week visit, an injection will be given. 
606 
• At and after the 24-week visit, the injection will be deferred.   
607 
 
608 
For study participants with two study eyes, if the re-treatment protocol determines that both eyes 
609 
are to receive an intravitreous injection at the visit, it is strongly recommended that both eyes are 
610 
treated on the same day.  If the investigator is not willing to perform bilateral injections on the 
611 
same day, the second study eye must receive the injection within 7 days. 
612 
 
613 
The protocol chair or designee must be contacted prior to deviating from the injection protocol.  
614 
See the DRCR.net Procedure Manual for additional details. 
615 
 
616 
Spectral domain OCT central subfield gender-specific thresholds: 
617 
 Zeiss Cirrus: 290µm in women and 305µm in men 
618 
 Heidelberg Spectralis: 305µm in women and 320µm in men 
619 
 
620 
4.3.2 Switch Criteria (Bevacizumab + Deferred Aflibercept group) 
621 
At the 12, 16 and 20 week visits, study eyes assigned to the bevacizumab + deferred aflibercept 
622 
group will switch from bevacizumab injections to aflibercept injections when all of the following 
623 
criteria have been met: 
624 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
4-3 
• OCT CSF thickness is above the following cutoffs: 
625 
 Zeiss Cirrus CSF: ≥290µm in women or ≥ 305µm in men 
626 
 Heidelberg Spectralis CSF: ≥ 305µm in women or ≥320µm in men 
627 
• VA not improved at least 5 letters from the prior two visits    
628 
• OCT CSF not improved at least 10% from the prior two visits  
629 
• Visual acuity is 20/50 or worse 
630 
 
631 
Beginning at the 24 week visit through the end of the study, study eyes assigned to the 
632 
bevacizumab + deferred aflibercept group that have not already switched to aflibercept will 
633 
switch from bevacizumab injections to aflibercept injections when all the following criteria have 
634 
been met: 
635 
• OCT CSF thickness is above the following cutoffs: 
636 
 Zeiss Cirrus CSF: ≥290µm in women or ≥ 305µm in men 
637 
 Heidelberg Spectralis CSF: ≥ 305µm in women or ≥320µm in men 
638 
• VA not improved at least 5 letters from the prior two visits    
639 
• OCT CSF not improved at least 10% from the prior two visits  
640 
• Visual acuity is 20/32 or worse 
641 
 
642 
 Note – If bevacizumab injections are deferred according to the criteria in section 4.3.1, and 
643 
then the eye worsens, injections will resume using bevacizumab.  Then, if the criteria above 
644 
is met following two consecutive bevacizumab injections, the eye will switch to aflibercept.   
645 
 
646 
Eyes that meet the switch criteria will switch to aflibercept injections and receive 2 monthly 
647 
injections of aflibercept, then continue with aflibercept injections through the end of the study 
648 
according to the retreatment protocol described in section 4.3.1. 
649 
 
650 
The protocol chair or designee must be contacted prior to deviating from the injection protocol.  
651 
See the DRCR.net Procedure Manual for additional details. 
652 
 
653 
4.3.3 Failure Criteria 
654 
For study eyes in both treatment groups, when failure criteria is met, treatment is up to the 
655 
investigator discretion.   
656 
 
657 
At or after the 24 week visit, if all of the following criteria are met, the eye has met failure 
658 
criteria and treatment is up to investigator discretion 
659 
• OCT CSF thickness ≥ eligibility machine and gender specific threshold 
660 
 Zeiss Cirrus CSF: ≥290µm in women or ≥ 305µm in men 
661 
 Heidelberg Spectralis CSF: ≥ 305µm in women or ≥320µm in men 
662 
• VA is 10 or more letters worse than baseline at 2 consecutive visits 
663 
• DME present on clinical exam that the investigator believes is the cause of the visual 
664 
acuity loss 
665 
• There has been no improvement in VA (>5 letters) or OCT ( >10% OCT CSF thickness) 
666 
since either of the last two injections  
667 
 
668 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
4-4 
For eyes in the bevacizumab + deferred aflibercept group, the failure criteria cannot be applied 
669 
prior to the eye switching to aflibercept and receiving 3 monthly injections of aflibercept.  
670 
  
671 
4.3.4 Laser for DME 
672 
Treatment with focal/grid laser will not be permitted in the study eye(s) during the study unless 
673 
failure criteria are met.  If the failure criteria listed in 4.3.3 is met, treatment (including laser) is 
674 
up to investigator discretion.
675 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
5-1 
CHAPTER 5                                                                                            
676 
MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
677 
 
678 
5.1 Endophthalmitis  
679 
Diagnosis and treatment of endophthalmitis is based on investigator’s judgment.  Obtaining 
680 
cultures of vitreous and aqueous fluid is highly recommended prior to initiating antibiotic 
681 
treatment for presumed endophthalmitis.  
682 
  
683 
5.2 Use of Intravitreous Anti-VEGF for Conditions Other than DME in the Study Eye 
684 
Treatment for conditions other than DME is at investigator discretion.  If a participant develops a 
685 
diabetic eye disease, e.g. proliferative diabetic retinopathy in the study eye, for which the 
686 
investigator intends to administer anti-VEGF treatment, it is recommended that the eye is treated 
687 
with the same anti-VEGF drug being given for DME. 
688 
 
689 
5.3 Treatment in Non-study Eye 
690 
Treatment of PDR or DME in the non-study eye is at investigator discretion.  
691 
 
692 
5.4 Diabetes Management 
693 
Diabetes management is left to the study participant’s medical care provider. 
694 
 
695 
5.5 Study Participant Withdrawal and Losses to Follow-up 
696 
A study participant has the right to withdraw from the study at any time.  If s/he is considering 
697 
withdrawal from the study, the principal investigator should personally speak to the individual 
698 
about the reasons, and every effort should be made to accommodate the study participant to 
699 
allow continued participation if possible.   
700 
 
701 
The goal for the study is to have as few losses to follow-up as possible.  The Coordinating Center 
702 
will assist in the tracking of study participants who cannot be contacted by the site.  The 
703 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 
704 
 
705 
Study participants who withdraw will be asked to have a final closeout visit at which the testing 
706 
described for the annual study visits will be performed.  Study participants who have an adverse 
707 
event attributable to a study treatment or procedure will be asked to continue in follow-up until 
708 
the adverse event has resolved or stabilized. 
709 
 
710 
Study participants who withdraw or are determined to have been ineligible post-randomization 
711 
will not be replaced. 
712 
 
713 
5.6 Discontinuation of Study 
714 
The study may be discontinued by the DRCR.net Executive Committee (with approval of the 
715 
Data and Safety Monitoring Committee) prior to the preplanned completion of follow-up for all 
716 
study participants. 
717 
 
718 
5.7 Contact Information Provided to the Coordinating Center 
719 
The Coordinating Center will be provided with contact information for each study participant.  
720 
Permission to obtain such information will be included in the Informed Consent Form.  The 
721 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
5-2 
contact information will be maintained in a secure database and will be maintained separately from 
722 
the study data. 
723 
 
724 
Phone contact from the Coordinating Center may be made with each study participant in the first 
725 
month after enrollment, and approximately every six months thereafter.  Additional phone 
726 
contacts or mailings from the Coordinating Center will be made to facilitate the scheduling of the 
727 
study participant for follow-up visits.  A study participant-oriented newsletter may be sent twice 
728 
a year.  A study logo item may be sent once a year.    
729 
 
730 
Study participants will be provided with a summary of the study results in a newsletter format 
731 
after completion of the study by all study participants.  
732 
  
733 
5.8 Study Participant Reimbursement 
734 
The study will be providing the study participant with a $25 merchandise or money card per 
735 
completed non-annual study visit and $100 in merchandise or money cards per completed annual 
736 
visit.  Additional travel expenses will be paid in select cases for study participants with higher 
737 
expenses.  
738 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
6-1 
CHAPTER 6                                                                                            
739 
ADVERSE EVENTS 
740 
6.1 Definition 
741 
An adverse event is any untoward medical occurrence in a study participant, irrespective of 
742 
whether or not the event is considered treatment-related.  An adverse event can therefore be any 
743 
unfavorable and unintended sign (including an abnormal lab finding), symptom or disease 
744 
temporally associated with the use of the treatment, whether or not related to the treatment. This 
745 
includes preexisting medical conditions (other than the condition being studied) judged by the 
746 
investigator to have worsened in severity or frequency or changed in character. 
747 
 
748 
6.2 
Recording of Adverse Events 
749 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
750 
events or untoward findings.  The first concern will be the safety of the study participant, and 
751 
appropriate medical intervention will be made. 
752 
 
753 
All adverse events whether volunteered by the subject, discovered by study personnel during 
754 
questioning, or detected through physical examination, laboratory test, or other means will be 
755 
reported on an adverse event form online.  Each adverse event form is reviewed by the 
756 
Coordinating Center to verify the coding and the reporting that is required.      
757 
 
758 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
759 
by determining if there is a reasonable possibility that the adverse event may have been caused 
760 
by the treatment. 
761 
 
762 
To ensure consistency of adverse event causality assessments, investigators should apply the 
763 
following general guideline when determining whether an adverse event is related: 
764 
 
765 
Yes 
766 
There is a plausible temporal relationship between the onset of the adverse event and 
767 
administration of the study treatment, and the adverse event cannot be readily explained by the 
768 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event 
769 
follows a known pattern of response to the study treatment; and/or the adverse event abates or 
770 
resolves upon discontinuation of the study treatment or dose reduction and, if applicable, 
771 
reappears upon re-challenge. 
772 
 
773 
No 
774 
Evidence exists that the adverse event has an etiology other than the study treatment (e.g., 
775 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
776 
medication); and/or the adverse event has no plausible temporal relationship to study treatment 
777 
administration (e.g., cancer diagnosed 2 days after first dose of study drug).    
778 
 
779 
The intensity of adverse events will be rated on a three-point scale:  (1) mild, (2) moderate, or (3) 
780 
severe.  It is emphasized that the term severe is a measure of intensity:  thus, a severe adverse 
781 
event is not necessarily serious.  For example, itching for several days may be rated as severe, 
782 
but may not be clinically serious. 
783 
 
784 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
6-2 
Adverse events will be coded using the MedDRA dictionary.  
785 
 
786 
Definitions of relationship and intensity are listed on the DRCR.net website data entry form.   
787 
 
788 
Adverse events that continue after the study participant’s discontinuation or completion of the 
789 
study will be followed until their medical outcome is determined or until no further change in the 
790 
condition is expected.   
791 
 
792 
6.3 
Reporting Serious or Unexpected Adverse Events 
793 
A serious adverse event is any untoward occurrence that: 
794 
• Results in death 
795 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
796 
become life-threatening, is not necessarily considered a serious adverse event) 
797 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
798 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
799 
to conduct normal life functions (sight threatening)  
800 
• Is a congenital anomaly/birth defect 
801 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
802 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
803 
the outcomes listed above) 
804 
 
805 
Unexpected adverse events are those that are not identified in nature, severity, or frequency in 
806 
the current Clinical Investigator’s Brochure, protocol, or informed consent form. 
807 
 
808 
Serious or unexpected adverse events must be reported to the Coordinating Center immediately 
809 
via completion of the online serious adverse event form. 
810 
 
811 
The Coordinating Center will notify all participating investigators of any adverse event that is 
812 
both serious and unexpected.  Notification will be made within 10 days after the Coordinating 
813 
Center becomes aware of the event.   
814 
 
815 
Each principal investigator is responsible for informing his/her IRB of serious study-related 
816 
adverse events and abiding by any other reporting requirements specific to their IRB.  
817 
 
818 
6.4 
Data and Safety Monitoring Committee Review of Adverse Events 
819 
A Data and Safety Monitoring Committee (DSMC) will advise the Coordinating Center 
820 
regarding the protocol, template informed consent form, and substantive amendments and will 
821 
provide independent monitoring of adverse events. Cumulative adverse event data are semi-
822 
annually tabulated for review by the DSMC.  Following each DSMC data review, a summary 
823 
will be provided to institutional review boards.  A list of specific adverse events to be reported to 
824 
the DSMC expeditiously, if applicable, will be compiled and included as part of the DSMC 
825 
Standard Operating Procedures document. 
826 
 
827 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
6-3 
6.5 
Risks 
828 
6.5.1 Potential Adverse Effects of Study Drugs 
829 
6.5.1.1 Aflibercept 
830 
The most common adverse reactions (≥5%) reported in patients receiving aflibercept were 
831 
conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and 
832 
vitreous detachment.   
833 
 
834 
Serious adverse reactions related to the injection procedure have occurred in <0.1% of 
835 
intravitreous injections with aflibercept including endophthalmitis and retinal detachment. 
836 
 
837 
The DA VINCI study, a phase II study evaluating aflibercept for treatment of DME, reported 
838 
common adverse events that were consistent with those previously seen with intravitreous 
839 
injections.  Over one year of follow-up, two cases of endophthalmitis and one case of uveitis 
840 
occurred (all in aflibercept treatment groups).  Seven deaths (4.0%) occurred in the groups 
841 
randomized to aflibercept treatment as compared with 1 (2.3%) in the group treated with laser.  
842 
Myocardial infarction or cerebrovascular accident occurred in 6 (3.4%) participants treated with 
843 
aflibercept as compared with 1 (2.3%) participant treated with laser alone.15  Percentages of 
844 
study participants that experienced events meeting APTC criteria were 5.1% (N = 9) in the 
845 
combined aflibercept groups and 4.5% (N = 2) in the laser group.16  
846 
  
847 
The DRCR.net Protocol T study assessed ocular and systemic adverse events in eyes with center-
848 
involved DME treated with aflibercept over 1 year.17  In the aflibercept-treated study eyes, there 
849 
were no cases of endophthalmitis and 2 cases of ocular inflammation. Non-study eyes treated 
850 
with aflibercept had 1 case of endophthalmitis and 3 cases of ocular inflammation. Systemic 
851 
adverse events were infrequent with only 6 APTC events (4 nonfatal myocardial infarctions, 2 
852 
deaths from a potential vascular cause or unknown cause, 6% of participants) over the 1 year 
853 
period in the aflibercept group. 
854 
 
855 
Additional safety data were published from phase III studies VISTA and VIVID, which included 
856 
872 eyes with DME with central involvement that received either intravitreous aﬂibercept every 
857 
4 weeks, intravitreous aflibercept every 8 weeks after 5 initial monthly doses, or macular laser 
858 
photocoagulation.  Overall, the incidences of ocular and non-ocular adverse events were similar 
859 
across treatment groups at 52 weeks.18  The incidence of APTC-defined thromboembolic events 
860 
was similar across treatment groups.  There were no reported cases of endophthalmitis, and 
861 
intraocular inflammation occurred in less than 1% of injections.  Through 100 weeks, an 
862 
integrated safety analysis found that the most frequent serious ocular adverse event was cataract 
863 
(2.4% and 1.0% in the aflibercept groups compared with 0.3% in the laser group).19   
864 
 
865 
There may be side effects and discomforts that are not yet known.   
866 
 
867 
6.5.1.2 Bevacizumab 
868 
In a meta-analysis performed by Genentech, Inc on all clinical trial results using intravenously 
869 
administered bevacizumab (usually dose 5 mg/kg every 14 days), it was found that study 
870 
participants were at an increased risk for certain adverse events, some of which were potentially 
871 
fatal.  These included wound healing complications, bowel perforation, hemorrhage, stroke, 
872 
myocardial infarction, hypertension, congestive heart failure, and proteinuria. Warnings and 
873 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
6-4 
precautions included in the bevacizumab package insert for intravenously administered drug fall 
874 
under the categories of gastrointestinal perforations, surgery and wound healing complications, 
875 
hemorrhage, non-gastrointestinal fistula formation and fistulae, arterial thromboembolic events, 
876 
venous thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, 
877 
proteinuria, infusion reactions, embryo-fetal toxicity and ovarian failure.20  
878 
 
879 
In contrast, available data suggest that intravitreally-administered bevacizumab in substantially 
880 
smaller doses (1.25 or 2.5 mg) appears to have a good safety profile with regard to ocular and 
881 
systemic adverse events. No increased rates of thromboembolic events or death in bevacizumab 
882 
versus control groups have been reported in smaller, prospective randomized studies including 
883 
the DRCR.net Protocol H or the BOLT study.21 Retrospective, observational data from larger 
884 
patient groups also does not appear to indicate an increased risk of ocular or systemic events with 
885 
intravitreal bevacizumab treatment. In 2006, an internet-based survey of 70 international sites 
886 
from 12 countries was reported that described outcomes after 7,113 injections given to 5,228 
887 
patients.  Rates were 0.21% or less for each category of doctor-reported adverse events, 
888 
including blood pressure elevation, transient ischemic attack, cerebrovascular accident, death, 
889 
endophthalmitis, retinal detachment, uveitis, or acute vision loss.22  The PACORES group 
890 
reported 12 month safety of intravitreal injections of 1.25 and 2.5 mg doses of bevacizumab 
891 
given for a variety of conditions in a large group of study participants including 548 patients with 
892 
diabetes.23  A total of 1,174 patients were followed for at least 1 year.  Systemic adverse events 
893 
were reported in 1.5% (N = 18), including elevated blood pressure in 0.6% (7), cerebrovascular 
894 
accidents in 0.5% (6), myocardial infarctions in 0.4% (5), iliac artery aneurysms in 0.2% (2), toe 
895 
amputations in 0.2% (2), and deaths in 0.4% (5) of patients.  The overall mortality rate of 
896 
diabetic patients in this study was low at 0.55% (3/548).  Ocular complication were reported as 
897 
bacterial endophthalmitis in 0.2% (7), traction retinal detachments in 0.2% (7), uveitis in 0.1% 
898 
(4), and a single case each of rhegmatogenous retinal detachment and vitreous hemorrhage.  
899 
Finally, when bevacizumab is used to treat DME it does not appear to have a worse safety profile 
900 
than other anti-VEGF agents.  In the DRCR.net Protocol T randomized trial of 660 participants, 
901 
Anti-Platelet Trialists’ Collaboration (APTC) events occurred in 5% with aflibercept, 8% with 
902 
bevacizumab, and 13 % with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 
903 
0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20).13  
904 
 
905 
Recently reported results from the CATT Research Group also suggest that intravitreal 
906 
bevacizumab is well tolerated.  At one year, four of 286 participants (1.4%) in the monthly 
907 
bevacizumab group had died and 11 of 300 participants (3.7%) in the bevacizumab given as 
908 
needed group had died.  Arteriothrombolic events occurred at a rate of 2.1% and 2.7% in the 
909 
monthly bevacizumab and as needed bevacizumab groups, respectively.  Venous thrombotic  
910 
events occurred at rates of 1.4% and 0.3% in the monthly bevacizumab and as needed 
911 
bevacizumab groups, respectively.  Endophthalmitis occurred after 0.07% of injections in 
912 
patients treated with bevacizumab. Although a higher rate of serious systemic adverse events was 
913 
present in the bevacizumab group as compared with the ranibizumab group, the excess events in 
914 
the bevacizumab group were primarily hospitalizations due to events not previously attributed to 
915 
anti-VEGF treatment.24 Differences in rates were largest for hospitalizations for infections (e.g., 
916 
pneumonia and urinary tract infections) and gastrointestinal disorders (e.g., hemorrhage and 
917 
nausea and vomiting). Two year follow-up safety data from the CATT study did not reveal 
918 
significant differences in rates of arterial thromboembolic events or death between bevacizumab 
919 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
6-5 
and ranibizumab treated participants.  Overall rates of serious adverse events, however, were 
920 
higher among bevacizumab-treated patients (39.9%) than ranibizumab-treated patients (31.7%), 
921 
with the greatest imbalance in gastrointestinal disorders not previously linked to anti-VEGF 
922 
therapy.25  In contrast,  at 1 year in the IVAN study, fewer arteriothrombotic events or heart 
923 
failure cases were seen in the bevacizumab treated group and there was no difference in the 
924 
percentage of patients experiencing serious adverse events between the bevacizumab and 
925 
ranibizumab treatment groupS.26   
926 
 
927 
As noted in the introduction, bevacizumab has been given intravitreally to several thousand 
928 
patients with age-related macular degeneration or diabetic macular edema in doses generally of 
929 
1.25 or 2.5 mg per injection (a fraction of the systemic dose).  There have not been consistent 
930 
reports suggestive of adverse systemic effects of the drug. This likely rules out serious systemic 
931 
events being common but does not rule out the possibility of such events occurring rarely.  
932 
Patients with diabetes are at increased risk for myocardial infarction, stroke, and renal disease.  
933 
Thus, if a study participant develops a cardiovascular or renal problems, it may be due to the 
934 
vascular effects of diabetes and other systemic factors and not related to bevacizumab.  It is 
935 
likely that only in a large study comparing adverse event rates between a bevacizumab-treated 
936 
group and a control group will it be possible to determine if there is an excess of systemic 
937 
adverse events with bevacizumab.  At this time, we believe the chances of a serious systemic 
938 
effect of bevacizumab are very small.  However, we cannot rule out this possibility and there is 
939 
evidence that systemic concentrations of VEGF may be reduced to an even greater extent with 
940 
intravitreal bevacizumab as compared with ranibizumab treatment.26  In view of the large 
941 
number of eyes treated with bevacizumab injections, it also seems unlikely that the drug has a 
942 
deleterious effect on the retina or other parts of the eye. 
943 
 
944 
6.5.2 Potential Adverse Effects of Intravitreous Injection 
945 
Rarely, the drugs used to anesthetize the eye before the study drug injections (proparacaine, 
946 
tetracaine, or xylocaine) can cause an allergic reaction, seizures, and an irregular heartbeat.   
947 
 
948 
Subconjunctival hemorrhage or floaters will commonly occur as a result of the intravitreous 
949 
injection.  Discomfort, redness, or itching lasting for a few days is also likely. 
950 
 
951 
Immediately following the injection, there may be elevation of intraocular pressure. It usually 
952 
returns to normal spontaneously, but may need to be treated with topical drugs or a 
953 
paracentesis to lower the pressure.  The likelihood of permanent loss of vision from elevated 
954 
intraocular pressure is less than 1%. 
955 
 
956 
As a result of the injection, endophthalmitis (infection in the eye) could develop.  If this occurs, it is 
957 
treated by intravitreous injection of antibiotics, but there is a risk of permanent loss of vision including 
958 
blindness.  The risk of endophthalmitis is less than 1%. 
959 
 
960 
As a result of the injection, a retinal detachment could occur.  If this occurs, surgery may be 
961 
needed to repair the retina.  The surgery is usually successful at reattaching the retina.  
962 
However, a retinal detachment can produce permanent loss of vision and even blindness.  The 
963 
risk of retinal detachment is less than 1%. 
964 
 
965 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
6-6 
The injection could cause a vitreous hemorrhage.  Usually the blood will resolve 
966 
spontaneously, but if not, surgery may be needed to remove the blood.  Although the surgery 
967 
usually successfully removes the blood, there is a small risk of permanent loss of vision and 
968 
even blindness.  The risk of having a vitreous hemorrhage due to the injection is less than 1%. 
969 
 
970 
6.5.3 Risks of Eye Examination and Tests 
971 
There is a rare risk of an allergic response to the topical medications used to anesthetize the eye 
972 
or dilate the pupil. Dilating drops rarely could cause an acute angle closure glaucoma attack, but 
973 
this is highly unlikely since the study participants in the study will have had their pupils dilated 
974 
many times previously.   
975 
 
976 
There are no known risks associated with OCT or fundus photographs.  The bright flashes used 
977 
to take the photographs may be annoying, but are not painful and cause no damage. 
978 
 
979 
For fluorescein angiography, both the skin and urine are expected to turn yellow/orange for up to 
980 
24 hours after the injection of fluorescein dye.  There is a small risk of discomfort or phlebitis at 
981 
the site of the injection.  Patients occasionally experience lightheadness or nausea after dye 
982 
injection which are usually transient and resolve after a few minutes without further intervention.  
983 
An allergic reaction to the dye used to do the fluorescein angiography imaging is rare.  A rash or 
984 
pruritus (itching) can develop, but true anaphylactic reactions are very rare.   
985 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
7-1 
CHAPTER 7                                                                                            
986 
STATISTICAL METHODS 
987 
 
988 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
989 
analysis plan will be written and finalized prior to any tabulation or analysis of study data.   
990 
 
991 
7.1 Primary Outcome 
992 
The sample size has been computed for the primary outcome, mean change in visual acuity over 
993 
two years, measured using area under the curve (AUC). 
994 
 
995 
7.2 Sample Size 
996 
7.2.1 Outcome Projections 
997 
Data from DRCR.net Protocol T was used to estimate visual acuity outcomes in the two groups.  
998 
Based on the switch criteria, it is estimated that approximately 58% of the bevacizumab group 
999 
will receive aflibercept during the 2 years of the trial.  It is anticipated that approximately half of 
1000 
these eyes will switch during the first 24 weeks of the trial, with the other half of the eyes that 
1001 
switch distributed across the remaining 18 months of the study. 
1002 
 
1003 
Projected group means and required sample sizes were estimated for various scenarios after 
1004 
switching. Figure 1 presents estimates of change in visual acuity over 2 years (AUC) assuming 
1005 
that switching to aflibercept increases visual acuity at each visit in the bevacizumab group from 
1006 
1 to 9 letters over what was observed in Protocol T. 
1007 
 
1008 
Figure 1. Change in visual acuity with aflibercept, bevacizumab, or bevacizumab assuming that 
1009 
after switch criteria are met the eye gains 1, 3, 5, 7, or 9 letters more than what was observed 
1010 
with bevacizumab alone in Protocol T. 
1011 
 
1012 
Weeks
Change in Visual Acuity Le
0
4
8
12
16
20
24
28
32
36
40
44
48
52
68
84
104
0
5
10
15
20
Aflibercept
Bevacizumab+9
Bevacizumab+7
Bevacizumab+5
Bevacizumab+3
Bevacizumab+1
Bevacizumab

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
7-2 
7.2.2 Sample Size Estimates 
1013 
Table 1 below shows sample size estimates under varying assumptions for the effect of the 
1014 
switch to aflibercept in bevacizumab eyes (for the primary outcome of change in visual acuity 
1015 
AUC over 2 years).  These calculations assume a Type I error rate of 4.9% (0.1% allocated for 
1016 
DSMC review), 90% power, and a two-sided test of superiority with a null hypothesis of no 
1017 
difference between groups. 
1018 
 
1019 
Table 1: Sample size calculations. 
1020 
 
Protocol T 
(Switch + 
0 letters) 
Switch + 
1 letter 
Switch + 
3 letters 
Switch + 
5 letters 
Switch + 
7 letters 
Switch + 
9 letters 
Mean Change in 
Visual Acuity AUC 
 
 
 
 
 
 
Aflibercept 
17.4 
17.4 
17.4 
17.4 
17.4 
17.4 
Bevacizumab + 
Deferred Aflibercept 
12.1 
12.5 
13.2 
13.9 
14.7 
15.4 
Difference 
5.3 
4.9 
4.2 
3.5 
2.7 
2.0 
Adjusted Standard 
Deviation* 
8.7 
8.7 
8.7 
8.7 
8.7 
8.7 
Total N 
116 
136 
184 
264 
442 
802 
*Adjusted for a correlation of 0.5 with baseline visual acuity. Standard deviation based on the Protocol T aflibercept 
1021 
group, which had a larger standard deviation than the bevacizumab group, making these estimates conservative. 
1022 
 
1023 
The final sample size was calculated with the following assumptions: 
1024 
 
1025 
• Mean change in visual acuity AUC in the aflibercept group = 17.4 letters 
1026 
• Mean change in visual acuity AUC in the bevacizumab + deferred aflibercept group = 
1027 
13.9 (assuming eyes that switch to aflibercept gain 5 letters more than they would have if 
1028 
the eye had remained on bevacizumab) 
1029 
• Treatment group difference = 3.5 letters; Adjusted standard deviation = 8.7 letters 
1030 
• Type I error rate = 4.9%; Power = 90% 
1031 
• 15% increase for expected lost to follow-up 
1032 
 
1033 
Based on the above assumptions, the total sample size is 312 participants (156 per treatment 
1034 
group). 
1035 
 
1036 
7.3 Primary Analysis Plan  
1037 
7.3.1 Principles for Analysis  
1038 
 
1039 
The primary analysis consists of a treatment group comparison of mean change in visual acuity 
1040 
AUC over 2 years adjusted for baseline visual acuity.  A linear mixed model with a random 
1041 
intercept term for participant will be used to control for correlations arising from participants 
1042 
contributing two study eyes to the analysis.  AUC will be calculated for each participant by the 
1043 
trapezoidal rule using the following formula: 
1044 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
7-3 
𝐴𝐴𝐴𝐴𝐴𝐴= ෍൬𝑉𝑉𝑖𝑖+ 𝑉𝑉𝑖𝑖+1
2
× (𝑑𝑑𝑖𝑖+1 −𝑑𝑑𝑖𝑖)൰
𝑛𝑛
𝑖𝑖=1
  
1045 
Where Vi is the change in visual acuity measured at the ith visit, di is the number of days between 
1046 
randomization and the ith visit, and n is the number of outcome visits included in the analysis.  
1047 
For presentation, AUC will be divided by the number of days between baseline and the nth visit 
1048 
so that the value shown will have units of letters rather than letter⋅days.  This statistic can then be 
1049 
interpreted as the average change in visual acuity over the time period between baseline and the 
1050 
nth visit. 
1051 
 
1052 
All 4-week visits through 52 weeks as well as the 104 week visit will be included in the 
1053 
calculation of AUC as these are common to both treatment groups.  Since visits can occur every 
1054 
4 to 16 weeks in year 2, depending upon disease progression, analysis windows will be defined 
1055 
around 68 and 84 weeks for the purposes of calculating AUC.  Thus, the visits to be included for 
1056 
calculation of the primary outcome are 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 68, 84, and 
1057 
104 weeks. 
1058 
 
1059 
The primary analysis is an “intent to treat analysis” that will include all randomized eyes 
1060 
according to treatment group assignment at randomization. Multiple imputation will be used to 
1061 
handle missing data.   
1062 
 
1063 
7.3.2 Sensitivity Analyses 
1064 
A sensitivity analysis using only observed data from eyes that complete the 104-week visit also 
1065 
will be conducted. If the analyses of imputed and observed data differ substantially, then 
1066 
exploratory analyses will be performed to evaluate factors that may have contributed to the 
1067 
differences. 
1068 
 
1069 
A per-protocol analysis will be conducted to estimate the treatment effect for each group among 
1070 
those not receiving any alternative treatment for DME (e.g., intravitreal corticosteroids). This 
1071 
analysis will include observed data from all randomized up to the time of alternative treatment 
1072 
for DME. Data collected after the alternative treatment will be set to missing prior to imputation. 
1073 
Imputation will otherwise be similar to the primary analysis.  
1074 
 
1075 
Imbalances between groups in important covariates are not expected to be of sufficient 
1076 
magnitude to produce confounding.  However, the presence of confounding will be evaluated 
1077 
using only observed data from eyes that complete the 104-week visit by including factors 
1078 
potentially associated with the outcome for which there is an imbalance between groups.  
1079 
 
1080 
7.3.3 Subgroup Analyses 
1081 
Pre-planned subgroup analyses, using observed data from eyes that complete the 104-week visit 
1082 
will be described in the Statistical Analysis Plan and will include analyses by prior treatment for 
1083 
DME, OCT CSF thickness, and baseline visual acuity. There are no data to suggest that the 
1084 
treatment effect will vary by gender or race/ethnicity.  However, both of these factors will be 
1085 
evaluated in exploratory analyses.   
1086 
 
1087 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
7-4 
7.3.4 Interim Analysis Plan  
1088 
There will be no formal interim analysis for efficacy or futility. 
1089 
 
1090 
7.4 Secondary Outcomes for Treatment Group Comparison 
1091 
The treatment groups will be compared on the following secondary outcomes of interest at the 52 
1092 
and 104-week visits: 
1093 
 
1094 
• 
Mean change in visual acuity from baseline (also compared at the 24-week visit)  
1095 
• 
Percentages of eyes with a gain (increase) or loss (decrease) of at least 10 or at least 15 
1096 
letters of visual acuity from baseline 
1097 
• 
Percentages of eyes with visual acuity 20/20 or greater, 20/40 or greater, and 20/200 or 
1098 
worse 
1099 
• 
Mean change in OCT central subfield thickness from baseline (also compared at the 24-
1100 
week visit) 
1101 
• 
Percentage of eyes with OCT central subfield thickness below the gender-specific 
1102 
spectral domain OCT equivalent of 250 µm on Zeiss Stratus OCT 
1103 
• 
Mean change in OCT retinal volume 
1104 
• 
Percentages of eyes with worsening or improvement of diabetic retinopathy on fundus 
1105 
photographs 
1106 
• 
Percentage of eyes receiving panretinal photocoagulation, vitrectomy, or occurrence of 
1107 
vitreous hemorrhage, traction retinal detachment, neovascularization of the iris, or 
1108 
neovascular glaucoma from proliferative diabetic retinopathy 
1109 
• 
Number of visits through 2 years  
1110 
• 
Number of injections 
1111 
• 
Percentage of eyes that met switch criteria by the 12, 24, 52, or 104-week visits 
1112 
(bevacizumab + deferred aflibercept group only) 
1113 
 
1114 
Binary outcomes will be analyzed using binomial regression with generalized estimation 
1115 
equations (GEE) to control for correlations arising from participants contributing two study eyes 
1116 
to the analysis.  If binomial regression fails to converge in one or more outcomes, then logistic 
1117 
regression with a random intercept for participant, conditional standardization, and the delta 
1118 
method (to estimate the risk difference)27 may be used instead for all binary outcomes.  Analyses 
1119 
will be adjusted for baseline measures where appropriate.  All model assumptions, including 
1120 
linearity, normality of residuals, and homoscedasticity, will be verified.  If model assumptions 
1121 
are not satisfied, then a transformation or a nonparametric analysis will be considered.  Methods 
1122 
for handling missing secondary outcome data will be specified in the Statistical Analysis Plan. 
1123 
 
1124 
7.5 Economic Analysis 
1125 
The purpose of the economic analysis is to compare the treatment groups with respect to cost. 
1126 
 
1127 
An incremental cost effectiveness ratio (ICER) will be calculated.  Data from the clinical trial on 
1128 
number of clinic visits completed, number of procedures performed (e.g., OCT, fundus 
1129 
photographs), and number of aflibercept and bevacizumab treatments will be used to estimate an 
1130 
average cost per patient for each treatment arm, using the Medicare Fee Schedule to estimate 
1131 
medical costs.   
1132 
 
1133 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
7-5 
For outcomes measured at the participant level, bilateral participants are non-informative with 
1134 
respect to the treatment comparison and will not be included in the analyses. 
1135 
 
1136 
7.6 Safety Analysis Plan 
1137 
Ocular adverse events will be tabulated separately for the two treatment groups.  The frequency 
1138 
of each event occurring at least once per eye will be calculated.  The percentage of eyes 
1139 
experiencing each outcome will be compared between treatment groups using Barnard’s 
1140 
unconditional exact test and considering the number of eyes in each treatment group as fixed. It 
1141 
is noted that this method does not adjust for the potential correlations arising from participants 
1142 
with two study eyes; however, given the low expected frequency of adverse events, and small 
1143 
proportion of bilateral subjects, the impact should be minimal. 
1144 
 
1145 
The following ocular adverse events are of primary interest:  
1146 
o Endophthalmitis 
1147 
o Retinal detachment  
1148 
o Traumatic cataract 
1149 
o Vitreous hemorrhage  
1150 
o Ocular inflammation  
1151 
o Intraocular pressure elevation 
1152 
o Neovascular glaucoma  
1153 
o Iris neovascularization  
1154 
 
1155 
Systemic adverse events will be reported in three groups: 1) unilateral participants randomized to 
1156 
bevacizumab + deferred aflibercept, 2) unilateral participants randomized to aflibercept, and 3) 
1157 
bilateral participants randomized to bevacizumab + deferred aflibercept in one eye and 
1158 
aflibercept in the other eye.  The frequency of each event occurring at least once per participant 
1159 
will be calculated.  The percentage of participants experiencing each outcome will compared 
1160 
with Fisher’s exact test.  If the overall test has P ≤ 0.05, then pairwise comparisons between 
1161 
groups also will be conducted using Fisher’s exact test without further adjustment for multiple 
1162 
comparisons.  
1163 
 
1164 
The following systemic adverse events are of primary interest: 
1165 
o Death 
1166 
o Serious adverse event (at least one) 
1167 
o Hospitalization (at least one) 
1168 
o Cardiovascular/cerebrovascular events according to Antiplatelet Trialists’ 
1169 
Collaboration (excerpted from BMJ Jan 8, 1994): 
1170 
 Non-fatal myocardial infarction 
1171 
 Non-fatal stroke (counted only if symptoms lasted at least 24 hours) 
1172 
 Death attributed to cardiac, cerebral, hemorrhagic, embolic, other vascular 
1173 
cause (does not need to be ischemic in origin), or unknown cause 
1174 
• Notes: Transient ischemic attacks, angina, and possible myocardial 
1175 
infarction or stroke are not counted. Nonfatal myocardial infarction or 
1176 
stroke require that the participant be alive at the end of the study.  If 
1177 
not, only the death is counted. 
1178 
 
1179 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
7-6 
o Secondary systemic adverse events of interest: 
1180 
 For each MedDRA system organ class, percentage of participants with at least 
1181 
one event  
1182 
 
1183 
A tabulation of all study eye ocular, non-study eye ocular, and systemic adverse events will be 
1184 
tabulated according to treatment group as described above. 
1185 
 
1186 
7.7 Additional Tabulations and Analyses 
1187 
The following will be tabulated according to treatment group: 
1188 
 
1189 
1) Baseline demographic and clinical characteristics 
1190 
2) Visit completion rate 
1191 
3) Treatment adherence 
1192 
 
1193 
7.8 
Multiple Testing 
1194 
 
1195 
The primary analysis will be conducted at alpha of 0.05. If the primary analysis demonstrates a 
1196 
significant treatment group difference, then mean change in visual acuity from baseline at 104 
1197 
weeks and mean change in OCT central subfield thickness from baseline at 104 weeks will be 
1198 
tested as secondary outcomes. The Holm method will be used to provide strong control of alpha 
1199 
at 0.05.28 If the primary analysis fails to show a significant difference, then outcomes will be 
1200 
described with summary statistics, model-based point estimates, and between-group 95% 
1201 
confidence intervals without P values. This approach controls the family-wise error rate at 5%. 
1202 
 
1203 
There will be no formal adjustment for multiplicity in sensitivity, subgroup, or safety analyses. 
1204 
For exploratory subgroup analyses, the number of significant results expected by chance given 
1205 
the number of comparisons will be noted. 
1206 

 
Aflibercept Switch Protocol 4.0 6-28-21 
 
 
 
 
 
 
8-1 
CHAPTER 8                                                                                            
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REFERENCES 
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