Conditions: Diabetic Macular Edema
Keywords: Diabetic Macular Edema anti-vascular endothelial growth factor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 270
Healthy volunteers: no

Brief summary:
Both aflibercept and bevacizumab have been shown to improve vision in eyes with DME. In eyes with DME and at least moderate vision loss, both aflibercept and bevacizumab were also shown to be successful in many eyes. However, aflibercept was shown to be more effective at improving vision, on average, at 1 year and at 2 years. Due to the large cost difference between the two drugs, many clinicians and patients are choosing to initiate treatment with bevacizumab and then switch to aflibercept depending on the eye's response to bevacizumab treatment. However, there is no scientific evidence that this treatment strategy is as effective at improving vision as initiating treatment with aflibercept. Patients and clinicians do not know if this approach ultimately has deleterious effects on visual acuity. If starting with aflibercept is not better than starting with bevacizumab and switching to aflibercept if needed, the potential cost savings to future patients and the health care system would be substantial. However, if starting with aflibercept is better, then patients, clinicians, and health care providers can make informed decisions for how to best treat patients with DME and at least moderate vision loss.

Study Objectives To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab + deferred aflibercept if needed in eyes with CI DME and moderate vision loss

Detailed description:

Arms:
arm 1: 2.0 mg intravitreous aflibercept arm 2: 1.25 mg intravitreous bevacizumab + deferred intravitreous 2.0 mg aflibercept if eye meets switch criteria

Interventions: intervention 1: intravitreous aflibercept intervention 2: Bevacizumab + Deferred Aflibercept Group
Intervention descriptions: intervention 1: Intravitreous aflibercept injection is made by Regeneron Pharmaceuticals, Inc. and is approved by the FDA for the treatment of neovascular age-related macular degeneration, macular edema due to central retinal vein occlusion, macular edema due to branch retinal vein occlusion, diabetic macular edema, and diabetic retinopathy in eyes with diabetic macular edema.

Study eyes assigned to receive aflibercept will receive a dose of 2.0 mg in 0.05 cc. Aflibercept will be obtained commercially by the clinical site. The physical, chemical, and pharmaceutical properties and formulation of aflibercept are provided in the Package Insert.

Intravitreous Injection Technique The injection is preceded by a povidone iodine prep of the conjunctiva. In general, topical antibiotics in the pre-, peri-, or post-injection period should not be used.

The injection will be performed using sterile technique intervention 2: Bevacizumab is made by Genentech, Inc. and is approved by the FDA for the treatment of metastatic colorectal cancer as well as the treatment of non-squamous non-small cell lung cancer, glioblastoma, and metastatic renal cell carcinoma.

Study eyes assigned to receive bevacizumab will receive a dose of 1.25 mg provided by a single compounding pharmacy identified by the Network and distributed by the Network. The volume of the injections will be 0.05 cc.

Intravitreous injection technique: The injection is preceded by a povidone iodine prep of the conjunctiva. In general, topical antibiotics in the pre-, peri-, or post-injection period should not be used.

The injection will be performed using a sterile technique.

Protocol document:
ICF_000.pdf: 
NCT03321513 
Randomized trial of intravitreous aflibercept versus intravitreous bevacizumab 
+deferred aflibercept for treatment of central-involved diabetic macular edema 
(Protocol AC) 
20 September 2018 
 


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 1 of 17
Today, you are being asked to take part in this research study because you have swelling in the 
1
center of your retina (the light-sensitive lining inside of the back of the eye) from diabetes.  This 
2
condition is called diabetic macular edema or “DME”. The goal of this research is to get new 
3
knowledge that may help other people, but it is not the same as treatment of DME. We want to 
4
find what works best for treating your and others with this condtion. 
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6
Your study doctor will be talking with you about this research and this document.  Please take 
7
your time deciding whether you want to participate in this research and please carefully read this 
8
document. 
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Before you decide to take part in this research study, we encourage you to speak with friends and 
11
family members about it.  If you do not understand all the information, please ask your study 
12
doctor or nurse to explain.  If you are taking part in another study, please tell us right away.
13
14
NON-PARTICIPATION STATEMENT
15
Participation in this study is voluntary and you must agree to take part. If you decide to stop 
16
participation in this research, that will happen immediately. No penalty or loss of medical care 
17
will result from your decision. While the study is occurring you may continue to receive medical 
18
care not related to this study.
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WHO IS DOING THE STUDY
21
This study is being conducted by the Diabetic Retinopathy Clinical Research Network 
22
(DRCR.net), which is a group of clinical sites dedicated to research of diabetic retinopathy and 
23
its associated conditions.
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Your study doctor(s) and/or clinic staff will carry out this study. Their names are listed on the 
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Cover Page of this form. The National Eye Institute (NEI), one of the National Institutes of 
27
Health of the U.S. Public Health Service, a part of the federal government is paying for this 
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research.    This funding will be used by the Jaeb Center for Health Research to organize the 
29
study and pay your study doctor(s).  The Jaeb Center for Health Research is the Coordinating 
30
Center for this study.
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WHY ARE WE DOING THIS STUDY?
33
Diabetic macular edema (DME) is the term used for swelling in the small central part of the 
34
retina.  The retina is the light-sensitive tissue which lines the back of the eye. The macula or 
35
center part of the retina is used for sharp, straight-ahead vision.  It is nourished by blood vessels 
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that may become affected by diabetes.  The blood vessels are weakened by diabetes and may 
37
become leaky.  This causes the retina to become thickened or swollen.  Swelling of the central 
38
part of the retina can lead to decreased vision.  
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40


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 2 of 17
HOW IS DME TREATED? 
41
DME can be treated with repeated injections of drug into the eye to try to make the swelling of 
42
the retina go away. The drug is used to block or decrease a substance called vascular endothelial 
43
growth factor (it is an “anti-VEGF drug”).  There are currently three different anti-VEGF drugs 
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that are used as injections in eyes.  However, only the following two, Avastin® and Eylea®, are 
45
being used in this study.
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Avastin is approved by the Food and Drug Administration (FDA) for the treatment of cancer. It 
48
is not approved for treating DME.  It needs to be specially prepared for injecting into the eye.  
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However, studies have shown that Avastin injections can be beneficial for DME.  Therefore, 
50
many doctors have been injecting it into the eye to treat DME.  
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Eylea is the other type of anti-VEGF drug being used in this study and was made for injection 
53
into the eye.  It has been approved by the FDA for treatment of DME.  
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55
A recent survey of eye doctors estimated that about 60% of the injections in the U.S. for DME 
56
are given with Avastin, about 25% of the injections are given with Eylea, and about 15% with a 
57
third anti-VEGF drug called Lucentis®.  
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DOES ONE OF THE TREATMENTS WORK BETTER?
60
Recently, a study was done by the DRCR.net comparing Avastin and Eylea for eyes with DME.  
61
The study showed that both drugs work very well to reduce DME and improve visual acuity.   
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However, when the starting vision was moderately or severely reduced (20/50 or worse), Eylea 
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was better on average than Avastin at improving vision. 
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Even though Eylea was better on average, most people who received Avastin still had very good 
66
results.  After 2 years, about half (50%) of eyes receiving Avastin injections improved at least 3 
67
lines on the vision chart, compared with slightly more than half (58%) with Eylea.  An example 
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of improving by 3 lines on a vision chart would be if vision started at 20/50 and improved to 
69
20/25 or better.      
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SO WHY IS AVASTIN BEING USED TO TREAT DME MORE OFTEN THAN EYLEA? 
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Avastin is much less expensive than Eylea.  Avastin costs about $60 per injection compared with 
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about $1,800 per injection for Eylea.  Most patients will receive about 9 injections within the 
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first year of treatment and 4 injections in the second year.    The out-of-pocket cost to each 
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patient may be different depending on his/her insurance.  In some cases the patient may be 
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responsible for the entire cost of the drug, or insurance may require the patient to pay some 
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portion of the drug cost.  For example, if insurance requires the patient to pay 20% coinsurance, 
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the cost of the more expensive drug would be $360 per injection ($3,240 for the first year if 9 
79


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 3 of 17
injections are needed).  Even if the patient was responsible for the full cost of Avastin, it would 
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only cost about $540 for the first year if 9 injections are needed.  
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Because of the large difference in cost between the two drugs, many patients and clinicians are 
83
choosing to start treatment with Avastin and then switch to Eylea if vision stops improving and is 
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still decreased.  In some cases insurance companies are requesting that clinicians start treatment 
85
with Avastin because of the large cost difference.  
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WHAT IS THE PURPOSE OF THIS STUDY?
88
The purpose of this study is to find out if starting with Eylea has better results than starting with 
89
the less expensive drug, Avastin, and only switching to Eylea if needed.  If starting with Eylea is 
90
not better than starting with Avastin and switching to Eylea if needed, the potential cost savings 
91
to future patients and the health care system would be substantial.  However, if starting with 
92
Eylea is better, then patients, clinicians, and health care providers can make informed decisions 
93
for how to best treat patients with DME and at least moderate vision loss.  
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95
If you agree to take part in the study, you will have a 50:50 chance of receiving Eylea from the 
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start or receiving Avastin to start and switching to Eylea only if needed.  If you start with 
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Avastin, you initially will get an injection once a month for 3 months.  At 3 months or anytime 
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thereafter, if there has not been enough improvement in your vision and DME, you will be 
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switched to Eylea.  We expect about half of the eyes to switch to Eylea during the study.  The 
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entire study will last 2 years.       
101
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To summarize, both Eylea and Avastin have been shown to work for DME treatment.  However, 
103
in patients with vision and DME like yours, Eylea has been shown to work better on average.  It 
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is possible that starting with Eylea will have similar results to starting with Avastin and 
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switching to Eylea only if needed.  By doing this study, we hope to be able to provide additional 
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information for people with DME on how these two approaches compare.
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HOW MANY PEOPLE ARE WE EXPECTING TAKE PART IN THIS STUDY?
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We expect about 260 people will take part in this study at 80 different medical locations. 
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WHO CAN PARTICIPATE IN THIS STUDY?
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To take part in this study, you must be or have the following: 
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•
Diabetic macular edema in at least one eye that meets certain criteria
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•
Visual acuity of 20/50 or worse
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116
There are some exclusion criteria that may prevent you from being part of the study.  Your study 
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doctor will check if you have these or not. 
118
•
You are on dialysis or have had a kidney transplant.
119


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 4 of 17
•
Your blood pressure is greater than 180/110 (systolic above 180 OR diastolic above 110).
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•
Pregnant or breastfeeding women cannot participate.  If you are a woman who has the 
121
potential to get pregnant we may do a urine test to be sure you are not pregnant before 
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you enter the study. 
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•
You have taken part in a study in which you received treatment within the last 30 days.
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To be eligible to be in this study, you must be willing to comply with all study procedures and 
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tests.  You must also agree to be present at the clinic for all scheduled visits.  If you are planning 
127
to move out of this area within the next two years and want to be in this study, please let us 
128
know.  We will see if we can arrange for you to still be in the study.
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WHAT HAPPENS IF I AGREE TO TAKE PART IN THIS STUDY?
131
First, testing will be done to find out if you are eligible for the study.  If you are eligible, we will 
132
explain the study to you and you will watch a short video (about 5 minutes).   Then you will 
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answer a few questions to show you understand the study.  You will need to sign this form if you 
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want to take part in the study.
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At least one eye must be eligible for you to enter the study.  However, both eyes can be entered 
137
into the study if both are eligible at the time of enrollment.  We call any eye that enters the study 
138
a “study eye”.  
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Then we will determine what treatment you will receive.  You will receive either Eylea from the 
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start or Avastin to start and switch to Eylea if needed.  A computer program will randomly pick 
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the treatment approach that will be used, with each treatment equally likely to be picked.  If you 
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have two study eyes, one eye will randomly be picked to receive Eylea from the start and the 
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other eye will receive Avastin from the start.  You will not be told which drug was selected for 
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your eye.  
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The study will last two years.  During that time, your visit schedule and treatment will vary.  All 
148
of this will be explained in more detail below.
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A. Screening for the Study
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We will ask you questions about your medical history and previous eye problems and treatment.  
152
Then, some tests will need to be completed, if they have not already been done, to find out if you 
153
are eligible for the study.  The tests include:
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155
1. Eye Exam
156
•
The eye exam will include measurement of your visual acuity (the ability to read 
157
letters on the vision chart). The pressure in your eye will be measured.  After drops 
158
have been placed in your eye to dilate your pupil the doctor will study your retina 
159


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 5 of 17
with an ophthalmoscope (an instrument with a strong light and a magnifying lens).  
160
The eye exam will be completed on both eyes.
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162
2. Optical Coherence Tomography 
163
•
Optical coherence tomography (referred to as OCT) uses a dim beam of light to 
164
measure the thickness of the retina.  During the study, OCT will be used to find out 
165
if the retinal swelling is getting worse, better, or staying the same.  You will look 
166
into a machine at a pattern of flashing and rotating red lights. 
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168
3. Photographs of the Retina
169
•
A special camera will be used to take photographs of your retina (referred to as 
170
fundus photographs) after drops have been placed in your eyes to dilate your pupil.  
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172
4. Measurement of Blood Pressure
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• Your blood pressure will be checked with a cuff that is placed on one of your arms.
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175
5. Laboratory Tests
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•
A blood test called HbA1c will be done to see how well your diabetes is controlled. 
177
Less than 3 teaspoons (15 mL) will be taken for HbA1c testing. If you have had this 
178
test recently, it may not need to be repeated.  
179
•
If there is any chance that you might be pregnant, a pregnancy test will also be done. 
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181
If the tests show that you are not eligible for the study or you decide not to take part, the eye 
182
doctor will discuss your options for treatment of your DME.  Whatever treatment is chosen, the 
183
results will not be part of the study.
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B. Study Treatments
186
If at least one of your eyes is eligible for the study and you sign this form, a computer program 
187
will determine what treatment will be received. This will be determined by chance similar to 
188
flipping a coin. There are two possible treatment groups:
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1. Group A: Eylea injections
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2. Group B: Avastin injections with deferred Eylea injections if needed 
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If you have one study eye, there is a 50:50 chance of the eye being in group A or group B.  If you 
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have two study eyes, one eye will be selected by chance for group A and the other eye for group 
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B. You will not know which treatment you are getting. 
196
  
197
The injection procedure is the same for both of the drugs.  To prepare for the injection, anesthetic 
198
(numbing) eye drops and eye drops to dilate your pupil will be placed on the surface of your eye.  
199


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 6 of 17
An antiseptic solution will be used to reduce the chance of infection.  The eye doctor may decide 
200
that you should also have an anesthetic injection under the surface of your eye.  After the 
201
preparation is complete, the Eylea or Avastin injection will be given.  The amount of drug that 
202
will be injected into your eye each time is less than the amount of liquid in 1 drop from a 
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medicine dropper.  After the injection, you will stay in the eye clinic until your doctor believes it 
204
is safe for you to leave.  
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C. Follow-Up Visits
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During the first year, you will have follow-up visits every 4 weeks.  During the second year, you 
208
will have follow-up visits every 4 weeks as long as you need monthly injections.  The frequency 
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of injections can often be decreased and if that happens you will have follow-up visits either 8 
210
weeks, or 16 weeks apart, depending on how your eye is doing.  At the end of each visit, your
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doctor will inform you of the timing of your next appointment.    You will also have a follow-up 
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visit at 2 years.  
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The testing at each of the visits includes the following:
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•
Visual acuity testing of both eyes
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•
Eye exam of the study eye (and both eyes at the one-year and two-year visits)
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•
OCT of the study eye 
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•
Photographs of the retina of the study eye (at the one-year and two-year visits only)
219
•
Blood pressure (at the one-year and two-year visits only)
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•
Laboratory test of HbA1c (at the one-year and two-year visits only)
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222
The eye doctor may decide you need to be seen more often or need more testing as part of 
223
standard care depending on how you are doing. 
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D. Treatment During Follow-Up
226
Injections During Follow-Up
227
At the enrollment visit and then again at the 4-week visit the study eye will receive an injection 
228
of Eylea or Avastin.  At and after the 8 week visit, the eye doctor will determine if another 
229
injection should be given.  This will be based on whether or not your vision and/or DME have 
230
changed.  After 8 weeks, if your vision and DME are not changing, monthly injections may no 
231
longer be necessary.    
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Switch from Avastin to Eylea
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If your study eye is selected to receive Avastin injections from the start, you may switch from 
235
Avastin injections to Eylea injections if certain criteria is met. At or after the 12 week visit, if 
236
your vision and DME are not improving over the previous two visits, your eye may receive 
237
Eylea.
238
239


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 7 of 17
In the table below you will find what will be done at each visit.
240
Visit
Initial Visit
1 and 2 
year visit
All other 
study visits
E-ETDRS best corrected visual 
acuity 
X
X
X
OCT  
X
X
X
Eye Exam
X
X
X
Fundus Photography  
X
X
Blood pressure
X
X
Hemoglobin A1c 
X
X
241
ARE THERE RISKS IN THIS STUDY?
242
If you decide to take part in the study, you will be at risk for the side effects listed below.  We 
243
encourage you to discuss these with your study doctor, your primary care provider, or another 
244
health care professional.  If a treatment or procedure has increased risks because it was not done 
245
according to study procedures due to error, you will be informed, and the necessary steps will be 
246
taken to care for you.
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248
Risks related to your normal medical care are not listed in this form.  We encourage you to 
249
discuss these with your study doctor, your primary care provider, or another health care 
250
professional.  
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252
There may be additional risks associated with the drug and/or with the administration method 
253
that are not known at this time.  If we become aware of any new risks, you will be told about 
254
them.  You will be able to decide if you want to continue to receive the study drug.
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256
For an eye with DME and decreased vision like yours we know that Eylea on average 
257
works better than Avastin.  It is possible that by starting with Avastin and switching to 
258
Eylea if needed you may not gain as much vision if you are not treated with Eylea initially.  
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260
A. Risks of Injections
261
Injections may cause none, some, or all of the below side-effects.
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263
1.
Risks Related to the Injection Procedure
264


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 8 of 17
•
It is unlikely that the drugs used to numb your eye before the study drug injections 
265
(proparacaine, tetracaine, or xylocaine) will cause any problems.  However, in rare 
266
instances, these drugs can cause an allergic reaction, seizures, and an irregular heartbeat.  
267
A serious allergic reaction occurs in less than 1 in 100,000.  Your doctor will monitor any 
268
effects these drugs may cause and treat them as necessary.  In addition to topical numbing 
269
drops your doctor may also give you a tiny injection of xylocaine to numb your eye 
270
before the study drug injection is given.  You may feel a temporary stinging sensation 
271
from the xylocaine injection.  If an injection is given, in very rare instances the injection 
272
can cause damage to your eyeball, damage to the optic nerve, or double vision lasting up 
273
to 24 hours or more.  Once your eye feels numb, you may still be able to feel touch or 
274
pressure within your eye, but you should not be able to feel pain.  Sensation usually 
275
returns within two hours.
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277
2. Risks Related to the Anti-VEGF Injection Procedure (but not the drug itself)
278
More common:
279
•
You may have pain, redness, discharge, irritation, increased tearing, itching, or a foreign 
280
body sensation in the eye for a few days after the injection.
281
282
•
After an injection, you may see spots in your vision (floaters). The spots may be more 
283
noticeable certain ways you look or with certain lighting.  They usually do not affect your 
284
vision.  The spots usually go away after a few days or weeks.
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286
•
You may experience bleeding in the clear layer of tissue covering the white of the eye 
287
and inner eyelid or inflammation of the eyelid. 
288
289
Less common:
290
•
In rare cases, you may experience temporary drooping of the eyelid lasting up to 24 
291
hours. In very rare cases the eyelid may droop indefinitely. In such rare cases, surgery on 
292
the eyelid may be the only treatment to correct the drooping. The surgical procedure is 
293
typically successful, but in some cases may not work, and the procedure is accompanied 
294
by other risks to the eyelid and/or vision.
295
296
•
The injection or drug could cause an increase in the pressure of the eye right after the 
297
injection.  The risk of developing an increase in eye pressure is less than 10 in 100.  If 
298
this happens, eye drops may be given to lower the pressure.  Your chance of permanently 
299
losing vision is much less than 1 in 100.
300
301
•
The injection could cause haziness in the lens of the eye.  This is called cataract.  The 
302
lens is involved in focusing so that the eye can see clearly.  The haziness causes vision to 
303
be blurred.  The risk of developing a cataract from the injection is much less than 1 in 
304


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 9 of 17
1000.  If a cataract develops, cataract surgery may be needed.  In most cases, this surgery 
305
is successful in improving vision.
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307
•
An infection can develop in the eye after the injection.  This is called endophthalmitis. 
308
Endophthalmitis is treated by injecting antibiotics into the eye.  This usually gets rid of 
309
the infection.  However, endophthalmitis can produce permanent loss of vision and even 
310
blindness.  Your chance of having endophthalmitis is less than 1 in 100.
311
312
•
The injection could cause the retina to separate from the back of the eye.  This is called a 
313
retinal detachment.  If this occurs, surgery may be needed to repair the retina.  The 
314
surgery is usually successful at reattaching the retina.  However, a retinal detachment can 
315
produce permanent loss of vision and even blindness.  Your chance of having a retinal 
316
detachment is much less than 1 in 100.
317
318
•
The injection could cause bleeding in the middle cavity of the eye.  This is called a 
319
vitreous hemorrhage.  Usually the blood will go away on its own.  If it does not go away, 
320
surgery may be needed to remove the blood.  This surgery usually removes the blood 
321
completely.  However, a vitreous hemorrhage can produce permanent loss of vision and 
322
even blindness.  Your chance of having a vitreous hemorrhage is less than 1 in 100.
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324
3. Risks in the Eye Related to Eylea and Avastin
325
Eylea and Avastin are well tolerated in people. Possible side effects to the eye from both drugs 
326
include:
327
•
Inflammation of the eye.  This is called uveitis.  Uveitis can be successfully treated with 
328
steroid eye drops, injections, or pills.  However, uveitis can lead to permanent loss of 
329
vision if not treated early.  In previous studies, approximately 2 out of 100 patients 
330
developed uveitis.
331
332
•
Traction retinal detachment.  It is possible that injection of Eylea or Avastin might 
333
increase the chance of developing a traction retinal detachment, but this risk has not been 
334
seen in large studies evaluating for this possibility.  A traction retinal detachment can 
335
lead to additional vision loss or possibly permanent vision loss and often requires surgery 
336
to try to re-attach the retina to the back wall of the eye. Your eye doctor for this study 
337
will monitor for this complication so that it can be managed appropriately if it develops.
338
339
4. Risks to the Rest of the Body Specific to Eylea and Avastin:
340
Anti-VEGF agents are used to treat certain types of cancer.  The dose of these drugs when used 
341
to treat cancer is much higher than comparable doses used for injections into the eye.  When used 
342
to treat cancer, these drugs have caused certain side effects including high blood pressure, blood 
343
clots in arteries such as heart attack or stroke, kidney problems, bleeding within the 
344


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 10 of 17
gastrointestinal (digestive) tract, vaginal bleeding, surgery and wound healing complications, 
345
joint pain, skin rash or hives, and breathing difficulties or shock. Since the dose used for the eye 
346
injections is so low, we do not expect any of these side effects to occur due to the drug. 
347
However, we cannot rule out the possibility of a small risk from the drug.  In our prior study 
348
comparing different anti-VEGF drugs in people with diabetes, we did not find an increased risk 
349
of serious events like heart attack or stroke from Eylea compared with other available anti-VEGF 
350
drugs, including Avastin.
351
352
5. Risks if You Become Pregnant
353
The effects of anti-VEGF drugs on a human fetus (unborn baby) or nursing (breast feeding) 
354
infant are unknown. It is possible that use of these drugs may be associated with unanticipated 
355
risks to a pregnancy or fetus. Therefore, you will not be allowed to participate in this study if 
356
you are pregnant, planning to become pregnant within the next 24 months, or if you are nursing 
357
an infant.  During the study, females who are capable of bearing children must agree to use an 
358
effective method of birth control to prevent pregnancy.  In the event of pregnancy during the 
359
study, injections will be discontinued.    
360
361
B. Risks of Eye Examination and Tests
362
363
1. Eye Exam:  As part of the eye exam, drops will be put in your eyes to dilate the pupils.  
364
The drops may blur your vision and make you sensitive to light.  The drops will wear off 
365
over several hours.  There is a small risk of an allergic reaction to the drops.  There is 
366
also a small risk that the drops could cause the eye pressure to rise.  If this happens, it 
367
will be treated, but there is a small risk of losing vision from the pressure rise.  Due to the 
368
blurring effect on your vision and possible light sensitivity, we recommend that you do 
369
not drive until the blurring effects of the drops have worn off.  If necessary, have 
370
someone come with you who can drive for you after the exam.
371
372
2. Blood Draw Risks: Possible risks from blood draws include the following: bruising, arm 
373
discomfort, clotting, excess bleeding, infection, or fainting.  Please note that although 
374
these are possible risks they are unlikely.
375
376
We encourage you to discuss the risks with your study doctor or any other health care 
377
professional who may understand our process.   
378
379
WHAT ARE THE BENEFITS OF TAKING PART IN THIS STUDY? 
380
There may be a possible medical benefit to you if you decide to take part in the study, but it is 
381
not a guarantee. You may receive no direct benefit from being in the study.  People who take part 
382
in this research study will add to new knowledge that may help other people with the same 
383
problem.
384


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 11 of 17
If you participate in this study, regardless of your initial treatment, you will have access to Eylea 
385
if needed during the study.  You may or may not have access to Eylea outside of the study.
386
387
WHAT ALTERNATIVE PROCEDURES OR TREATMENT ARE AVAILABLE IF I DO 
388
NOT TAKE PART IN THIS STUDY?
389
If you do not take part in this study, you might be able to receive Avastin or Eylea outside of the 
390
study.  You also could receive Lucentis, a third anti-VEGF drug which is FDA approved for 
391
DME treatment.  This treatment is approximately $1,200 per injection. It has shown to work a 
392
little better than Avastin but not quite as well as Eylea.
393
394
We encourage you to discuss these alternative procedures and treatments with your study doctor, 
395
your primary care physician, or another health care professional who has knowledge of DME. 
396
397
WHAT IF I WANT TO WITHDRAW FROM THE STUDY, OR I AM ASKED TO 
398
WITHDRAW FROM THE STUDY?
399
You can stop participating in this study at any time.  You may continue to receive medical care 
400
not related to this study. However, we encourage you to talk to a member of the research group 
401
so they know why you are stopping the study.
402
403
If there are any new findings during the study that may affect whether your participation, you 
404
will be told about them so you can decide if you want to continue.
405
406
No penalty or loss of medical care will result from your decision.  You may continue to receive 
407
medical care not related to this study.  
408
409
The investigators, physicians or funding source may stop the study or take you out of the study at 
410
any time. They may remove you from the study for various administrative and/or medical 
411
reasons. They can do this without your consent. 
412
Some reasons why you may be removed from include:
413
•
The doctors judge that it is in your best interest
414
•
The doctors think that being in the study may cause you harm
415
•
If you experience a study-related injury
416
•
If you need additional or different medication
417
•
If you do not follow the study plan. 
418
If you are removed from the study or the study is stopped, you may continue to receive medical 
419
care not related to this study.
420
421
ARE THERE COSTS RELATED TO TAKING PART IN THE STUDY?
422
Testing that is specifically for this study will be paid for by the study. The costs of treatment, 
423


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 12 of 17
office visits, and tests that are part of your usual eye care will be your or your insurance 
424
company’s responsibility.  The study will pay for:
425
•
Visual acuity using an electronic tester at each visit.
426
•
The eye exam and OCT at the baseline visit
427
•
Fundus photographs when required for the study.
428
•
The drug and injection procedure for study Avastin
429
•
Any Eylea expense, including the cost of the drug and injection procedure, if not covered 
430
by your insurance (see additional details below) 
431
432
All other tests and procedures, including the following, are your or your insurance company’s 
433
responsibility:
434
•
The eye exam and OCTs at 4 week-20 week visits, 32, 52 and 104 weeks, and any visit at 
435
or after a study injection is considered standard care.  Eye exam and OCT at additional 
436
visits required when treatment is no longer needed will be paid for by the study.  
437
•
Laser or any other treatments (other than study injections), if needed.
438
•
Exams, tests, procedures for the eye not in the study.
439
440
Depending on your insurance plan, it is possible that your insurance will not pay for some of the 
441
procedures and testing; if they do not pay, the study may become responsible for these costs if 
442
you have a financial hardship.  In addition, although Eylea injections will initially be billed to 
443
your insurance, the study will pay for any portion of the Eylea drug and injection procedure cost
444
that is not paid for by your insurance company.  By signing this form, you certify that you 
445
understand that not all of the tests and procedures will be paid by the study and that you are 
446
aware that you or your insurance company will be charged for standard care procedures.
447
448
If you have travel expenses that make it difficult for you to return for study visits, additional 
449
funds may be available.
450
451
IS THERE COMPENSATION FOR TAKING PART IN THIS STUDY?
452
If you take part in the study, you will be given a $25 gift or money card for each visit required 
453
for the study.  This gift or money card is being given to you to help with the additional costs that 
454
may result from completing study visits.  If you do not complete all of the visits or discontinue 
455
the study before it ends, you will only receive a gift card for the visits that you did complete.  
456
You will not receive a gift or money card for extra visits your doctor believes are needed for 
457
your usual care.
458
459
WHAT HAPPENS IF I EXPERIENCE A RESEARCH RELATED INJURY?
460
Medical care is available if you have a research-related injury. If you have an emergency, you 
461
can get emergency care. If possible, you should tell the emergency care medical staff that you are 
462


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 13 of 17
in a research study. You should also tell your study doctor about the emergency as soon as 
463
possible.  
464
465
The study will not provide costs for medical expenses or any other costs for research-related 
466
injuries. The costs of care are your or your insurance company’s responsibility.  Money for lost 
467
wages and/or direct or indirect losses is not available. 
468
469
If you have questions about the study or research-related injuries, contact DRCR.net staff at 1-
470
866-372-7601 during normal business hours. 
471
472
CONTACT INFORMATION FOR QUESTIONS OR PROBLEMS
473
If you have questions about this study, a research-related injury, have concerns, suggestions or 
474
questions about the study, contact your study team using the provided contact information on the 
475
Cover Page.
476
477
If you have unanswered questions about your rights as a research participant, wish to talk about 
478
your concerns or suggestions linked to the research study, want additional information about the 
479
research, or want to provide comments about the research, contact the Jaeb Center for Health 
480
Research Institutional Review (IRB) Office at 813-975-8690 or irb@jaeb.org
481
482
HOW WILL MY INFORMATION BE PROTECTED AND KEPT CONFIDENTIAL?
483
As required by law, study related records with identifying information will be kept confidential. 
484
Safeguards for authorized access, security, and privacy of your information have been put in 
485
place by the Federal Privacy Regulations.  Unless the law requires it, your name, address, social 
486
security number, telephone number, or any other direct identifying information will not be used 
487
to identify you. 
488
489
Certificate of Confidentiality
490
The National Institutes of Health (NIH) has given us a Certificate of Confidentiality for this 
491
study. This adds special protection for study information that identifies you and allows us, in 
492
some cases, to refuse to give out information that could identify you without your consent. This 
493
could be done when the information is requested by a federal, state, local court or public agency. 
494
If you need medical help, we may still share your identifiable information. As described in this 
495
form or in other cases, we may share identifiable information. For example, if the government 
496
inspects us, they may see your identifiable information. The study doctor and research team will 
497
follow local laws and will tell the local or state authorities:
498
•
if certain diseases are present;
499
•
if they suspect neglect, abandonment, or abuse of you; and
500
•
if the study doctor or research team learn that you plan to harm yourself or 
501
someone else
502


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 14 of 17
503
A. Purpose of Authorization
504
We have rules to protect information about you.  Federal and state laws and the federal medical 
505
Privacy Rule also protect your information.  By signing this form you provide your permission, 
506
called your “authorization,” for the use and disclosure of information protected by the Privacy 
507
Rule. 
508
509
You must sign the Protected Health Information Authorization at the end of this form if you 
510
want to be in the study.  When you sign the form, you give permission for the use and disclosure 
511
of your Protected Health Information (PHI) for the study.  PHI is health information that 
512
identifies you.  Your authorization is beneficial and important for the study.  Without your 
513
authorization, you will not be able to be in this research study.
514
515
B. Use and Disclosure of the PHI
516
Your study doctor will collect information about you.  This information includes things learned 
517
from procedures listed and described in this form as well as your name, address, date of birth, 
518
and information from your medical records.  Your name, address, telephone number, and social 
519
security number are examples of identifiable information.
520
521
A code number will replace your name, address, telephone number, or social security number in 
522
the results given to the study coordinating center which is the Jaeb Center for Health Research in 
523
Tampa, Florida.   
524
525
The study doctor’s office will not disclose study results that have your identifiable information 
526
except as explained in Section C. or when required by law.  The Jaeb Center and this doctor’s 
527
office will guard the privacy of your study PHI.
528
529
Study results without the protected information may be shared in medical journals and at 
530
scientific meetings.  Your records will be confidential.  No one will disclose your identity in a 
531
medical journal or at a scientific meeting.  
532
533
C. Authorized Recipients and Users
534
It is possible that people outside of this doctor’s office and the Jaeb Center may need to see or 
535
receive your information from this study.  Some examples include: 
536
1. The people who work for this doctor’s office
537
2. The people who work for the Jaeb Center
538
3. The scientific investigators who help run the study
539
4. Any review board that oversees human investigations rules for your doctor’s office
540
5. Any federal agency that oversees clinical trials
541


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 15 of 17
6. If you have an adverse (unfavorable) event, the people outside this doctor’s office who 
542
assist in your care.
543
7. Your doctor may send your blood sample to the central laboratory for this study at the 
544
Advanced Research and Diagnostic Laboratory in Minneapolis, MN.
545
8. The OCTs and photographs of your eye may be sent to a central reading center and their 
546
collaborators.
547
548
In most cases the information will have a code number with it instead of your name, address, 
549
telephone number, or social security number. 
550
551
There are some situations where the information will not have a code number but may include 
552
your name, address, telephone number or social security number (PHI). If so, people outside this 
553
doctor’s office who assist in your care may see your study PHI.  They may not be covered by the 
554
federal Privacy Rule.  Everyone who needs to see your information will be told it is confidential 
555
– but we cannot guarantee fully confidentiality. 
556
557
Other Considerations
558
The data collected in the study may be provided to other researchers to use; however, the data 
559
that are provided will not contain any information that could identify you.  
560
561
When the results are made public, all of the study data collected may also be made public. 
562
However, there will be no identifying information included. 
563
564
Separately from your research data, the Jaeb Center for Health Research in Tampa, Florida will 
565
be provided with information on how to contact you.
566
567
•
About every 6 months, you may receive a phone call from a staff member at the Jaeb
568
Center to check on your condition and to see if you have any questions.  You will be
569
called at a time that you indicate is most convenient for you.  If you are not available at
570
the time of the call and prefer to call the coordinating center yourself, you can call the 
571
coordinating center toll-free at 1-866-372-7601
572
573
•
If we are not able to locate you when we try to schedule your follow-up visit, the Jaeb 
574
Center may try to contact you through the alternative contact information you have given
575
us.  If this is not successful, the Jaeb Center may use a third-party search service.
576
577
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
578
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
579
Web site will include a summary of the results.  You can search this Web site at any time.
580
581


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 16 of 17
D. Cancellation of HIPAA Authorization
582
You may cancel your permission for the use and disclosure of your study PHI at any time.  You 
583
need to contact your study doctor and give him/her a notice of cancellation in writing.  When you 
584
cancel your permission or when you withdraw from the study directly, you are no longer part of 
585
the study.  No new information about you will be gathered for the study except when there is an 
586
adverse (unfavorable) event that is related or potentially related to the study.  If an adverse event 
587
happens, your entire medical record may need to be reviewed.  
588
589
The Jaeb Center will receive all the information that was collected for the study up to the time of 
590
cancellation or withdrawal.  The Jaeb Center will receive any new information about any adverse 
591
(unfavorable) event that is related or potentially related to the study.
592
593
E. 50 Year Expiration Date and Indefinite Expiration Date 
594
Some of your study PHI does not have a code number with it.  Your permission for the use and 
595
disclosure of this PHI lasts 50 years from the date of your signature or until the end of the study, 
596
whichever is sooner.  
597
598
The rest of your study PHI does have a code number with it.  When it is collected, it becomes a 
599
research report.  Your permission for the use and disclosure of these coded data will never end.  
600
These coded data do not have your name, address, telephone number, or social security number. 
601
The above supports the HIPAA Privacy Rule – 45 CFR 164.508
602
603
Some of your information from this study (for example, your treatment) may be stored separately 
604
from or added to your medical record.  You will not be able to see this information until the 
605
study ends. If your non-study physician requires it for your care, he/she will be able to view it. 
606
607


Consent to Participate in a Research Study
Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab +Deferred 
Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (Protocol AC)
AC Informed Consent Version 3.0 8-30-18   
[Protocol Version 2.0]
Page 17 of 17
Your Full Name (printed) 
608
609
Description of Representative’s Authority to Act for the Subject
610
________________________________________________ (if applicable)
611
612
Protected Health Information Authorization
613
614
615
Study Enrollment
616
617
You will be given a signed copy of this document in case you want to read it again.
618
By signing, you authorize the use and disclosure of your protected health information.  This 
information is collected as part of your participation in this study.
Signature
Date
By signing, you agree to take part in this study.  Your signature means that:
•
you have read this informed consent form about the study named below;
•
you have been given the chance to discuss the study and to ask questions;
•
you have verbally summarized your understanding of the study to the person who is 
explaining it to you; and
•
you freely choose to participate.
Name of Study: Protocol AC
Signature
Date
I certify that to the best of my knowledge the participant understands the nature, demands, 
risks, and benefits involved in his/her participation in this study. 
_______________________        _______________________        ___________ 
Investigator’s Printed Name         Investigator’s Signature 
Date

SAP_002.pdf: 
DRCR Retina Network 
Randomized Trial of Intravitreous Aflibercept Versus Intravitreous 
Bevacizumab + Deferred Aflibercept for Treatment of  
Center-Involved Diabetic Macular Edema 
(Protocol AC) 
Statistical Analysis Plan 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0 
Wesley Beaulieu 
Michele Melia 
02 Feb 2019 
Initial version for Protocol version 2.0 
1.1 
Wesley Beaulieu 
Michele Melia 
24 Apr 2020 
Increased upper limit of 2-year visit window 
due to COVID-19 pandemic. Implemented 
strategies for controlling the Type I error rate. 
Modified diabetic retinopathy progression scale 
per specifications from fundus photograph 
reading center. Made clarifications. Revisions 
were made prior to initial data analysis. Applies 
to Protocol version 3.0 
1.2 
Wesley Beaulieu 
Danni Liu 
Maureen Maguire 
28 July 2021 
Added methods to control for multiplicity. 
Other minor changes. Revisions were made 
prior to initial data analysis. Applies to Protocol 
version 4.0.  
1.2 
Danni Liu 
Maureen Maguire 
24 March 2022 
Minor changes and clarifications to Sections 3.3 
and 4.0. 
 
SIGNATURES 
AUTHOR 
 
 
 
 
APPROVER 
 
 
 
 
PROTOCOL 
DIRECTOR 
 
 
 
 
 


Protocol AC Statistical Analysis Plan 
 
Page 2 of 16 
1.0 Introduction 
1 
This document outlines the statistical analysis plan for the DRCR Retina Network protocol 
2 
comparing the anti-vascular endothelial growth factor (anti-VEGF) drug aflibercept versus 
3 
bevacizumab + deferred aflibercept for the treatment of center-involved diabetic macular edema 
4 
(CI-DME) in eyes with at least moderate vision loss (Protocol AC). Moderate vision loss is 
5 
defined as an Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) letter score of 
6 
68 to 24, which corresponds to an approximate Snellen equivalent of 20/50 to 20/320. 
7 
The primary objective of the protocol is to determine whether there is a treatment group 
8 
difference in mean change in visual acuity from baseline over two years (area under the curve 
9 
[AUC]). Participants will have visits every 4 weeks in year 1 and every 4 to 16 weeks in year 2, 
10 
depending on the clinical course. 
11 
Study eyes will be assigned randomly to the two treatment groups in a 1:1 ratio. Participants may 
12 
have one or two study eyes. Randomization of participants with one study eye will be stratified 
13 
by site. Participants with two study eyes will have one eye randomized to each treatment, 
14 
stratified by visual acuity of the eye with better visual acuity. If visual acuity is the same in both 
15 
eyes, then the right eye will be considered to have better visual acuity than the left eye.  
16 
2.0 Primary Outcome Analysis 
17 
The primary analysis will consist of a treatment group comparison of mean change in visual 
18 
acuity from baseline over two years adjusting for baseline visual acuity and the number of study 
19 
eyes for the participant (one or two). Correlation arising from participants contributing two eyes 
20 
to the analysis will be modeled by including a random intercept term for participant using a 
21 
linear mixed effects model with robust variance estimation. The mathematical form of this model 
22 
for eye i from participant j is as follows: 
23 
𝐴𝐴𝐴𝐴𝐴𝐴𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1 × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝑛𝑛𝑖𝑖𝑖𝑖+ 𝛽𝛽2 × 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑠𝑠𝑗𝑗+ 𝛽𝛽3 × 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑡𝑡𝑖𝑖𝑖𝑖+ 𝑢𝑢𝑗𝑗+ 𝜖𝜖𝑖𝑖𝑖𝑖 
24 
𝑢𝑢𝑗𝑗~𝑁𝑁(0, 𝜎𝜎𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
2
) 
25 
𝜖𝜖𝑖𝑖𝑖𝑖~𝑁𝑁(0, 𝜎𝜎2) 
26 
The primary analysis is an intention-to-treat analysis. It will include all randomized eyes 
27 
according to treatment group assignment at baseline. For each eye, AUC will be calculated by 
28 
the trapezoidal rule using the following formula: 
29 
𝐴𝐴𝐴𝐴𝐴𝐴= ෍൬𝑉𝑉𝑖𝑖+ 𝑉𝑉𝑖𝑖+1
2
× (𝑑𝑑𝑖𝑖+1 −𝑑𝑑𝑖𝑖)൰
𝑛𝑛
𝑖𝑖=1
  
30 
Where Vi is the visual acuity measured at the ith visit, di is the number of days from 
31 
randomization to the ith visit, and n is the number of outcome visits included in the analysis. For 
32 
presentation, AUC will be divided by the number of days between baseline and the nth visit so 
33 


Protocol AC Statistical Analysis Plan 
 
Page 3 of 16 
that the value shown will have units of letters rather than letter⋅days (e.g., 728 days for the 
34 
primary outcome at 104 weeks). This statistic can then be interpreted as the average change in 
35 
visual acuity over the time between baseline and the nth visit. All analysis visits will be included 
36 
for calculation of AUC and the number of days will be calculated based on the target date for the 
37 
visit: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 68, 84, and 104 weeks (see Section 8.2 for a 
38 
description of analysis windows). 
39 
The P value, adjusted difference, and associated 95% confidence interval will be reported for the 
40 
treatment group effect. If the P value for the test of the treatment effect is less than or equal to 
41 
.05, then it will be concluded that there is a significant difference for change in visual acuity over 
42 
two years between the groups. In other words, if P ≤ .05, then the null hypothesis of β3 = 0 will 
43 
be rejected. 
44 
Markov Chain Monte Carlo (MCMC) multiple imputation with 100 imputations will be used to 
45 
impute missing data. The imputation will be performed separately for each treatment group and 
46 
the imputation model will include baseline visual acuity, change in visual acuity from baseline at 
47 
all analysis visits, and the number of study eyes for the participant. Any imputed value outside of 
48 
the range for electronic visual acuity measurements (<0 or >100 letters) will be truncated at the 
49 
closest measurable value (i.e., 0 or 100). 
50 
A plot showing the change in visual acuity from baseline by treatment group over time will be 
51 
constructed using observed data. In general, summary statistics (e.g., within-group means and 
52 
standard deviations), will be based on observed data while estimates from statistical models (e.g., 
53 
treatment group differences, confidence intervals, and P values) will be based on imputed data. 
54 
2.1 Sensitivity Analyses 
55 
Complete Case Analysis 
56 
A sensitivity analysis including only observed data from participants completing the 104-week 
57 
visit (no imputation) will be conducted. If the analyses of imputed and observed data differ 
58 
substantially, then exploratory analyses will be performed to evaluate factors that may have 
59 
contributed to the difference. The sensitivity analysis of completers will only be performed if 
60 
more than 10% of randomized participants do not complete the 104-week visit.  
61 
Tipping Point Analysis 
62 
Multiple imputation assumes that data are missing at random (MAR). In the present study, this 
63 
would mean that whether change in visual acuity is missing or observed may be a function of 
64 
observed baseline characteristics included in the imputation model, but not a function of the 
65 
unobserved follow-up data being imputed. This assumption cannot be tested directly since these 
66 
data are unknown. However, a tipping point analysis will be conducted to adjust the imputed 
67 
values using a shift parameter and thereby determine how severe the departure from MAR must 
68 
be to change the outcome of the analysis with respect to rejecting or failing to reject the null 
69 
hypothesis. 
70 


Protocol AC Statistical Analysis Plan 
 
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A shift parameter will be applied to the imputed values in the aflibercept group to determine the 
71 
tipping point at which the results of the primary analysis are nullified. That is, if one group is 
72 
found to be superior (P ≤ .05), the tipping point will identify the shift parameter necessary to 
73 
yield P > .05. Conversely, if the null hypothesis is not rejected (P > .05), two tipping points will 
74 
be identified – one that would make aflibercept superior and one that would make bevacizumab 
75 
+ deferred aflibercept superior. In either case, this tipping point will be evaluated to determine if 
76 
it is plausible. If not, then the MAR assumption is likely reasonable. For example, if the tipping 
77 
point were 100 letters, then this would be evidence that the MAR assumption is reasonable.  
78 
Per-Protocol Analysis 
79 
A per-protocol analysis will be conducted to estimate the treatment effect for each group among 
80 
those not receiving any alternative treatment for DME (e.g., intravitreal corticosteroids). This 
81 
analysis will include observed data from all randomized up to the time of alternative treatment 
82 
for DME. Data collected after the alternative treatment will be set to missing prior to imputation. 
83 
Imputation will otherwise be similar to the primary analysis. Note that focal/grid laser is allowed 
84 
only if failure criteria have been met. The intention-to-treat analysis is considered the primary 
85 
analysis. If the results of the primary and per-protocol analyses differ substantially, then 
86 
exploratory analyses will be performed to evaluate factors that may have contributed to the 
87 
difference. The per-protocol analysis will only be performed if more than 10% of randomized 
88 
participants would be excluded by these criteria. 
89 
Confounding Analysis 
90 
Imbalances between groups in important covariates are not expected to be of sufficient 
91 
magnitude to produce confounding in the primary analysis. However, the presence of 
92 
confounding in the primary analysis will be evaluated in additional regression models using 
93 
observed data (no imputation) by including baseline participant and study eye covariates 
94 
including but not limited to the following:  
95 
• Age 
96 
• Duration of diabetes 
97 
• HbA1c 
98 
• Mean arterial blood pressure 
99 
• Prior PRP 
100 
• Prior treatment for DME 
101 
• Diabetic retinopathy severity level on fundus photographs as graded by the reading center 
102 
• Each of the following within 500 µm of the center of the macula on OCT as graded by 
103 
the reading center (minimum 20 eyes in the cohort with and without the characteristic): 
104 
o Epiretinal membrane 
105 
o Vitreomacular traction 
106 
o Cystoid abnormalities 
107 
o Subretinal fluid 
108 


Protocol AC Statistical Analysis Plan 
 
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• Each of the following within 1800 µm of the center of the macula on fundus photography 
109 
as graded by the reading center (minimum 20 eyes in the cohort with and without the 
110 
characteristic): 
111 
o Hemorrhages/microaneurysms 
112 
o Hard exudates 
113 
o Surface wrinkling retinopathy 
114 
Additional variables associated with the outcome will be included in regression models if there is 
115 
an imbalance in the variables between treatment groups. Imbalance by treatment group will not 
116 
be judged using statistical testing. Instead, imbalance will be judged by whether the size of the 
117 
imbalance is clinically important, i.e., whether the imbalance is large enough to have a clinically 
118 
important effect on the primary outcome. 
119 
2.2 Subgroup Analyses 
120 
Pre-planned subgroup analyses will repeat the primary analysis while including an interaction 
121 
term for the baseline subgroup factor by treatment. Missing data will be imputed by treatment 
122 
group similarly to the primary analysis except that the subgroup factor will be included in the 
123 
imputation model.1  
124 
A significant (P ≤ .05) type III test of the interaction term will be taken as an indication that 
125 
subgroup effects need to be explored for full interpretation of the trial results. It is recognized 
126 
that the study is not powered to detect subgroup effects and that lack of significance for the 
127 
subgroup tests of interaction is not necessarily an indication that subgroup effects do not exist.  
128 
Interpretation of subgroup analyses will depend on whether the overall analysis demonstrates a 
129 
significant treatment effect. In the absence of a significant treatment effect in the primary 
130 
analysis, subgroup analyses will be interpreted with caution. 
131 
Baseline variables to be evaluated for subgroup effects include the following: 
132 
• OCT central subfield thickness: < 400 µm vs ≥ 400 µm (Stratus equivalent) 
133 
• Visual acuity: 20/50 to 20/63 vs. 20/80 to 20/320 
134 
Subgroups will only be analyzed if there are at least 20 eyes in each treatment group for each 
135 
subgroup to increase statistical precision. Cutoffs of continuous outcomes may be modified to 
136 
achieve a reasonable number of eyes in each group.  
137 
The above subgroups are considered of primary interest. For each variable, the rationale for 
138 
performing the analysis is listed in Table 1 below. 
139 


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Table 1. Subgroup analyses. 
140 
Variable 
Rationale 
OCT central subfield thickness 
Eyes with greater OCT central subfield thickness may have higher anti-
VEGF levels, leading to a larger relative treatment effect for the drug 
with stronger VEGF binding affinity (aflibercept). 
Baseline visual acuity 
Eyes with lower visual acuity may have higher VEGF levels, leading to a 
larger relative treatment effect for the drug with stronger VEGF binding 
affinity (aflibercept). 
The following subgroup factors will be evaluated in exploratory analyses. Only point estimates 
141 
and 95% confidence intervals for the within-subgroup treatment effects will be presented – P 
142 
values will not be presented. The finding of a subgroup effect for any of these factors will be 
143 
interpreted as hypothesis generating only and in need of confirmation from further studies. 
144 
• Prior treatment for DME: yes vs. no 
145 
• HbA1c: < 7.5% vs. ≥ 7.5% 
146 
• Sex: female vs. male 
147 
• Race/Ethnicity: Non-Hispanic White vs. Non-Hispanic Black/African American vs. 
148 
Hispanic or Latino (exclude all other groups due to anticipated small sample size)  
149 
2.3 Center Effects 
150 
The number of study participants per center is expected to be small for many centers. Therefore, 
151 
center effects will not be included in the statistical model. However, for centers with a large 
152 
number of study participants (N ≥ 20 in either treatment group), heterogeneity across centers will 
153 
be explored using random center effects by estimating empirical best linear unbiased predictors 
154 
along with 95% confidence intervals. 
155 
3.0 Secondary Outcome Analyses 
156 
3.1 Visual Acuity and OCT 
157 
Additional analyses of visual acuity will use the imputed data sets created for the primary 
158 
outcome. For OCT outcomes, new imputed data sets will be created similarly by substituting 
159 
baseline central subfield thickness (converted to a common scale based on the most accurate 
160 
conversion algorithms available) and change in central subfield thickness from baseline for 
161 
baseline visual acuity and change in visual acuity from baseline, respectively. A plot of mean 
162 
change in OCT central subfield thickness over time by group will be constructed using observed 
163 
data. 
164 
Analyses will be conducted at 24, 52 and 104 weeks unless otherwise noted. P values will be 
165 
calculated for mean change in visual acuity and mean change in OCT central subfield thickness 
166 
at 104 weeks only. All other secondary outcomes will be summarized with a model-based point 
167 
estimate and 95% between-group confidence interval (no P value). 
168 


Protocol AC Statistical Analysis Plan 
 
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Analyses of continuous outcomes will be conducted in a manner similar to the primary analysis 
169 
using linear mixed effects models and substituting central subfield thickness for visual acuity, 
170 
depending on the outcome.  
171 
Analyses of binary outcomes will be conducted using binomial regression with an identity link 
172 
(estimating risk difference),2 robust variance estimation, and adjustment for baseline visual 
173 
acuity or OCT central subfield thickness (depending on the outcome). Generalized estimating 
174 
equations (GEE) will be used to control for correlations arising from participants contributing 
175 
two study eyes to the analysis. Baseline visual acuity (for visual acuity outcomes) or central 
176 
subfield thickness (for central subfield thickness outcomes) and the number of study eyes will be 
177 
included as covariates. The proportion of eyes meeting the outcome at the visit will be reported 
178 
for each treatment group. In addition, the between-group risk difference and 95% confidence 
179 
interval for the treatment effect will be presented; the P value will not be presented. If binomial 
180 
regression fails to converge in one or more outcomes, then logistic regression with a random 
181 
intercept for participant, conditional standardization, and the delta method (to estimate the risk 
182 
difference)3 may be used instead for all binary outcomes.  
183 
Table 2. Analyses of Secondary Visual Acuity and OCT Outcomes. 
184 
Outcome 
Analysis Technique 
Mean change in visual acuity from baseline 
Linear mixed model a 
Success proportion: visual acuity gain ≥ 15 letters 
Binomial regression with GEE b 
Success proportion: visual acuity gain ≥ 10 letters 
Binomial regression with GEE b 
Failure proportion: visual acuity loss ≥ 10 letters 
Binomial regression with GEE b  
Failure proportion: visual acuity loss ≥ 15 letters 
Binomial regression with GEE b  
Success proportion: visual acuity ≥ 84 letters (~20/20) 
Binomial regression with GEE b  
Success proportion: visual acuity ≥ 69 letters (~20/40) 
Binomial regression with GEE b  
Failure proportion: visual acuity ≤ 38 letters (~20/200) 
Binomial regression with GEE b  
Mean change in OCT central subfield thickness from baseline 
Linear mixed model a 
Proportion of eyes with OCT central subfield thickness below the 
gender-specific spectral domain OCT threshold for CI-DME c 
Binomial regression with GEE b  
Mean change in OCT retinal volume from baseline 
Linear mixed model b  
a At 24 and 52 weeks, a point estimate and 95% CI will be provided, but a P value will not be provided. At 104 
185 
weeks, a P value will be provided only if the primary analysis demonstrates a significant difference. 
186 
b A point estimate and 95% CI will be provided, but a P value will not be provided. 
187 
c For Zeiss Cirrus, ≥ 290 µm for women and ≥ 305 µm for men. For Heidelberg Spectralis, ≥ 305 µm for women and 
188 
≥ 320 µm for men. No imputation for this outcome because the threshold values are machine specific and not Stratus 
189 
equivalents, which are being imputed. 
190 


Protocol AC Statistical Analysis Plan 
 
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3.2 Changes in Diabetic Retinopathy 
191 
The proportion of eyes with 2-step improvement or worsening of diabetic retinopathy on fundus 
192 
photographs (defined in Table 3) will be assessed at 52 and 104 weeks using observed data only 
193 
(no imputation). Analyses will be conducted with binomial regression while adjusting for 
194 
baseline diabetic retinopathy severity (ordinal transformation) and using GEE to control for the 
195 
correlation arising from participants contributing two study eyes to the analysis. Baseline ordinal 
196 
diabetic retinopathy severity and the number of study eyes will be included as covariates. The 
197 
proportion of eyes meeting the outcome at the visit will be reported for each treatment group. In 
198 
addition, the risk difference and 95% confidence interval for the treatment effect will be 
199 
reported, but not a P value. 
200 
Table 3. Definitions of Diabetic Retinopathy Improvement and Worsening for Eyes 
201 
Baseline 
Worsening 
(if follow up ≥) 
Improvement 
(if follow up ≤) 
NPDR 
10/12 
35 
Exclude 
14/15/20 
43 
Exclude 
35 
47 
10/12 
43 
53 
14/15/20 
47 
61 
35 
53 
61 
43 
PDR 
61 
71 
53 
65 
75 
53 
71 
81 
61 
75 
81 
65 
81 
Exclude 
71 
85 
Exclude 
75 
Abbreviations: NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. 
202 
3.3 Additional Secondary Outcomes 
203 
Additional secondary outcomes will be evaluated 104 weeks, unless otherwise specified below.  
204 
Table 4. Additional Secondary Outcomes. 
205 
Outcome 
Analysis Technique a 
Time to receipt of panretinal photocoagulation, vitrectomy, or occurrence 
of vitreous hemorrhage, traction retinal detachment, neovascularization of 
the iris, or neovascular glaucoma b 
Marginal Cox proportional hazards 
regression 
Number of injections up to the visit c 
Linear mixed model  
(52 and 104 weeks) 
Number of visits d 
Independent samples t-test 
a Point estimates and 95% confidence intervals will be presented, but P values will not be presented. 
206 
b Includes all randomized eyes, regardless of visit completion, and all visits up to and including the 104-week visit 
207 


Protocol AC Statistical Analysis Plan 
 
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c Limited to eyes that complete the visit or any later common visit 
208 
d Evaluated at 104 weeks for 104-week completers among participants with one study eye. Bilateral participants are 
209 
excluded because number of visits is a participant-level outcome and treatment group is an eye-level variable. 
210 
Kaplan-Meier estimates for the time to receipt of panretinal photocoagulation, vitrectomy or 
211 
occurrence of vitreous hemorrhage, traction retinal detachment, neovascularization of the iris, or 
212 
neovascular glaucoma will be provided. A marginal Cox proportional hazards model with a 
213 
robust sandwich estimate of the covariance matrix will be used to control for correlations arising 
214 
from bilateral participants.4 Baseline ordinal diabetic retinopathy severity and the number of 
215 
study eyes will be included as covariates. The model will adjust for ordinal baseline diabetic 
216 
retinopathy severity because these events all represent worsening of diabetic retinopathy, and 
217 
eyes with more advanced diabetic retinopathy at baseline are more likely to experience 
218 
worsening. The treatment effect will be measured as a hazard ratio and will be reported with the 
219 
associated 95% confidence interval, but not a P value. When the number of events is low (i.e., 
220 
less than 10 in either treatment group), these time-to-event analyses will be replaced by 
221 
comparing the percentage in each treatment group with the PDR event at any time during follow-
222 
up.  A 95% confidence interval  on the difference in proportions will be calculated by inverting 
223 
two separate one-sided exact tests that are based on the score statistic. 
224 
For comparison of the number of injections, a linear mixed model will be used with the number 
225 
of study eyes included as a covariate. For comparison of the number of visits, an independent 
226 
samples t-test limited to participants with one study eye will be used. 
227 
4.0 Outcomes within Treatment Groups 
228 
Within each treatment group, the following outcomes will be tabulated without formal statistical 
229 
comparisons. 
230 
• Distribution and mean (standard deviation) number of intravitreous injections performed 
231 
up to 24, 52, and 104 weeks as well as the intervening periods for eyes completing any 
232 
common visit at or beyond the upper limit (e.g., for injections through 52 weeks, eyes 
233 
must have completed the 52-, 68-, 84-, or 104-week visit). 
234 
o Intervals will be closed on the left and open on the right (e.g., for injections 
235 
through 24 weeks, an injection given at 24 weeks will not be counted towards the 
236 
total; however, an injection given at 24 weeks will count for the interval of 24 to 
237 
52 weeks), unless the upper boundary is at 104 weeks in which case the interval is 
238 
closed on the left and right. 
239 
• Proportion of eyes that met switch criteria by the 12, 24, 52, or 104-week visits. 
240 
o Estimated using the Kaplan-Meier method. 
241 
5.0 Economic Analysis 
242 
The purpose of the economic analysis is to compare the treatment groups with respect to cost. An 
243 
incremental cost effectiveness ratio (ICER) will be calculated. Data from the clinical trial on the 
244 


Protocol AC Statistical Analysis Plan 
 
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number of clinic visits completed, number of procedures performed (e.g., OCT, fundus 
245 
photographs), and number of aflibercept and bevacizumab treatments will be used to estimate an 
246 
average cost per patient for each treatment arm. The Medicare Fee Schedule will be used to 
247 
estimate medical costs. For outcomes measured at the participant level, bilateral participants are 
248 
non-informative with respect to the treatment comparison and will not be included in the 
249 
economic analyses. 
250 
6.0 Safety Analysis 
251 
Adverse events will be categorized as study eye, fellow eye, or systemic. A full listing of adverse 
252 
events will be tabulated by treatment. An additional tabulation will be made for adverse events 
253 
possibly related to study treatment.  
254 
All randomized eyes will be included in the safety analysis and analyzed according to treatment 
255 
assignment at randomization, regardless of treatment actually received. Any adverse event that 
256 
occurred up to and including the 104-week visit (or, if the participant did not complete the 104-
257 
week visit, 896 days from randomization, the end of the 2-year analysis window) will be 
258 
reported.  
259 
6.1 Study Eye Adverse Events 
260 
The frequency of the event occurring at least once will be calculated for study eyes in each 
261 
treatment group. The proportion of eyes experiencing each outcome will be compared between 
262 
treatment groups using Barnard’s unconditional exact test, considering the number of eyes in 
263 
each treatment group fixed. It is noted that this method does not adjust for the potential 
264 
correlation arising from participants with two study eyes; however, given the low expected 
265 
frequency of adverse events and small proportion of bilateral subjects, the impact should be 
266 
minimal. Adjustment for such correlations would be statistically problematic due to the low 
267 
frequency of events. 
268 
The following ocular adverse events will be assessed: 
269 
o Endophthalmitis 
270 
o Retinal detachment (rhegmatogenous, traction, combined rhegmatogenous and 
271 
traction, or not otherwise specified) 
272 
 Rhegmatogenous retinal detachment (tabulated without formal analysis) 
273 
 Traction retinal detachment (tabulated without formal analysis) 
274 
o Traumatic cataract due to intravitreous injection 
275 
 Analysis limited to eyes with phakic lens at baseline 
276 
o Vitreous hemorrhage 
277 
o Ocular inflammation 
278 


Protocol AC Statistical Analysis Plan 
 
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o Intraocular pressure (IOP) elevation (composite outcome; individual components 
279 
below will be tabulated without formal analysis): 
280 
 Increase in IOP ≥ 10 mmHg from baseline (at a follow-up visit) 
281 
 IOP ≥ 30 mmHg (at a follow-up visit) 
282 
 Initiation of medication to lower IOP that was not in use at baseline 
283 
 Glaucoma procedure 
284 
o Neovascularization of the iris 
285 
o Neovascular glaucoma 
286 
6.2 Systemic Adverse Events 
287 
Systemic adverse events will be reported in three groups: (1) unilateral participants randomized 
288 
to bevacizumab + deferred aflibercept, (2) unilateral participants randomized to aflibercept, and 
289 
(3) bilateral participants randomized to bevacizumab + deferred aflibercept in one eye and 
290 
aflibercept in the other eye. The frequency of each event occurring at least once per participant 
291 
will be calculated. The proportion of participants with each systemic adverse event will be 
292 
compared among groups using Fisher’s exact test. If the overall test has P ≤ 0.05, then pairwise 
293 
comparisons between groups will be conducted using Fisher’s exact test without the need to 
294 
adjust for multiple comparisons.5 The following systemic adverse events will be assessed: 
295 
o Primary: 
296 
 Death 
297 
 Serious adverse event 
298 
 Hospitalization 
299 
 Cardiovascular and cerebrovascular events according to the Antiplatelet 
300 
Trialists’ Collaboration (excerpted from BMJ Jan 8, 1994): 
301 
• Nonfatal myocardial infarction 
302 
• Nonfatal stroke (counted only if symptoms lasted at least 24 hours) 
303 
• Death attributed to cardiac, cerebral, hemorrhagic, embolic, other 
304 
vascular (does not need to be ischemic in origin), or unknown cause 
305 
• At least one event (nonfatal myocardial infarction, nonfatal stroke, or 
306 
death attributed to potential vascular or unknown cause) 
307 
Note that transient ischemic attack, angina, possible myocardial infarction, and possible stroke 
308 
are not counted. Nonfatal myocardial infarction and nonfatal stroke require that the patient be 
309 
alive at the end of the study. If not, then only the death is counted. 
310 


Protocol AC Statistical Analysis Plan 
 
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o Secondary (for tabulation without statistical comparison): 
311 
 Frequency of at least one event per participant in each Medical Dictionary for 
312 
Regulatory Activities (MedDRA) system organ class 
313 
7.0 Additional Tabulations 
314 
The following will be tabulated according to treatment group: 
315 
• Baseline demographic and clinical characteristics 
316 
• Visit completion rate for each annual visit (excluding deaths) 
317 
• Treatment adherence 
318 
8.0 General Principles for Analysis 
319 
8.1 Analysis Cohort 
320 
Unless otherwise stated, all treatment comparison analyses will follow the intention-to-treat 
321 
principle with all randomized eyes included and each eye analyzed according to the randomized 
322 
treatment assignment, regardless of treatment actually received.  
323 
8.2 Visit Windows for Analysis 
324 
For common visits, the analysis windows will be defined according to Table 5. Note that all eyes 
325 
have visits every 4 weeks in year 1, but the protocol visit schedule varies in year 2 depending on 
326 
the clinical course. Therefore, visit windows at 68 and 84 weeks have been defined for analysis 
327 
purposes. 
328 
If multiple visits fall within the same analysis window, the following algorithm will be used to 
329 
prioritize which visit will be used for analysis: 
330 
• Visits with non-missing visual acuity data will be prioritized over visits with missing data 
331 
• If there is no protocol visit in the analysis window, then the visit closest to the target will 
332 
be used 
333 
o For visits falling in more than one window, priority will be given to the 24-, 52-, 
334 
and 104-week visits. Otherwise, the visit will be assigned to the earlier window.  
335 


Protocol AC Statistical Analysis Plan 
 
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Table 5. Analysis Windows for Outcome Visits 
336 
Protocol Visit 
Target 
Analysis Window 
4 weeks 
28 days 
14 – 42 days  
(4 ± 2 weeks) 
8 weeks 
56 days 
42 – 70 days  
(8 ± 2 weeks) 
12 weeks 
84 days 
70 – 98 days  
(12 ± 2 weeks) 
16 weeks 
112 days 
98 – 126 days  
(16 ± 2 weeks) 
20 weeks 
140 days 
126 – 154 days 
(20 ± 2 weeks) 
24 weeks 
168 days 
154 – 182 days 
(24 ± 2 weeks) 
28 weeks 
196 days 
182 – 210 days 
(28 ± 2 weeks) 
32 weeks 
224 days 
210 – 238 days 
(32 ± 2 weeks) 
36 weeks 
252 days 
238 – 266 days 
(36 ±2 weeks) 
40 weeks 
280 days 
266 – 294 days 
(40 ± 2 weeks) 
44 weeks 
308 days 
294 – 322 days 
(44 ± 2 weeks) 
48 weeks 
336 days 
322 – 350 days 
(48 ± 2 weeks) 
52 weeks 
364 days 
308 – 420 days 
(52 ± 8 weeks) 
68 weeks 
476 days 
420 – 532 days 
(68 ± 8 weeks) 
84 weeks 
588 days 
532 – 644 days 
(84 ± 8 weeks) 
104 weeks 
728 days 
644 – 896 days 
(92–128 weeks) 
8.3 Missing Data 
337 
In general, the strategy for handling missing data is included with the description of each 
338 
individual analysis. Where not otherwise specified, only participants with non-missing data are 
339 
included in the analysis. 
340 
8.4 Outliers 
341 
To help ensure that statistical outliers do not have undue impact on analyses of continuous visual 
342 
acuity and OCT outcomes (including the primary outcome), change in visual acuity change in 
343 
central subfield thickness, and change in retinal volume will be truncated to ± 3 standard 
344 
deviations. The standard deviations will be based on observed data from 104-week completers at 
345 
the 104-week visit, irrespective of treatment group. Truncation will be performed after 
346 
imputation of missing data, where applicable (i.e., raw data will be used for imputation). For the 
347 
primary outcome, AUC will be calculated based on the imputed values after truncation. There 
348 
will be no truncation of the AUC outcome itself. 
349 
8.5 Model Assumptions 
350 
All model assumptions, including linearity, normality of residuals, heteroscedasticity, and 
351 
proportional hazards will be verified. If model assumptions are not reasonably satisfied, then 
352 
covariates may be categorized or excluded, and a nonparametric approach, transformation, or 
353 
robust method may be considered. 
354 


Protocol AC Statistical Analysis Plan 
 
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8.6 Multiple Testing 
355 
The primary analysis will be conducted at alpha of 0.05. If the primary analysis demonstrates a 
356 
significant treatment group difference, then mean change in visual acuity from baseline at 104 
357 
weeks and mean change in OCT central subfield thickness from baseline at 104 weeks will be 
358 
tested as secondary outcomes. The Holm method will be used to provide strong control of alpha 
359 
at 0.05.5 If the primary analysis fails to show a significant difference, then outcomes will be 
360 
described with summary statistics, model-based point estimates, and between-group 95% 
361 
confidence intervals without a P value. This approach controls the family-wise error rate at 5%. 
362 
There will be no formal adjustment for multiplicity in sensitivity, subgroup, or safety analyses. 
363 
For exploratory subgroup analyses, the number of significant results expected by chance given 
364 
the number of comparisons will be noted. 
365 
9.0 Example SAS Code 
366 
Below is an example of SAS code for the primary outcome analysis. The actual code used might 
367 
differ due to variable naming conventions. 
368 
/* Generate Imputed Data Sets */ 
369 
proc mi data=studyEyes nimpute=100 seed=9999 out=outMI; 
370 
  var va0 vaChg4 vaChg8 vaChg12 vaChg16 vaChg20 vaChg24 vaChg28 
371 
      vaChg32 vaChg36 vaChg40 vaChg44 vaChg48 vaChg52 vaChg68 
372 
      vaChg84 vaChg104 switchGrpFlg bilateralFlg; 
373 
run; 
374 
/* ...DATA steps to truncate changes in visual acuity and calculate primary 
375 
outcome (vaChgAUC104)... */ 
376 
/* Linear Mixed Model for Each Imputation */ 
377 
proc mixed data=outMI empirical; 
378 
  by _imputation_; 
379 
  class PtID; 
380 
  model vaChgAUC104=va0 bilateralFlg switchGrpFlg / solution 
381 
    covb ddfm=kr2; 
382 
  random int / subject=PtID; 
383 
  ods output solutionF=mixParms covb=mixCovB; 
384 
run; 
385 


Protocol AC Statistical Analysis Plan 
 
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/* Combine Results */ 
386 
proc mianalyze data=mixParms covb(effectvar=rowcol)=mixCovB  
387 
  edf=308;  
388 
/* 312 eyes minus 3 fixed effects + intercept = 308 degrees of freedom */ 
389 
  modeleffects va0 bilateralFlg switchGrpFlg; 
390 
run; 
 
391 


Protocol AC Statistical Analysis Plan 
 
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10.0 
References 
392 
1. 
Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the 
393 
method of choice for handling missing data in randomized trials? Stat Methods Med Res. 
394 
2018;27(9):2610-2626. 
395 
2. 
Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and 
396 
differences. Am J Epidemiol. 2005;162(3):199-200. 
397 
3. 
Localio AR, Margolis DJ, Berlin JA. Relative risks and confidence intervals were easily 
398 
computed indirectly from multivariable logistic regression. J Clin Epidemiol. 
399 
2007;60(9):874-882. 
400 
4. 
Lee EW, Wei LJ, Amato DA. Cox-type regression analysis for large numbers of small 
401 
groups of correlated failure time observations. Dordrecht: Kluwer Academic; 1992. 
402 
5. 
Dmitrienko A, D'Agostino RB, Sr. Multiplicity Considerations in Clinical Trials. N Engl 
403 
J Med. 2018;378(22):2115-2122. 
404 
 

Prot_001.pdf: 
 
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 


 
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8-1 
CHAPTER 8                                                                                            
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REFERENCES 
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8-2 
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