Conditions: Proliferative Diabetic Retinopathy Vitreous Hemorrhage
Keywords: Anti-VEGF Vitrectomy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 205
Healthy volunteers: no

Brief summary:
Although vitreous hemorrhage (VH) from proliferative diabetic retinopathy (PDR) can cause acute and dramatic vision loss for patients with diabetes, there is no current, evidence-based clinical guidance as to what treatment method is most likely to provide the best visual outcomes once intervention is desired. Intravitreous anti-vascular endothelial growth factor (anti-VEGF) therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to stabilize or regress retinal neovascularization. However, clinical trials are lacking to elucidate the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared with initial anti-VEGF treatment. The Diabetic Retinopathy Clinical Research Network Protocol N demonstrated short-term trends consistent with a possible beneficial effect of anti-VEGF treatment in eyes with VH from PDR, including greater visual acuity improvement and reduced rates of recurrent VH as compared with saline injection. It is possible that a study with a longer duration of follow-up with structured anti-VEGF retreatment would demonstrate even greater effectiveness of anti-VEGF for VH to avoid vitrectomy and its attendant adverse events while also improving visual acuity. On the other hand, advances in surgical techniques leading to faster operative times, quicker patient recovery, and reduced complication rates may make prompt vitrectomy a more attractive alternative since it results in the immediate ability to clear hemorrhage and to perform PRP if desired, often as part of one procedure. This proposed study will evaluate the safety and efficacy of two treatment approaches for eyes with VH from PDR: prompt vitrectomy + PRP and intravitreous aflibercept injections.

Detailed description:
A participant could have only one eye enrolled in the study.

Arms:
arm 1: Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. arm 2: For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage.

Interventions: intervention 1: 2-mg Intravitreous Aflibercept Injection intervention 2: Prompt Vitrectomy Plus Panretinal Photocoagulation
Intervention descriptions: intervention 1: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor. intervention 2: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser

Protocol document:
ICF_002.pdf: 
 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 1 of 29 
 
1 
NCT 02858076 
2 
Date 6-24-16 
 
3 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 2 of 29 
Today, you are being asked to take part in this research study because you have bleeding in a 
4 
part of the eye called the “vitreous”.  The vitreous is the jelly-like fluid that fills the large space 
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between the lens in front of the eye and the retina, which lines the back of the eye (see Figure). 
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The bleeding is caused by a condition called diabetic 
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retinopathy, which causes abnormal blood vessel growth on the 
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surface of your retina.   
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Research is done to obtain new knowledge that may help other 
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people in the future.  Participation in this study is on a voluntary 
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basis.  You can decide not to take part in this study at any time.  
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Your study doctor will be talking with you regarding this 
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document.  However, any study-certified doctor from the 
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practice may take care of you during the study if you decide 
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to participate.  If you do not clearly understand information 
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in this document, please ask your study doctor to explain.  
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This study is being conducted by the Diabetic Retinopathy Clinical Research Network 
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(DRCR.net), which is a group of clinical sites dedicated to research of diabetic retinopathy and 
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its associated conditions.  
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Before you decide to take part in this research study, we encourage you to speak with friends and 
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family members.  Take your time making a decision. Carefully read this document.  Your 
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decision will not affect your regular medical care.  If you are taking part in another research 
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study, please tell your study doctor. 
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Important information about this study is found in this consent form.  This form is part of the 
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process to inform you about the research study.  
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Your doctor(s) and/or clinic staff will carry out this study; see their names on the last page.  
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Funding for the study is being provided by the National Eye Institute (NEI), one of the National 
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Institutes of Health of the U.S. Public Health Service, a part of the federal government. 
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Additional support is being provided Regeneron Pharmaceuticals, Inc, which is the company 
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providing drug for this study.  This funding will be used by the Jaeb Center for Health Research 
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https://nei.nih.gov/health/diabetic/retinopathy 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 3 of 29 
to organize the research study and will be paid to your doctor’s office for conducting the study.   
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The Jaeb Center for Health Research is the Coordinating Center for this study. 
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WHY ARE WE DOING THIS STUDY? 
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The purpose of this study is to compare two available treatment approaches for the bleeding in 
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your eye: 
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1) Initial surgical treatment (called “vitrectomy”) OR 
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2) Injections into the eye to start and surgery only if the blood does not go away 
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1) Initial Surgical Treatment 
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When blood in the eye is affecting vision and is not going away on its own, surgery is often done 
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to remove the blood.  This is called a vitrectomy. The surgery involves making a few small 
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incisions in the white of your eye. Then an instrument is put into the eye to remove the blood 
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with the vitreous.  As the blood and vitreous are removed, the eye is usually filled with a saline 
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solution that is gradually replaced after surgery by the eye’s natural fluids.  Laser treatment also 
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is done at the time of surgery to treat the diabetic retinopathy that caused the bleeding.   
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2) Injections into the Eye 
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Another recently available treatment is an injection of a drug through the white part of the eye 
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directly into the middle cavity of the eye.  The injection of drug may stop or reduce the amount 
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of bleeding in your eye enough to avoid surgery, while also treating the diabetic retinopathy that 
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caused it. The type of drug that is injected blocks or decreases a substance in the retina called 
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Vascular Endothelial Growth Factor (“VEGF”).  VEGF plays a role in the development of the 
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diabetic retinopathy that has caused the bleeding in your eye. Drugs that block VEGF are called 
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“anti-VEGF” drugs. There are several anti-VEGF drugs that are used to treat diabetic eye 
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diseases; however Eylea® is the anti-VEGF drug being used in this study.  Eylea injections into 
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the eye have been approved by the U.S. Food and Drug Administration for treatment of DME 
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and also for treatment of diabetic retinopathy in eyes with DME.  Injections of Eylea have not 
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been approved for treatment of vitreous hemorrhage.  Therefore, injections in this study are 
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considered experimental.     
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The information collected from this study will be used to weigh the costs and benefits of the two 
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treatment approaches described above.   
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Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 4 of 29 
HOW MANY PEOPLE ARE WE EXPECTING TAKE PART IN THIS STUDY? 
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We expect about 200 people will take part in this study at about 60 different medical locations.  
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WHAT HAPPENS IF I AGREE TO TAKE PART IN THIS STUDY? 
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To take part in the study, you will need to carefully read and sign this document.  Your 
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participation is VOLUNTARY. You can decide not to take part in this study.  You can decide to 
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stop your participation in this study at any time.  You may continue to receive medical care not 
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related to this study.  No penalty or loss of medical care will result from your decision. 
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The study will last 2 years.  During that time, your visit schedule and treatment will vary.  All of 
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this will be explained in more detail below. 
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First, testing will be done to find out if you are eligible for the study. If both of your eyes have 
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bleeding and are eligible for the study, you and the eye doctor will select one eye to be included 
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in the study.  We will refer to an eligible eye as a study eye.   
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To take part in this study, you must have the following:  
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• Vitreous hemorrhage (bleeding in the eye) from diabetic retinopathy 
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• Decreased vision (about 20/32 or worse) 
90 
 
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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. Some conditions that would exclude you include: 
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• The eye being considered for the study has already had vitrectomy surgery. 
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• You are on dialysis or have had a kidney transplant. 
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• Your blood pressure is greater than 180/110 (systolic above 180 OR diastolic above 110). 
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• You are pregnant or intending to become pregnant in the next 2 years or are nursing an 
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infant.  If you are a woman who has the potential to become pregnant, a pregnancy test 
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may be done to be sure you are not pregnant before you enter the study.  BE CERTAIN 
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TO TELL US IF THERE IS ANY POSSIBILITY YOU COULD BE PREGNANT, AND WE 
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WILL OBTAIN A PREGNANCY TEST. 
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Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 5 of 29 
• You have taken part in a study in which you received investigational treatment within the 
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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 
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to move out of this area within the next two years and want to be in this study, please let us 
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know.  We will see if we can arrange for you to still be in the study. 
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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.  
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Then, some tests will need to be completed, if they have not already been done, to find out if you 
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are eligible for the study.  The tests include: 
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1. Vision Testing 
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• This will include measurement of your visual acuity (the ability to read letters on the 
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vision chart) using an electronic tester.  This measurement will be done of each eye 
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separately.   
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2. Eye Exam 
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• An eye exam will be performed as is done typically for anyone with diabetic 
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retinopathy.   The structures inside the eye will be examined through a special 
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microscope after drops have been placed in your eyes to dilate your pupil.  The 
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pressure in your eye will be measured.  The eye exam will be completed on both 
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eyes, even if only one eye is being evaluated for the study. 
125 
 
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3. Ultrasound 
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• As part of standard care, an ultrasound might be performed in the eye being 
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evaluated for the study to determine if the retina is attached to the back wall of the 
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eye. The ultrasound uses sound waves and measures the echo of those waves to 
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determine the status of the retina structures behind the blood.  
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Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 6 of 29 
 
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4. Optical Coherence Tomography  
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• Optical coherence tomography (referred to as OCT) uses a dim beam of light to 
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measure the thickness of the retina.  You will look into a machine at a pattern of 
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flashing and rotating red lights. This test is done to make sure you do not have 
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swelling of the center of the retina to start. During the study, OCT will be used to 
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find out if retinal swelling has developed and requires treatment.    OCT will only be 
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done on the eye being evaluated for the study. 
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5. 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. 
143 
 
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6. Laboratory Tests 
145 
• A blood test called HbA1c will be done to see how well your diabetes is controlled. 
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In most cases, a fingerstick will be done for HbA1c testing.  If needed, a blood 
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sample less than 3 teaspoons (15 mL) may be taken instead. 
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• If there is any chance that you might be pregnant, a pregnancy test will also be done.  
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7. Questionnaire 
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• You will also be asked to complete a questionnaire about how your vision affects 
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your daily life.   
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If any of the screening tests above show that you are not eligible for the study or you decide not 
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to take part, the eye doctor will discuss your options for treatment of the bleeding in your eye.  
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Whatever treatment is chosen, the results will not be part of the study. 
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B. Study Treatments 
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If you are eligible and agree to take part, we will then determine whether your study eye will 
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receive: 
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1) Initial surgical treatment (“Surgical Group”) OR 
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2) Injections into the eye to start and surgery only if the blood does not go away 
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(“Injection Group”) 
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Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 7 of 29 
 
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A computer program will be used to select whether or not you will be receive initial surgical 
168 
treatment or injections in the eye to start.  This is similar to flipping a coin to decide which 
169 
treatment approach you will receive.  There is an equal chance of getting each treatment 
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approach.   
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Surgical Group 
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If you are in the Surgical Group, surgery must be scheduled within 2 weeks.  The surgery will be 
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done however your eye doctor would perform the surgery in usual practice.  In general, a 
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vitrectomy involves the surgeon removing the vitreous gel and replacing it with saline.  
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Occasionally, the surgeon will add silicone oil or a gas to restore normal pressure in the eye or 
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help to attach the retina to the back wall of the eye.  The surgery usually lasts about 1 to 3 hours.   
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During surgery, you likely will have laser treatment to the retina.  The laser is done to make the 
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blood vessels that caused the bleeding go away.   
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After surgery, you will be monitored to make sure the blood has gone away.  If the blood does 
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not completely go away or comes back, injections into the eye may be given, similar to the 
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Injection Group described below.  If the injections do not work, it is possible another surgery 
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may be needed to remove the blood, although this is not expected to be very common.   
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It is possible that a cataract could develop as a result of the surgery.  “Cataract” is haziness in the 
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lens of the eye.  The lens is involved in focusing so that the eye can see clearly.  The haziness 
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causes vision to be blurred.  If a cataract develops, cataract surgery may be needed.  The cataract 
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surgery itself is not part of the study.  The cataract surgery will be done however your surgeon 
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would do it if you were not in the study.  In most cases, this surgery is successful in improving 
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vision. 
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Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 8 of 29 
The figure below summarizes the Vitrectomy Group treatment for the bleeding and PDR: 
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Injection Group 
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If you are in the Injection Group, you will receive at least 4 monthly injections to start.  To 
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prepare for the injection, anesthetic (numbing) eye drops and eye drops to dilate your pupil will 
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be placed on the surface of your eye.  An antiseptic solution will be used to reduce the chance of 
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infection.  The eye doctor may decide that you should also have an anesthetic injection under the 
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surface of your eye.  After the preparation is complete, the injection will be given.  The amount 
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of drug that will be injected into your eye each time is less than the amount of liquid in 1 drop 
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from a medicine dropper.  After the injection, you will stay in the eye clinic until your doctor 
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believes it is safe for you to leave.   
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After the first 4 monthly injections, your study doctor will decide whether injections should 
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continue based on how your eye is doing.  If the blood is not going away after 4 months, you 
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may need to have a vitrectomy.  If your eye doctor decides you need a vitrectomy, it will be done 
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as described for the Surgical Group above. 
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Even if a vitrectomy is not needed but injections are not enough to also treat the abnormal blood 
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vessels that caused the bleeding in the first place, laser treatment may be given if your eye doctor 
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thinks it is needed.  Laser treatment is a method that has been commonly used for many years as 
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part of standard care. 
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Surgery
Injections
• If the blood does not go completely away or 
comes back, injections may be given
Cataract 
Surgery
Laser
• Cataract could develop within 2 years of initial 
surgery, requiring cataract surgery 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 9 of 29 
 
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The figure below summarizes the Injection Group treatment for the bleeding and PDR: 
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Treatment for DME in Both Groups 
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During the study, you may have or develop swelling of the center of your retina. This is called 
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diabetic macular edema or “DME”.  Anti-VEGF injections have already been shown to be 
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beneficial for DME and are an FDA approved treatment.  For both groups, injections of Eylea 
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will be given to treat DME if your eye doctor thinks it is needed. 
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Treatment of the Non-Study Eye 
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If you and your doctor decide that the eye that is not in the study also needs anti-VEGF treatment 
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during the study, then the non-study eye will receive the same anti-VEGF drug as the study eye 
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(Eylea).  The study will provide this treatment.  If you and your doctor decide that a different 
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anti-VEGF drug should be used, this will not be provided by the study.  All other treatment in 
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your non-study eye will not be provided by the study. 
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Monthly 
Injections
• At least 4 monthly injections to start and then as 
needed
Surgery
• After 4 months, surgery may be needed if the blood does not 
go away
Laser
• If injections not enough to treat the cause of the bleeding, 
laser may be given, without surgery


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 10 of 29 
C. Follow-Up Visits 
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The study will last two years for each participant. All participants will have visits at the 
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following time points: 
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Year 1: 1 month, 3 months, 6 months, 9 months, 12 months  
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Year 2: 16 months, 20 months, 24 months  
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Eyes receiving injections will also be seen as often as every 4 weeks to receive treatment.  If you 
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no longer need injections, you will still have follow-up visits every four to sixteen weeks 
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depending on how your eye is doing. 
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At the end of each visit, you doctor’s office will inform you of the timing of your next 
246 
appointment.   
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In the following table you will find what will be done at each visit. 
249 
 
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0 
1 week 
after 
surgerya 
Treatment 
Assessment 
Visitsb 
Non-
Annual 
Study  
Visitsc 
6-Month and 
Annual visits 
 
Vision testing 
X 
 
X 
X 
X 
OCT 
X 
 
X 
X 
X 
Ultrasound (if needed) 
X 
X 
X 
X 
X 
Eye exam 
X 
X 
X 
X 
X 
Blood pressure 
X 
 
 
 
X 
HbA1c 
X 
 
 
 
X 
Questionnaire 
X 
 
 
X 
X 
Vitreous/aqueous 
sampling* 
X* 
 
 
 
 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
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a = Surgical Group at baseline and Injection Group if vitrectomy is performed during follow-up. 
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b = Every 4 to 16 weeks if receiving injections. 
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c = 1 month, 3 months, 9 months, 16 months, 20 months  
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*At the time of surgery (optional procedure) 
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If you decide not to take part in this study and do not sign this document, you may continue 
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receiving medical care not related to this study.  You can decide to stop your participation in this 
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study at any time.  No penalty or loss of medical care will result from your decision not to take 
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part in this study.   
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ARE THERE RISKS IN THIS STUDY? 
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If you decide to take part in the study, you will be at risk for the side effects listed below.  We 
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encourage you to discuss these with your study doctor, your primary care provider, or another 
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health care professional.  If a treatment or procedure has increased risks because it was not done 
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according to study procedures due to error, you will be informed, and the necessary steps will be 
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taken to care for you. 
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Risks related to your normal medical care are not listed in this form.  We encourage you to 
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discuss these with your study doctor, your primary care provider, or another health care 
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professional.    
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There may be additional risks associated with the drug and/or with the administration method 
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that are not known at this time.  If we become aware of any new risks, you will be told about 
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them.  You will be able to decide if you want to continue to receive the study drug. 
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A. Risks of Vitrectomy Surgery 
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The risks of vitrectomy surgery listed here are general risks.  Your eye doctor may discuss 
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more specific risks with you depending on the exact procedure that is planned. 
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1. Risks Related to Anesthesia 
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Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 12 of 29 
Surgery may be done under general anesthesia or under sedation with numbing of the eye.  
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Numbing of the eye is done with an injection.  Your eye doctor will inform you of the approach 
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that will be used.    
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• Very rare risks of sedation and general anesthesia include cardiac arrhythmia and death 
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(less than 1 in 10,000). 
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• Risks of the injection to numb the eye include: less common side effects such as double 
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vision lasting up to 24 hours or more, drooping of the eye lid lasting up to 24 hours or 
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more, bleeding behind your eyeball or around the eyelids, and rare side effects including 
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damage to your eyeball by the needle, damage to the optic nerve; difficulty speaking or 
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breathing, lightheadedness or fainting, allergy to any components of the injection, or a 
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life threatening response due to the spread of anesthesia to the brain stem, resulting in 
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seizures, drowsiness, confusion, loss of ability to talk, convulsions, stoppage of 
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breathing, or stoppage of heartbeat.   
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2. Risks Related to the Procedure Itself 
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Common risks: 
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• For eyes that have not already had cataract surgery, there is a risk of development of a 
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cataract.  A cataract causes haziness in the lens of the eye, which blurs vision. The lens is 
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involved in focusing so that the eye can see clearly. The haziness causes vision to be 
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blurred.  There is a considerable possibility that a cataract will develop. A previous study 
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found that almost half of eyes that had vitrectomy developed cataract within the first two 
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years after vitrectomy.   If a cataract develops, cataract surgery may be needed.  In most 
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cases, this surgery is successful in improving vision. 
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Less common risks include: 
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• Vitrectomy can affect the surface of the cornea in patients with diabetes.   Some mild 
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irregularity can commonly affect vision short term.  Corneal edema is the temporary 
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swelling of the cornea following ocular surgery and occurs in about 1 in 4 patients. When 
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the cornea swells, it can effect vision.  Topical drops or ointments can be used to relieve 
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the swelling.  Corneal erosion, a more severe problem of the corneal surface can also 
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happen (approximately 2 in 100 chance). Symptoms include pain, tearing and foreign 
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Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
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body sensation which are commonly helped by the use of eye drops. Usually cornea 
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problems heal on their own or with drops but sometimes the problem can be long lasting. 
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• A tear in the retina (approximately 10 in 100 chance).  If a retinal tear occurs, it can be 
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usually be treated with laser treatment or cryotherapy (freezing treatment). If properly 
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treated, a retinal tear may not affect your vision, but should be addressed as quickly as 
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possible by your doctor to prevent loss of vision. 
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• Separation of the retina from the back of the eye (1 in 100 chance).  This is called a 
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retinal detachment and can lead to loss of vision.  If this occurs, surgery may be needed 
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to repair the retina.    
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Rare (uncommon) risks include: 
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• An infection can develop in the eye after the surgery.  This is called endophthalmitis. 
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Endophthalmitis is treated by injecting antibiotics into the eye.  This usually gets rid of 
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the infection.  However, endophthalmitis can produce permanent loss of vision and even 
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blindness.  Your chance of having endophthalmitis is less than 1 in 100. 
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• More serious hemorrhage (1 in 5,000) that can lead to decreased vision if the hemorrhage 
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does not clear.   
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• Very rare risks include  a defect in your peripheral (non-central) vision, vision loss due to 
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excessive bright light, trauma to the retina or retinal dyes used during surgery, and 
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damage to the optic nerve 
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B. Risks of Laser Treatment 
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The laser burns are part of routine care for your diabetic retinopathy. Laser treatment can cause 
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loss of areas of retinal function that may lead to noticeable loss of peripheral (side), color vision 
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or night vision and some worsening of macular edema (swelling of the central retina) that can 
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affect central vision.  One or more of these side effects can occur in up to 50% of persons treated 
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Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
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with laser.  After several years, the scars caused by the laser may also enlarge and cause vision to 
348 
decrease further.  
349 
 
350 
Other serious, but rare (less than 1 in 1000) side effects which may reduce vision include, but are 
351 
not limited to:  
352 
 
353 
• Laser burn too close to the center of vision.  This could cause a permanent black spot in 
354 
your vision. 
355 
 
356 
• Damage to the membrane underneath the retina, sometimes resulting in growth of 
357 
abnormal blood vessels under the retina. 
358 
 
359 
• Increase in pressure inside the eye, which can occur right after the laser or at a later time 
360 
 
361 
• Damage to the optic nerve, iris, or lens  
362 
 
363 
• A tear or small break in the retina called a retinal hole.  Treatments for retinal holes 
364 
include surrounding the hole with laser or freezing.  These treatments are usually 
365 
successful in sealing the hole so it does not get bigger. However, there is a small risk that 
366 
a retinal hole could grow and lead to a retinal detachment. 
367 
 
368 
• Blindness  
369 
 
370 
C. Risks of Eylea Injections 
371 
Injections may cause none, some, or all of the below side-effects. 
372 
 
373 
1.  Risks Related to the Injection Procedure  
374 
 
375 
• It is unlikely that the drugs used to numb your eye before the study drug injections 
376 
(proparacaine, tetracaine, or xylocaine) will cause any problems.  However, in rare 
377 
instances, these drugs can cause an allergic reaction, seizures, and an irregular heartbeat.  
378 
A serious allergic reaction occurs in less than 1 in 100,000.  Your doctor will monitor any 
379 
effects these drugs may cause and treat them as necessary.  In addition to topical numbing 
380 
drops your doctor may also give you a tiny injection of xylocaine to numb your eye 
381 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 15 of 29 
before the study drug injection is given.  You may feel a temporary stinging sensation 
382 
from the xylocaine injection.  If an injection is given, in very rare instances the injection 
383 
can cause damage to your eyeball, damage to the optic nerve, or double vision lasting up 
384 
to 24 hours or more.  Once your eye feels numb, you may still be able to feel touch or 
385 
pressure within your eye, but you should not be able to feel pain.  Sensation usually 
386 
returns within two hours. 
387 
 
388 
More common: 
389 
• You may have pain, redness, discharge, irritation, increased tearing, itching, or a foreign 
390 
body sensation in the eye for a few days after the injection. 
391 
 
392 
• After an injection, you may see spots in your vision (floaters). The spots may be more 
393 
noticeable certain ways you look or with certain lighting.  They usually do not affect your 
394 
vision.  The spots usually go away after a few days or weeks. 
395 
 
396 
• You may experience bleeding in the clear layer of tissue covering the white of the eye 
397 
and inner eyelid or inflammation of the eyelid.  
398 
 
399 
Less common: 
400 
• In rare cases, you may experience temporary drooping of the eyelid lasting up to 24 
401 
hours. In very rare cases the eyelid may droop indefinitely. In such rare cases, surgery on 
402 
the eyelid may be the only treatment to correct the drooping.  The surgical procedure is 
403 
typically successful, but in some cases may not work, and the procedure is accompanied 
404 
by other risks to the eyelid and/or vision. 
405 
 
406 
• The injection or drug could cause an increase in the pressure of the eye right after the 
407 
injection.  The risk of developing an increase in eye pressure is less than 10 in 100.  If 
408 
this happens, eye drops may be given to lower the pressure.  Your chance of permanently 
409 
losing vision is much less than 1 in 100. 
410 
 
411 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 16 of 29 
• The injection could cause haziness in the lens of the eye.  This is called cataract.  The 
412 
lens is involved in focusing so that the eye can see clearly.  The haziness causes vision to 
413 
be blurred.  The risk of developing a cataract from the injection is much less than 1 in 
414 
1000.  If a cataract develops, cataract surgery may be needed.  In most cases, this surgery 
415 
is successful in improving vision. 
416 
 
417 
• An infection can develop in the eye after the injection.  This is called endophthalmitis. 
418 
Endophthalmitis is treated by injecting antibiotics into the eye.  This usually gets rid of 
419 
the infection.  However, endophthalmitis can produce permanent loss of vision and even 
420 
blindness.  Your chance of having endophthalmitis is less than 1 in 100. 
421 
 
422 
• The injection could cause the retina to separate from the back of the eye.  This is called a 
423 
retinal detachment.  If this occurs, surgery may be needed to repair the retina.  The 
424 
surgery is usually successful at reattaching the retina.  However, a retinal detachment can 
425 
produce permanent loss of vision and even blindness.  Your chance of having a retinal 
426 
detachment is much less than 1 in 100. 
427 
 
428 
• The injection could cause bleeding in the middle cavity of the eye.  This is called a 
429 
vitreous hemorrhage.  Usually the blood will go away on its own.  If it does not go away, 
430 
surgery may be needed to remove the blood.  This surgery usually removes the blood 
431 
completely.  However, a vitreous hemorrhage can produce permanent loss of vision and 
432 
even blindness.  Your chance of having a vitreous hemorrhage is less than 1 in 100. 
433 
 
434 
2. Risks in the Eye Related to Eylea 
435 
Eylea is well tolerated in people. Possible side effects to the eye from the drug itself include: 
436 
 
437 
• Inflammation of the eye.  This is called uveitis.  Uveitis can be successfully treated with 
438 
steroid eye drops, injections, or pills.  However, uveitis can lead to permanent loss of 
439 
vision if not treated early.  In previous studies, approximately 2 out of 100 patients 
440 
developed uveitis. 
441 
 
442 
• Traction retinal detachment.  It is possible that injection of Eylea might increase the 
443 
chance of developing a traction retinal detachment, but this risk has not been seen in large 
444 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 17 of 29 
studies evaluating for this possibility.  A traction retinal detachment can lead to additional 
445 
vision loss or possibly permanent vision loss and often requires surgery to try to re-attach 
446 
the retina to the back wall of the eye. Your eye doctor for this study will monitor for this 
447 
complication so that it can be managed appropriately if it develops. 
448 
 
449 
3. Risks to the Rest of the Body Specific to Eylea: 
450 
Anti-VEGF agents are used to treat certain types of cancer.  The dose of these drugs when used 
451 
to treat cancer is much higher than comparable doses used for injections into the eye.  When used 
452 
to treat cancer, these drugs have caused certain side effects including high blood pressure, blood 
453 
clots in arteries such as heart attack or stroke, kidney problems, bleeding within the 
454 
gastrointestinal (digestive) tract, vaginal bleeding, surgery and wound healing complications, 
455 
joint pain, skin rash or hives, and breathing difficulties or shock. Since the dose used for the eye 
456 
injections is so low, we do not expect any of these side effects to occur due to the drug. 
457 
However, we cannot rule out the possibility of a small risk from the drug.  In our prior study 
458 
comparing different anti-VEGF drugs in people with diabetes, we did not find an increased risk 
459 
of serious events like heart attack or stroke from Eylea compared with other available anti-VEGF 
460 
drugs. 
461 
4. Risks if You Become Pregnant 
462 
The effects of Eylea on a human fetus (unborn baby) or nursing (breast feeding) infant are 
463 
unknown. It is possible that use of these drugs may be associated with unanticipated risks to a 
464 
pregnancy or fetus. Therefore, you will not be allowed to participate in this study if you are 
465 
pregnant, planning to become pregnant within the next 24 months, or if you are nursing an 
466 
infant.  During the study, females who are capable of bearing children must agree to use an 
467 
effective method of birth control to prevent pregnancy.  In the event of pregnancy during the 
468 
study, injections will be discontinued.     
469 
 
470 
D. Risks of Eye Examination and Tests 
471 
1. Eye Exam:   
472 
• As part of the eye exam, drops will be put in your eyes to dilate the pupils. The 
473 
drops may blur your vision and make you sensitive to light.  The drops will wear 
474 
off over several hours.  There is a small risk of an allergic reaction to the drops.  
475 
There is also a small risk that the drops could cause the eye pressure to raise.  If 
476 
this happens, it will be treated, but there is a small risk of losing vision from the 
477 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 18 of 29 
pressure rise.  Due to the blurring effect on your vision and possible light 
478 
sensitivity, we recommend that you do not drive until the blurring effects of the 
479 
drops have worn off.  If necessary, have someone come with you who can drive 
480 
for you after the exam. 
481 
 
482 
3. OCT:  There are no known risks associated with OCT. 
483 
 
484 
4. Risks of Ultrasound (if performed):     
485 
• These sound waves are of no risk to your retina, although the probe used to 
486 
produce the sound waves rarely can cause some slight irritation to the surface of 
487 
the eye; this irritation almost always resolves within a short time without 
488 
treatment.  
489 
 
490 
5. Blood Draw Risks: Possible risks from blood draws include the following: bruising, arm 
491 
discomfort, clotting, excess bleeding, infection, or fainting.  Please note that although 
492 
these are possible risks they are unlikely. 
493 
 
494 
 
495 
WHAT ARE THE BENEFITS OF TAKING PART IN THIS STUDY?  
496 
The study treatment may help clear the bleeding in your eye and help preserve your vision, but it 
497 
is not a guarantee.  You may receive no direct benefit from being in the study.  People who take 
498 
part in this research study will add to new knowledge that may help other people with the same 
499 
problem. 
500 
 
501 
WHAT ALTERNATIVE PROCEDURES OR TREATMENT ARE AVAILABLE IF I DO 
502 
NOT TAKE PART IN THIS STUDY? 
503 
If you do not take part in this study, you could receive the alternative procedures or treatment 
504 
listed below: 
505 
• 
Observation outside of the study to see if the blood clears on its own 
506 
• 
An anti-VEGF drug outside of the study 
507 
• 
Vitrectomy surgery outside of the study 
508 
 
509 
Any of the above alternatives may be done with or without laser treatment.   
510 
 
511 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 19 of 29 
We encourage you to discuss these alternative procedures and/or treatment with your study 
512 
doctor, your primary care physician, or another health care professional.   
513 
 
514 
WHAT IF I WANT TO WITHDRAW FROM THE STUDY, OR I AM ASKED TO 
515 
WITHDRAW FROM THE STUDY? 
516 
 
517 
You can stop participating in this study at any time.  You may continue to receive medical care 
518 
not related to this study.  No penalty or loss of medical care will result from your decision.  
519 
However, we encourage you to talk to a member of the research group so that they know why 
520 
you are leaving the study.  If there are any new findings during the study that may affect whether 
521 
you want to continue participating, you will be told about them. 
522 
 
523 
The investigator may decide to stop your participation without your permission, if he or she 
524 
thinks that being in the study may cause you harm. 
525 
 
526 
HOW WILL MY INFORMATION BE PROTECTED AND KEPT CONFIDENTIAL? 
527 
As required by law, study related records with identifying information will be kept confidential. 
528 
Safeguards for authorized access, security, and privacy of your information have been put in 
529 
place by the Federal Privacy Regulations.  Unless the law requires it, your name, address, social 
530 
security number, telephone number, or any other direct identifying information will not be used 
531 
to identify you.  
532 
 
533 
A. Purpose of Authorization 
534 
We have rules to protect information about you.  Federal and state laws and the federal medical 
535 
Privacy Rule also protect your information.  By signing this form you provide your permission, 
536 
called your “authorization,” for the use and disclosure of information protected by the Privacy 
537 
Rule.  
538 
 
539 
You must sign the Protected Health Information Authorization at the end of this form if you 
540 
want to be in the study.  When you sign the form, you give permission for the use and disclosure 
541 
of your Protected Health Information (PHI) for the study.  PHI is health information that 
542 
identifies you.  Your authorization is beneficial and important for the study.  Without your 
543 
authorization, you will not be able to be in it. 
544 
 
545 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 20 of 29 
B. Use and Disclosure of the PHI 
546 
Your study doctor will collect information about you.  This information includes things learned 
547 
from procedures listed and described in this form as well as your name, address, date of birth, 
548 
and information from your medical records.  Your name, address, telephone number, and social 
549 
security number are examples of identifiable information. 
550 
 
551 
A code number will go with your study results instead of your name, address, telephone number, 
552 
or social security number.  Your study results will be given to the Jaeb Center for Health 
553 
Research.  The Jaeb Center is the coordinating center for the study.  It is located in Tampa, 
554 
Florida.   
555 
 
556 
This doctor’s office will not disclose study results that have your identifiable information except 
557 
as explained in Section C. or when required by law.  The Jaeb Center and this doctor’s office will 
558 
guard the privacy of your study PHI. 
559 
 
560 
Study results without your protected information may appear in medical journals and be shared 
561 
at scientific meetings.  Your records will be kept confidential.  No one will disclose your identity 
562 
in a medical journal or at a scientific meeting.    
563 
 
564 
C. Authorized Recipients and Users 
565 
People outside of this doctor’s office and the Jaeb Center may need to see or receive your 
566 
information from this study.  Some examples include: 
567 
1. The people who work for this doctor’s office. 
568 
2. The people who work for the Jaeb Center. 
569 
3. The scientific investigators who help run the study. 
570 
4. Any review board that oversees human investigations rules for your doctor’s office 
571 
5. Any federal agency that oversees clinical trials. 
572 
6. If you have an adverse (unfavorable) event, the people outside this doctor’s office who 
573 
assist in your care. 
574 
7. Your doctor may send your blood sample for HbA1c to a central laboratory for this study. 
575 
8. The OCTs of your eye may be sent to a central reading center. 
576 
9. The industry partner, Regeneron Pharmaceuticals, Inc., their agents, collaborators, and 
577 
representatives.   
578 
 
579 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 21 of 29 
In most cases the information will have a code number with it instead of your name, address, 
580 
telephone number, or social security number.  
581 
 
582 
There are some situations where the information will not have a code number with it.  If so, 
583 
people outside this doctor’s office who assist in your care may see your study PHI.  They may 
584 
not be covered by the federal Privacy Rule.  We try to make sure that everyone who needs to see 
585 
your information keeps it confidential – but we cannot guarantee that your information will not 
586 
be disclosed.  
587 
 
588 
Other Considerations 
589 
The data collected in the study may be provided to other researchers to use; however, the data 
590 
that are provided will not contain any information that could identify you.   
591 
 
592 
After the results are made public, all of the study data collected may also be made public.  
593 
However, there will be no identifying information included. You will be informed of the study 
594 
results when they are made public.   
595 
 
596 
Separately from your research data, the Jaeb Center for Health Research in Tampa, Florida will  
597 
be provided with information on how to contact you. 
598 
 
599 
• About every 6 months, you may receive a phone call from a staff member at the Jaeb 
600 
Center to check on your condition and to see if you have any questions.  You will be 
601 
called at a time that you indicate is most convenient for you.  If you are not available at 
602 
the time of the call and prefer to call the coordinating center yourself, you can call the 
603 
coordinating center toll-free at 1-866-372-7601 
604 
 
605 
• If we are not able to locate you when we try to schedule your follow-up visit, the Jaeb  
606 
Center may try to contact you through the alternative contact information you have given 
607 
us.  If this is not successful, the Jaeb Center may use the information you have given us to 
608 
try to locate you through the use of a third-party search service.  
609 
 
610 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
611 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
612 
Web site will include a summary of the results.  You can search this Web site at any time. 
613 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 22 of 29 
 
614 
D. Cancellation of Authorization 
615 
You may cancel your permission for the use and disclosure of your study PHI at any time.  You 
616 
need to contact your study doctor and give him/her a notice of cancellation in writing.  When you 
617 
cancel your permission or when you withdraw from the study directly, you are no longer part of 
618 
the study.  No new information about you will be gathered for the study except when it is on an 
619 
adverse (unfavorable) event that is related or potentially related to the study.  If one happens, 
620 
your entire medical record may need to be reviewed.   
621 
 
622 
The Jaeb Center will receive all the information that has already been collected for the study up 
623 
to the time of cancellation or withdrawal.  Any new information about any adverse (unfavorable) 
624 
event that is related or potentially related to the study will also be sent to the Jaeb Center. 
625 
 
626 
E. 50 Year Expiration Date and Indefinite Expiration Date  
627 
Some of your study PHI does not have a code number with it.  Your permission for the use and 
628 
disclosure of this PHI lasts 50 years from the date of your signature or until the end of the study, 
629 
whichever is sooner.   
630 
 
631 
The rest of your study PHI does have a code number with it.  When it is collected, it becomes a 
632 
research report.  Your permission for the use and disclosure of these coded data will never end.  
633 
These coded data do not have your name, address, telephone number, or social security number.  
634 
The above supports the HIPAA Privacy Rule – 45 CFR 164.508 
635 
 
636 
ARE THERE COSTS RELATED TO TAKING PART IN THE STUDY? 
637 
Testing that is specifically for this study will be paid for by the study. The costs of treatment, 
638 
office visits, and tests that are part of your usual eye care will be your or your insurance 
639 
company’s responsibility.  The study will pay for: 
640 
• Visual acuity using an electronic tester at each visit. 
641 
• The eye exam at 1 month, 9 months, 16 months, and 20 months in both groups, and 
642 
treatment assessment visits required in the Injection Group 
643 
• The OCT at baseline, 6 months, and annual visits. 
644 
• All study injections, including Eylea injections in the non-study eye if needed. 
645 
 
646 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 23 of 29 
All other tests and procedures, including the following, are your or your insurance company’s 
647 
responsibility: 
648 
• The eye exam at 1 week post-vitrectomy, 3 months, 6 months, 12 months, 24 months 
649 
• OCT as needed for DME assessment. 
650 
• Vitrectomy surgery 
651 
• Laser treatment 
652 
• Cataract surgery (if needed) 
653 
 
654 
Depending on your insurance plan, it is possible that your insurance will not pay for some of the 
655 
procedures and testing listed above; if they do not pay, the study may become responsible for 
656 
these costs if you have a financial hardship.  For surgical costs (vitrectomy and cataract), for 
657 
cases of financial hardship, the study is able to reimburse up to a certain amount.  It is possible 
658 
that costs above that amount will not be covered.  Costs for other tests and procedures not listed 
659 
above that are done as part of your usual eye care, including testing and other treatment in an eye 
660 
not in the study, will not be covered by the study.   
661 
 
662 
By signing this form, you certify that you understand that not all of the tests and procedures will 
663 
be paid by the study and that you are aware that you or your insurance company will be charged 
664 
for standard care procedures. 
665 
 
666 
If you have travel expenses that make it difficult for you to return for study visits, additional 
667 
funds may be available. 
668 
 
669 
IS THERE COMPENSATION FOR TAKING PART IN THIS STUDY? 
670 
If you take part in the study, you will be given a $25 gift or money card for each visit required 
671 
for the study.  This gift or money card is being given to you to help with the additional costs that 
672 
may result from completing study visits.  If you do not complete all of the visits or discontinue 
673 
the study before it ends, you will only receive a gift card for the visits that you did complete.  
674 
You will not receive a gift or money card for extra visits your doctor believes are needed for 
675 
your usual care.  
676 
 
677 
WHAT HAPPENS IF I EXPERIENCE A RESEARCH RELATED INJURY? 
678 
Medical care is available if you have a research-related injury.  If you have an emergency, you 
679 
can get emergency care.  If possible, you should tell the emergency care medical staff that you 
680 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 24 of 29 
are in a research study.  You should also tell your study doctor about the emergency as soon as 
681 
possible.   
682 
 
683 
The study will not provide costs for medical expenses or any other costs for research-related 
684 
injuries. The costs of care are your or your insurance company’s responsibility.  Money for lost 
685 
wages and/or direct or indirect losses is not available.  
686 
 
687 
If you have questions about the study or research-related injuries, contact DRCR.net staff at 1-
688 
866-372-7601 during normal business hours.  
689 
 
690 
WHO SHOULD I CONTACT, IF I SHOULD EXPERIENCE ANY PROBLEMS OR 
691 
HAVE ANY QUESTIONS? 
692 
If you have questions about this study, a research-related injury, have concerns, suggestions or 
693 
questions about the study, please see the contact information on the last page.  
694 
 
695 
If you have questions about your rights as a research participant, wish to talk about your 
696 
concerns or suggestions linked to the research study, want additional information about the 
697 
research, or want to provide comments about the research, contact the Jaeb Center for Health 
698 
Research Institutional Review (IRB) Office at 813-975-8690 or irb@jaeb.org 
699 
 
700 
WITHDRAWAL BY INVESTIGATOR, PHYSICIAN, OR FUNDING SOURCE 
701 
The investigators, physicians or funding source may stop the study or take you out of the study at 
702 
any time should they judge that it is in your best interest to do so, if you experience a study-
703 
related injury, if you need additional or different medication, or if you do not comply with the 
704 
study plan. They may remove you from the study for various other administrative and medical 
705 
reasons. They can do this without your consent. 
706 
 
 
707 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 25 of 29 
Your Full Name (printed)  
 
 
 
 
 
 
708 
 
709 
Description of Representative’s Authority to Act for the Subject 
710 
________________________________________________ (if applicable) 
711 
 
712 
Protected Health Information Authorization 
713 
 
714 
 
715 
Study Enrollment 
716 
 
717 
You will be given a signed copy of this document in case you want to read it again. 
718 
 
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:    Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage 
from Proliferative Diabetic Retinopathy (Protocol AB) 
 
 
 
 
 
 
 
Participant 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 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 26 of 29 
**Optional Sample Collection During Surgery** 
 
Your eye doctor’s office may be part of an ancillary study to collect fluid samples at the time of surgery 
that will be studied to look at different factors related to diabetic retinopathy or other conditions.   If so, 
you will be asked to complete this section.  
 
 This box will be checked if your eye doctor is NOT participating (leave next page blank); 
otherwise continue reading and complete next page. 
 
If you have vitrectomy surgery during the study and agree to take part in this sample collection study, one 
sample can be taken from the vitreous that is already being removed, without any additional procedures or 
risk.  A second sample may be taken, which will likely require an additional needle stick through the 
cornea, the clear surface on the front of the eye. A common risk of this second needle stick is the 
formation of a small corneal scar which is unlikely to be visible or to affect the vision.  Less common risks 
include substantial leakage of fluid from the eye or damage to the lens.  An eye infection may rarely 
develop and may be treated with antibiotics or surgery if it develops. 
 
If you agree to take part in this additional sample collection, you will have the option to provide one or 
both samples.    
 
The samples will be stored at a facility located in the United States until the researchers are ready to 
analyze them.  All identifiable information about you will be removed from the research specimen. Your 
sample and study data will be linked only by a code. The results from these samples will be used for 
research purposes only and you will not be told the results of the tests. 
 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 27 of 29 
 
Sample Collection Study Enrollment 
 
I have read the explanation above about the optional sample collection during surgery.  I have been given 
the opportunity to discuss the study and to ask questions.  I understand if I consent to provide additional 
samples, they will be used by investigators within the DRCR.net for research purposes only.   
 
I authorize the use and disclosure of my protected health information collected as part of this study. I 
acknowledge that I will not be contacted or asked for my consent again at the time when my sample is 
used.   
 
Please choose only one of the options below: 
 
1.  ____ I hereby give my consent to have both samples drawn during surgery.  I acknowledge that there 
is additional risk to the second sample, which will likely require an additional needle stick.  
 
2.  ____ I hereby give my consent to have only the vitreous sample drawn during surgery (no additional 
needle stick).    
 
3.  ____ I do not want to provide any additional samples for this ancillary study. 
 
If you consent, you have the right to request at any time that your samples be destroyed.  Your sample can 
be destroyed (when possible) on your written request.  However, if the sample has already been tested, the 
information obtained from the sample will not be destroyed.   
 
Participant Signature: _________________________ 
 
Date:  ______________ 
I certify that to the best of my knowledge the subject understands the nature, demands, risks and 
benefits involved in participating in this ancillary study. 
 
Investigator’s Signature:  _______________________  
 
Date:  ______________ 
 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 28 of 29 
Appendix – Glossary of Terms 
719 
 
720 
Anti-VEGF – the type of drug being used in this study, which blocks a substance called 
721 
Vascular Endothelial Growth Factor (VEGF).  Anti-VEGF drugs decrease the growth of new 
722 
blood vessels and prevent leakage of fluid.   
723 
Diabetic Retinopathy – a condition that causes abnormal blood vessel growth on the surface of 
724 
the retina.   
725 
DME –diabetic macular edema (DME) is the term used for swelling in the small central part of 
726 
the retina.   
727 
DRCR.net – the Diabetic Retinopathy Clinical Research Network (DRCR.net) is conducting the 
728 
study under a grant from the National Eye Institute, one of the National Institutes of Health of 
729 
the U.S. Public Health Service, a part of the federal government 
730 
HbA1c - A blood test to see how well your diabetes is controlled 
731 
Jaeb Center - the coordinating center for the study located in Tampa, Florida.   
732 
OCT - optical coherence tomography (referred to as OCT) uses a dim beam of light to measure 
733 
the thickness of the retina 
734 
PHI – protected health information, which may be collected as part of the study 
735 
Retina - the light-sensitive tissue which lines the back of the eye.  
736 
Study eye - the eye to be included in the study  
737 
Visual Acuity Testing - the ability to read letters on the vision chart 
738 
Vitreous Hemorrhage – bleeding in a part of the jelly-like fluid that fills the large space in front 
739 
of the retina. 
740 
Vitrectomy – surgery in which an instrument is put into the eye to remove the blood with the 
741 
vitreous.   
742 
743 


 
 
 
Consent to Participate in a Research Study 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative 
Diabetic Retinopathy (Protocol AB) 
 
AB Informed Consent Version 1.0 6-24-16             [Protocol Version 1.0] 
Page 29 of 29 
INVESTIGATOR CONTACT INFORMATION 
744 
 
745 
 
746 
 
747 
Name of Investigators:  _<list all investigators at site>_________ 
748 
 
_____________________________ 
749 
 
_____________________________ 
750 
 
_____________________________ 
751 
 
_____________________________ 
752 
 
753 
 
754 
Address:  __________________________________________ 
755 
___________________________________________________ 
756 
 
757 
 
758 
 
759 
Telephone:  ________________________________________ 
760 
 
761 
 
762 
 
763 
After hours telephone:  ______________________________ 
764 
 
765 
 
766 

Prot_000.pdf: 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
 
 
1 
Diabetic Retinopathy Clinical Research 
2 
Network 
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5 
Intravitreous Anti-VEGF vs. Prompt 
6 
Vitrectomy for Vitreous Hemorrhage 
7 
from Proliferative Diabetic Retinopathy 
8 
NCT 02858076 
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10 
Version 1.0 
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12 
 
13 
July 28, 2016 
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Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
 
Table of Contents 
31 
 
32 
Chapter 1. Background Information and Study Synopsis ..................................................... 1-1 
33 
1.1 Background and Rationale ............................................................................................... 1-1 
34 
1.1.1 Public Health Impact of Diabetic Retinopathy ........................................................... 1-1 
35 
1.1.2 Treatment Options for VH from PDR ........................................................................ 1-1 
36 
1.1.3 Aflibercept .................................................................................................................. 1-3 
37 
1.1.4 Summary of Study Rationale ...................................................................................... 1-4 
38 
1.2 Study Objectives .............................................................................................................. 1-4 
39 
1.3 Study Design and Synopsis of Protocol ........................................................................... 1-4 
40 
1.4 General Considerations .................................................................................................... 1-7 
41 
Chapter 2. Study Participant Eligibility and Enrollment ...................................................... 2-1 
42 
2.1 Identifying Eligible Participants and Obtaining Informed Consent .................................. 2-1 
43 
2.2 Participant Eligibility Criteria ............................................................................................ 2-1 
44 
2.2.1 Participant-level Criteria ............................................................................................. 2-1 
45 
2.2.2 Study Eye Criteria ....................................................................................................... 2-2 
46 
2.2.3 Non-Study Eye Criteria............................................................................................... 2-4 
47 
2.3 Screening Evaluation and Baseline Testing ....................................................................... 2-4 
48 
2.3.1 Historical Information ................................................................................................. 2-4 
49 
2.3.2 Baseline Testing Procedures ....................................................................................... 2-4 
50 
2.4 Enrollment/Randomization of Eligible Participants .......................................................... 2-5 
51 
Chapter 3. Follow-Up Visits and Testing ................................................................................. 3-1 
52 
3.1 Visit Schedule .................................................................................................................... 3-1 
53 
3.2 Testing Procedures ............................................................................................................. 3-1 
54 
Chapter 4. Treatment Regimen ................................................................................................ 4-1 
55 
4.1 Introduction ........................................................................................................................ 4-1 
56 
4.2 Intravitreous Injections ...................................................................................................... 4-1 
57 
4.2.1 Inravitreous Aflibercept Injection (Eylea®) ............................................................... 4-1 
58 
4.2.2 Intravitreous Injection Technique ............................................................................... 4-1 
59 
4.2.3 Delay in Giving Injections .......................................................................................... 4-1 
60 
4.2.4 Deferral of Injections Due to Pregnancy .................................................................... 4-1 
61 
4.2.5 Non-Study Eye Injections ........................................................................................ 4-2 
62 
4.3 Aflibercept Group Follow-Up Treatment .......................................................................... 4-2 
63 
4.3.1 Retreatment with Intravitreous Injections of Aflibercept for Vitreous Hemorrhage and 
64 
underlying PDR ................................................................................................................... 4-2 
65 
4.3.2 PRP during Follow-Up ............................................................................................... 4-2 
66 
4.3.3 Vitrectomy during Follow-Up .................................................................................... 4-3 
67 
4.4 Vitrectomy ......................................................................................................................... 4-3 
68 
4.4.1 Vitreous and Aqueous Sample Collection .................................................................. 4-4 
69 
4.4.2 Deferral or Cancellation of Surgery in the Vitrectomy Group ................................... 4-4 
70 
4.5 Vitrectomy Group Intra- and Post-Operative Treatment ................................................... 4-4 
71 
4.5.1 Panretinal Photocoagulation in the Vitrectomy Group ............................................... 4-4 
72 
4.5.2 Treatment for Recurrent Vitreous Hemorrhage in the Vitrectomy Group ................. 4-5 
73 
4.6 Cataract Surgery (Both Groups) ........................................................................................ 4-5 
74 
4.7 Treatment for Diabetic Macular Edema (Both Groups) .................................................... 4-5 
75 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
 
4.7.1. Intravitreous Injection Retreatment for DME ............................................................ 4-5 
76 
4.7.2. Focal/Grid Laser Treatment for DME ....................................................................... 4-6 
77 
Chapter 5. Miscellaneous Considerations in Follow-up ......................................................... 5-1 
78 
5.1 Endophthalmitis ................................................................................................................. 5-1 
79 
5.2 Treatment of Diabetic Retinopathy in Non-study Eye ...................................................... 5-1 
80 
5.3 Use of Intravitreal Anti-VEGF for Conditions Other than DME in the Study Eye ........... 5-1 
81 
5.4 Diabetes Management ........................................................................................................ 5-1 
82 
5.5 Study Participant Withdrawal and Losses to Follow-up.................................................... 5-1 
83 
5.6 Discontinuation of Study ................................................................................................... 5-1 
84 
5.7 Contact Information Provided to the Coordinating Center ................................................ 5-2 
85 
5.8 Study Participant Reimbursement...................................................................................... 5-2 
86 
Chapter 6. Adverse Events ........................................................................................................ 6-1 
87 
6.1 Definition ........................................................................................................................... 6-1 
88 
6.2 Recording of Adverse Events ............................................................................................ 6-1 
89 
6.3 Reporting Serious or Unexpected Adverse Events ............................................................ 6-2 
90 
6.4 Data and Safety Monitoring Committee Review of Adverse Events ................................ 6-2 
91 
6.5 Risks ................................................................................................................................... 6-2 
92 
6.5.1 Potential Adverse Effects of Aflibercept .................................................................... 6-2 
93 
6.5.2 Potential Adverse Effects of Intravitreous Injection ................................................... 6-3 
94 
6.5.3  Risks of Vitrectomy ................................................................................................... 6-3 
95 
6.5.4  Risks of Panretinal Photocoagulation Treatment ....................................................... 6-4 
96 
6.5.5 Risks of Eye Examination and Tests .......................................................................... 6-4 
97 
Chapter 7. Statistical Methods.................................................................................................. 7-1 
98 
7.1 Sample Size ........................................................................................................................ 7-1 
99 
7.1.1 Sample Size Assumptions ........................................................................................... 7-1 
100 
7.1.2 Sample Size Estimation .............................................................................................. 7-2 
101 
7.1.3 Statistical Power.......................................................................................................... 7-3 
102 
7.2 Primary Analysis Plan........................................................................................................ 7-4 
103 
7.2.1 Principles for Analysis ................................................................................................ 7-4 
104 
7.2.2 Per-Protocol Analysis ................................................................................................. 7-4 
105 
7.2.3 Interim Analysis Plan .................................................................................................. 7-5 
106 
7.3 Secondary Outcomes ......................................................................................................... 7-5 
107 
7.3.1 Outcomes within Treatment Groups ........................................................................... 7-5 
108 
7.3.2 Economic Analysis ..................................................................................................... 7-5 
109 
7.4 Safety Analysis Plan .......................................................................................................... 7-6 
110 
7.5 Additional Tabulations and Analyses ................................................................................ 7-7 
111 
7.6 Statistical Modeling Techniques ........................................................................................ 7-7 
112 
Chapter 8. References ................................................................................................................ 8-1 
113 
 
114 
 
115 
 
116 
 
117 
 
 
118 
 
119 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
1-1 
 
120 
CHAPTER 1.                                                                                         
121 
BACKGROUND INFORMATION AND STUDY SYNOPSIS                                            
122 
 
123 
1.1 Background and Rationale 
124 
1.1.1 Public Health Impact of Diabetic Retinopathy 
125 
Diabetic Retinopathy (DR) is the leading cause of visual loss and new-onset blindness in the 
126 
United States for those 20 through 74 years of age.1 As of 2010, 3.63 million people worldwide 
127 
are estimated to have at least moderate vision loss due to the complications of DR, and 850 
128 
thousand are estimated to suffer from blindness due to DR.2  Proliferaitve diabetic retinopathy 
129 
(PDR) can lead to vitreous hemorrhage (VH) which may affect vision and is a leading indication 
130 
for vitrectomy. Vitreous hemorrhage also can preclude performing panretinal photocoagulation 
131 
(PRP), as well as the evaluation and treatment of other diabetic and non-diabetic retinal 
132 
pathology such as diabetic macular edema (DME) and age-related macular degeneration.  Even 
133 
in the modern era of using either PRP or anti-vascular endothelial growth factor (anti-VEGF) 
134 
therapy to treat PDR, a Diabetic Retinopathy Clinical Research Network (DRCR.net) clinical 
135 
trial showed that 27% to 34% of eyes developed VH over 2 years even after treatment was 
136 
initiated with either anti-VEGF or PRP, respectively.3  Given the increasing prevalence of 
137 
diabetes in the United States and worldwide, the public health impact of PDR and its 
138 
complications are large.2, 4  
139 
 
140 
1.1.2 Treatment Options for VH from PDR 
141 
Although VH by itself is not detrimental to the eye, rapid clearance of the hemorrhage is 
142 
desirable for both functional and anatomic reasons and also allows evaluation and treatment of 
143 
the eye for other pathology such as DME.  Functional central and peripheral visual acuity (VA) 
144 
is commonly affected adversely by intraocular hemorrhage. As long as the retinal status remains 
145 
stable, VA usually improves once the blood resolves.  However, vitreous traction on or 
146 
contraction of fibrous proliferans associated with retinal neovascularization, leading to VH, can 
147 
lead to further complications causing VA loss if left unchecked.  Prior to the advent of anti-
148 
VEGF therapy, in most cases of VH, PRP was performed as soon as the media cleared 
149 
sufficiently to allow visibility and laser uptake.  The goal of the PRP was to achieve regression 
150 
of new vessels or at least stabilization of the neovascularization in order to decrease the 
151 
probability of new or worsening VH or traction or rhegmatogenous retinal detachment while 
152 
further clearing of the hemorrhage occurred.  PRP generally leads to regression or quiescence of 
153 
retinal neovascularization after a limited number of treatments and results in a reduction of 
154 
severe vision loss over 5 years to rates as low as 4%. 5  
155 
 
156 
Although PRP has been the standard care for PDR for several decades, results from the 
157 
DRCR.net Protocol S (Prompt Panretinal Photocoagulation versus Intravitreal Ranibizumab with 
158 
Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy) published in 
159 
November 2015 suggest that anti-VEGF therapy is a safe and effective treatment alternative for 
160 
PDR, with advantages over PRP in reductions in visual field sensitivity loss, need for vitrectomy 
161 
and development of DME.3  This study demonstrated  non-inferiority of mean visual acuity letter 
162 
improvement at 2 years for eyes treated with ranibizumab and deferred PRP as compared to 
163 
those given prompt PRP for baseline PDR (difference +2.2, 95% confidence interval [CI]: -0.5 to 
164 
+5.0, non-inferiority P<0.001).  Although visual change at 2 years was not superior in the anti-
165 
VEGF group, the average visual acuity over 2 years (area under the curve) was significantly 
166 
better in eyes that received anti-VEGF with a mean treatment group difference of +4.2 (95% CI: 
167 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
1-2 
+3.0 to +5.4, P<0.001).  In addition, eyes that underwent prompt PRP had greater visual field 
168 
sensitivity loss (mean dB difference 372; 95% CI: 213 to 531, P<0.001), more frequent 
169 
vitrectomy (15% versus 4%, difference 9%, 95% CI: 4% to 15%, P<0.001), and, among those 
170 
without DME causing VA loss at baseline, were more likely to develop DME causing VA loss 
171 
(28% versus 9%, difference 19%, 95% CI: 10% to 28%, P<0.001) over the course of 2 years. 
172 
 
173 
Two approaches for the management of VH from PDR are vitrectomy and treatment with anti-
174 
VEGF agents, the latter being highly effective even at small doses in regressing PDR.6 Although 
175 
clinical results suggest that both these methods are effective at improving retinal 
176 
neovascularization, to date there has not been a randomized clinical trial with head to head 
177 
comparison of their relative efficacy in improving VA in eyes with VH from PDR.  
178 
 
179 
A standard approach for treatment of VH associated with PDR is to proceed to prompt 
180 
vitrectomy in order to provide the fastest possible improvement in VA.  Vitrectomy, or surgical 
181 
removal of the vitreous gel and associated hemorrhage, enables rapid clearance of VH and 
182 
concurrent delivery of panretinal endolaser.  In cases in which traction retinal detachments or 
183 
rhegmatogenous detachments occur, vitrectomy can also eliminate extensive neovascularization 
184 
and treat existing retinal detachments.7  Many advances in instrumentation and technique have 
185 
resulted in dramatically faster surgical times, easier patient recovery and a reduction in 
186 
complications over the last few decades.8  In particular, the advent of 23 gauge surgical 
187 
techniques, and smaller, have resulted in smaller surgical incisions and the possibility of 
188 
sutureless surgery in addition to smaller instruments that allow more delicate manipulations of 
189 
fibrovascular retinal tissue.8  According to Castellarin et al,  surgical complications still remain, 
190 
including recurrent hemorrhage,9 neovascular glaucoma, retinal detachment, fibrinoid syndrome, 
191 
endophthalmitis and hypotony with subsequent phthisis bulbi.10  It should be noted that many 
192 
reports of vitrectomy outcomes in the diabetic population combine results from eyes with 
193 
complex traction retinal detachments together with those from uncomplicated VH.11, 12  
194 
However, data acquired from a cross-sectional population based study in the United Kingdom 
195 
suggest that eyes with simple VH have substantially better functional and anatomic outcomes 
196 
than those with any component of traction retinal detachment.13   
197 
 
198 
The Diabetic Retinopathy Vitrectomy Study from the 1980s found a benefit for early vitrectomy 
199 
within 6 months as compared to delayed vitrectomy after 12 months, particularly in eyes of type 
200 
1 diabetic patients with severe vision loss from dense VH.14  In addition, a retrospective 
201 
comparison of immediate versus delayed vitrectomy for VH from PDR found that although final 
202 
vision did not differ significantly between the groups, the area under the curve for logMAR 
203 
visual acuity from first presentation to last follow-up was significantly greater, meaning more 
204 
time with decreased vision, for eyes that had delayed versus immediate vitrectomy, suggesting a 
205 
possible visual benefit over time in eyes undergoing vitrectomy sooner.15  Recent large scale, 
206 
multi-center randomized trials of vitrectomy for the sole indication of VH from PDR are lacking. 
207 
At this time, there is rationale for comparing current outcomes utilizing newer surgical 
208 
techniques to alternative treatment modalities for PDR associated VH, including anti-VEGF 
209 
therapy. 
210 
 
211 
VEGF is a major causative factor in eye diseases that are characterized by neovascularization or 
212 
increased vascular permeability, such as DR.16-25  Anti-VEGF drugs are highly effective at 
213 
causing regression of retinal neovascularization, and therefore can be useful in cases of VH due 
214 
to PDR by reducing the chance of additional VH or traction or rhegmatogenous retinal 
215 
detachments from new vessels. Once the hemorrhage is reabsorbed and the neovascularization is 
216 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
1-3 
temporarily stabilized by the anti-VEGF drug, either PRP can be completed or a longer-term 
217 
course of anti-VEGF can be initiated to increase the chance of permanent regression of the PDR 
218 
and lower the likelihood of subsequent VH or traction detachment of the macula or both without 
219 
having to perform vitrectomy.   
220 
 
221 
Anti-VEGF therapy has been evaluated in eyes with VH from PDR in the DRCR.net Protocol N 
222 
(An Evaluation of Intravitreous Ranibizumab for Vitreous Hemorrhage Due to Proliferative 
223 
Diabetic Retinopathy), although the endpoint of this study was short-term avoidance of 
224 
vitrectomy (16 weeks after randomization) rather than VA recovery.26 This study compared the 
225 
safety and efficacy of anti-VEGF treatment with saline injection for prevention of vitrectomy in 
226 
eyes with VH from PDR.  Although Protocol N did not show a difference in vitrectomy rates at 
227 
16 weeks comparing ranibizumab with saline injections, both treatment groups had lower than 
228 
expected vitrectomy rates (12% vs. 17% respectively), and the ranibizumab group had greater 
229 
visual acuity improvements (22±23 vs. 16±31, P = 0.04), increased PRP completion rates (44% 
230 
vs. 31%, P = 0.05), and a reduced rate of recurrent VH (6% vs. 17%, P = 0.01) compared with 
231 
saline injections. 26  Therefore, it is possible that anti-VEGF drugs have at least a short term 
232 
biologic effect.  Rates of vitrectomy at 16 weeks in Protocol N were substantially lower than 
233 
those suggested by previous studies with observation arms, suggesting that the management of 
234 
eyes with VH from PDR with anti-VEGF therapy might avoid further surgical intervention in 
235 
many eyes.  Indeed, by 52 weeks (with 12 weeks through 52 weeks of treatment at investigator 
236 
discretion), only 40% of eyes in both groups received vitrectomy; thus, by 1 year approximately 
237 
60% of eyes did not need vitrectomy. The efficacy of anti-VEGF treatment in allowing clearance 
238 
of VH while avoiding surgery, especially in eyes that have already received PRP is supported by 
239 
another recent case series, which reported treatment with bevacizumab in 18 eyes of 18 patients 
240 
with new onset VH after previous full PRP.27  By 12 months, 72.2% of eyes had complete 
241 
clearing of VH.  However, although 9 (50%) of the eyes gained vision, overall there was no 
242 
statistically significant visual gain over 12 months (mean best corrected VA improved from 
243 
1.32±1.03 to 1.09±1.10 logMAR, p = 0.433), and 2 eyes (11%) had severe vision loss of 3 or 
244 
more lines of vision due to traction retinal detachment.   
245 
 
246 
1.1.3 Aflibercept 
247 
The anti-VEGF agent to be used in this trial is intravitreous aflibercept injection, also known as 
248 
VEGF Trap-Eye or Aflibercept (Eylea®), which is a soluble decoy receptor fusion protein that 
249 
has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.  
250 
Aflibercept received approval by the United States Food and Drug Administration (FDA) for the 
251 
treatment of neovascular age-related macular degeneration in 201128, treatment of macular 
252 
edema due to central retinal vein occlusion in 201229-31, and treatment of macular edema due to 
253 
branch retinal vein occlusion and treatment of DME in 2014.32   
254 
 
255 
Based on data from the VIVID and VISTA phase III DME studies, aflibercept also became 
256 
approved for treatment of diabetic retinopathy in patients with DME in 2015.  Change in diabetic 
257 
retinopathy severity level among eyes with DME and DR at baseline was a pre-specified 
258 
secondary efficacy outcome, and the proportion of patients improving by at least 2 steps was 
259 
significantly greater in aflibercept-treatment groups compared to the control group at 100 weeks 
260 
in both trials.33 
261 
 
262 
Although there is no currently available head-to-head data on the available anti-VEGF agents for 
263 
treatment of PDR, a comparative effectiveness trial in DME reported that aflibercept was more 
264 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
1-4 
effective than ranibizumab and bevacizumab in improving vision in eyes starting with CI-DME 
265 
and worse levels of visual acuity (approximately 20/50 or worse).34    
266 
 
267 
1.1.4 Summary of Study Rationale 
268 
Although VH from PDR can cause acute and dramatic vision loss for patients with diabetes, 
269 
there is no current, evidence-based clinical guidance as to what treatment method is most likely 
270 
to provide the best visual outcomes once intervention is desired.  Intravitreous anti-VEGF 
271 
therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to 
272 
stabilize or regress retinal neovascularization.  However, clinical trials are lacking to elucidate 
273 
the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared 
274 
with initial anti-VEGF treatment.  The DRCR.net Protocol N demonstrated short-term trends 
275 
consistent with a possible beneficial effect of anti-VEGF treatment in eyes with VH from PDR, 
276 
including greater VA improvement and reduced rates of recurrent VH as compared with saline 
277 
injection.  It is possible that a study with a longer duration of follow-up with structured anti-
278 
VEGF retreatment would demonstrate even greater effectiveness of anti-VEGF for VH to avoid 
279 
vitrectomy and its attendant adverse events while also improving visual acuity.  On the other 
280 
hand, advances in surgical techniques leading to faster operative times, quicker patient recovery, 
281 
and reduced complication rates may make prompt vitrectomy a more attractive alternative since 
282 
it results in the immediate ability to clear hemorrhage and to perform PRP if desired, often as 
283 
part of one procedure.  This proposed study will evaluate the safety and efficacy of two treatment 
284 
approaches for eyes with VH from PDR:  prompt vitrectomy + PRP and intravitreous aflibercept 
285 
injections. 
286 
1.2 Study Objectives  
287 
The objectives of this study are to 1) evaluate and compare visual acuity outcomes over the 
288 
course of the study of a prompt vitrectomy + PRP regimen and an intravitreous aflibercept  
289 
regimen in eyes with VH from PDR for which intervention is deemed necessary, and 2) 
290 
characterize the follow-up course for the two treatment regimens, including but not limited to 
291 
post-operative complications for the vitrectomy group, and number of injections needed and 
292 
percent requiring vitrectomy in the intravitreous aflibercept group.   
293 
1.3 Study Design and Synopsis of Protocol 
294 
 
295 
A. Study Design 
296 
• Multi-center randomized clinical trial  
297 
 
298 
B. Major Eligibility Criteria 
299 
• Age >=18 years 
300 
• Type 1 or type 2 diabetes 
301 
• Study eye with:  
302 
o Vitreous hemorrhage causing vision impairment, presumed to be from 
303 
proliferative diabetic retinopathy, for which intervention is deemed necessary 
304 
• Note: Prior PRP is neither a requirement nor an exclusion  
305 
o Best corrected visual acuity letter score 78 or worse (approximate Snellen 
306 
equivalent 20/32 or worse) with at least light perception  
307 
• Investigators should use particular caution when considering enrollment 
308 
of an eye with visual acuity letter score 78 to 69 (approximate Snellen 
309 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
1-5 
equivalent 20/32 to 20/40) to ensure that the need for vitrectomy and its 
310 
potential benefits outweigh the potential risks.   
311 
o No evidence of rhegmatogenous retinal detachment or evidence of traction retinal 
312 
detachment involving or threatening the macula 
313 
• If the density of the hemorrhage precludes a visual assessment on clinical 
314 
exam to confirm eligibility, then it is recommended that assessment be 
315 
performed with ultrasound as standard care. 
316 
o No history of vitrectomy 
317 
 
318 
C. Treatment Groups 
319 
Eligible eyes, one per participant, will be assigned randomly (1:1) to one of the following 
320 
groups: 
321 
 
322 
A. Intravitreous 2 mg aflibercept injections 
323 
B. Prompt vitrectomy + PRP 
324 
 
325 
For the intravitreous aflibercept group, the initial injection must be given on the day of 
326 
randomization.  Follow-up injections will be performed as often as every 4 weeks unless criteria 
327 
for deferral are met (see section 4.3.1).  Vitrectomy and PRP can only be performed if protocol 
328 
criteria are met (see sections 4.3.2 and 4.3.3). 
329 
 
330 
For the prompt vitrectomy + PRP group, the vitrectomy must be scheduled to be performed 
331 
within 2 weeks of randomization. Vitrectomy will be performed according to the investigator’s 
332 
usual routine, including pre-operative care, surgical procedure, and post-operative care, although 
333 
anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage (see section 
334 
4.5.2). 
335 
 
336 
D. Sample Size 
337 
A minimum of 200 study eyes, one per participant, will be randomized.   
338 
 
339 
E. Duration of Follow-Up 
340 
Primary outcome: 24 weeks 
341 
Total duration: 104 weeks  
342 
 
343 
F. Follow-up Schedule 
344 
➢ Outcome Visits: 
345 
All participants in both groups will have visits at the following times post-randomization: 
346 
• Year 1: 4, 12, 24, 36, 52 weeks 
347 
• Year 2: 68 weeks, 84 weeks, 104 weeks 
348 
 
349 
It is recognized that the time between initial treatment and outcome visits will differ 
350 
between the two groups due to the timing of the initial treatment; however, the 
351 
differential timing of treatments is representative of clinical care in which anti-VEGF can 
352 
be given immediately and vitrectomy would need to be scheduled in advance.  Therefore, 
353 
the area under the curve analysis will be representative of clinical care based on the time 
354 
point that the decision is made to intervene.   
355 
 
356 
➢ Treatment Visits: 
357 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
1-6 
• Participants receiving intravitreous aflibercept also will have treatment 
358 
assessment visits as often as every 4 weeks, depending on recent treatment 
359 
administered. 
360 
 
361 
➢ Additional Visits:  
362 
• Participants undergoing vitrectomy will have a study visit 1 week post-vitrectomy 
363 
for safety evaluation.  Investigators may schedule an initial (e.g. 1 day) post-
364 
operative visit earlier as standard care at their discretion. 
365 
 
366 
G. Main Efficacy Outcomes 
367 
 
368 
Treatment Group Comparisons 
369 
 
370 
Primary Outcome:  Visual acuity area under the curve between randomization and 24 weeks  
371 
 
372 
Additional Key Outcomes (at 24, 52, and 104 weeks unless otherwise indicated): 
373 
• Visual acuity area under the curve between randomization and 52 and 104 weeks 
374 
• Mean visual acuity at 4, 12, and 24 weeks, and annual visits 
375 
• Percent 20/20 or better, 20/32 or better, 20/40 or better, 20/200 or worse, and 20/800 
376 
or worse at 4, 12, and 24 weeks, and annual visits  
377 
• Proportion of eyes with at least 15 and at least 30 letter gains or losses from baseline 
378 
• Rates of recurrent VH on clinical exam 
379 
• Percentage of eyes with retinal neovascularization  
380 
• Mean OCT central subfield thickness  
381 
• Treatment and follow-up costs 
382 
• Mean change in four Workplace Productivity and Activity Impairment Questionnaire 
383 
(WPAIQ) scales and area under the curve analyses of the Work Productivity Loss and 
384 
Activity Impairment scales at 4, 12, and 24 weeks, and annual visits  
385 
 
386 
Key Outcomes within Treatment Groups 
387 
• Percent undergoing vitrectomy (initial vitrectomy in aflibercept group or repeat 
388 
vitrectomy in vitrectomy group) 
389 
• Number of aflibercept injections performed 
390 
• Percent receiving PRP (aflibercept group only) 
391 
 
392 
The primary outcome of visual acuity area under the curve at 24 weeks was primarily selected 
393 
for sample size considerations.  The long-term additional key outcomes and within-group 
394 
outcomes will be equally important as the area under the curve outcome for evaluating the 
395 
overall follow-up course for these two treatment approaches.  Therefore, publication is not 
396 
planned until the full 104 week follow-up has closed.  
397 
 
398 
H. Main Safety Outcomes 
399 
Ocular: endophthalmitis, retinal detachment, visually significant cataract, cataract surgery 
400 
Systemic: Antiplatelet Trialist Collaboration (APTC) events 
401 
I. Schedule of Study Visits and Procedures 
402 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
1-7 
 
403 
 
0 
1w post-
vitrectomy* 
Treatment 
Assessment 
Visits** 
Non-
Annual 
Outcome 
Visits† 
24-Week 
Visit and 
Annual visits 
Visit window 
 
±3d 
±1w 
±1 to4w 
±4w 
E-ETDRS best corrected 
visual acuitya 
X 
 
X 
X 
X 
OCTb 
X 
 
X 
X 
X 
Ultrasoundc 
X 
X 
X 
X 
X 
Eye examd 
X 
X 
X 
X 
X 
Blood pressure 
X 
 
 
 
X 
HbA1ce 
X 
 
 
 
X 
Questionnairef 
X 
 
 
X 
X 
Vitreous/aqueous 
samplingg 
X* 
 
 
 
 
*Vitrectomy group at baseline and aflibercept group if vitrectomy is performed during follow-up 
404 
**Every 4 to 16 weeks, as needed, for eyes receiving aflibercept 
405 
†At 12, 36, 68 and 84 weeks 
406 
a=both eyes including protocol refraction in the study eye only at outcome visits and DME treatment visits and on both 
407 
eyes at annual visits.   E-ETDRS refers to electronic ETDRS testing using the Electronic Visual Acuity Tester that has 
408 
been validated against 4-meter chart ETDRS testing.  
409 
b=study eye only; at annual visits and if evaluating for DME treatment  
410 
c= study eye only if needed as part of standard care if the density of the vitreous hemorrhage precludes assessment of 
411 
retinal detachment. 
412 
d=both eyes at baseline and study eye only at follow-up. Includes slit lamp exam (including assessment of lens), 
413 
measurement of intraocular pressure, and dilated ophthalmoscopy; examination of the angle required if NVI or 
414 
increased intraocular pressure present. 
415 
e=can be obtained up to 3 weeks after randomization; does not need to be repeated if HbA1c is available from within 
416 
the prior 3 months 
417 
f= Workplace Productivity and Activity Impairment Questionnaire 
418 
g=if investigator has agreed to perform sample collection and participant consents to this ancillary component; 
419 
participants will be given the option of providing vitreous sample only or both vitreous and aqueous samples at the time 
420 
of vitrectomy. 
421 
 
422 
1.4 General Considerations 
423 
The study is being conducted in compliance with the policies described in the DRCR.net Policies 
424 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
425 
the protocol described herein, and with the standards of Good Clinical Practice. 
426 
 
427 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
1-8 
The DRCR.net Procedures Manuals (Visual Acuity-Refraction Testing Procedures Manual, OCT 
428 
Procedures Manual, and Study Procedures Manual) provide details of the examination 
429 
procedures and intravitreous injection procedure.   
430 
 
431 
Visual acuity testers will be masked to treatment group at all outcome visits.  Investigators and 
432 
study participants are not masked to treatment group. 
433 
   
434 
Data will be directly collected in electronic case report forms, which will be considered the 
435 
source data. 
436 
 
437 
There is no restriction on the number of study participants to be enrolled by a site. 
438 
 
439 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
440 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
441 
2013). 
442 
 
443 
The risk level is considered to be research involving greater than minimal risk. 
444 
 
445 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
2-1 
                                                                                                                                   
446 
CHAPTER 2. STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 
447 
2.1 Identifying Eligible Participants and Obtaining Informed Consent 
448 
A minimum of 200 eyes (1 per participant) are expected to be enrolled into the randomized trial.  
449 
As the enrollment goal approaches, sites will be notified of the end date for recruitment.  Study 
450 
participants who have signed an informed consent form can be randomized up until the end date, 
451 
which means the recruitment goal might be exceeded.   
452 
 
453 
Potential eligibility will be assessed as part of a routine-care examination.  Prior to completing 
454 
any procedures or collecting any data that are not part of usual care, written informed consent 
455 
will be obtained.  For patients who are considered potentially eligible for the study based on a 
456 
routine-care exam, the study protocol will be discussed with the potential study participant by a 
457 
study investigator and clinic coordinator.  The potential study participant will be given the 
458 
Informed Consent Form to read.  Potential study participants will be encouraged to discuss the 
459 
study with family members and their personal physician(s) before deciding whether to participate 
460 
in the study.   
461 
 
462 
Consent may be given in two stages (if approved by the IRB).  The initial stage will provide 
463 
consent to complete any of the screening procedures needed to assess eligibility that have not 
464 
already been performed as part of a usual-care exam.  The second stage will be obtained prior to 
465 
randomization and will be for participation in the study.  A single consent form will have two 
466 
signature/date lines for the study participant:  one for a study participant to give consent for the 
467 
completion of the screening procedures and one for the study participant to document consent for 
468 
the randomized trial.  Study participants will be provided with a copy of the signed Informed 
469 
Consent Form. 
470 
 
471 
Once a study participant is randomized, that participant will be counted regardless of whether the 
472 
assigned treatment is received.  Thus, the investigator must not proceed to randomize an 
473 
individual until he/she is convinced that the individual is eligible and will accept assignment to 
474 
either of the two treatment groups, including ability to undergo vitrectomy within 2 weeks of 
475 
randomization.   
476 
 
477 
2.2 Participant Eligibility Criteria 
478 
2.2.1 Participant-level Criteria 
479 
Inclusion 
480 
To be eligible, the following inclusion criteria must be met: 
481 
1. Age >= 18 years  
482 
• Participants <18 years old are not being included because proliferative diabetic 
483 
retinopathy is so rare in this age group that the diagnosis may be questionable.  
484 
2. Diagnosis of diabetes mellitus (type 1 or type 2)  
485 
• Any one of the following will be considered to be sufficient evidence that diabetes is 
486 
present:  
487 
➢ Current regular use of insulin for the treatment of diabetes 
488 
➢ Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes 
489 
➢ Documented diabetes by ADA and/or WHO criteria (see Procedures Manual for 
490 
definitions) 
491 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
2-2 
3. At least one eye meets the study eye criteria listed in section 2.2.2. 
492 
4. Able and willing to provide informed consent. 
493 
5. Patient is willing and able to undergo vitrectomy within next 2 weeks and the vitrectomy can 
494 
be scheduled within that time frame. 
495 
Exclusion 
496 
A potential participant is not eligible if any of the following exclusion criteria  are present:  
497 
6. History of chronic renal failure requiring dialysis (including placement of fistula if performed 
498 
in preparation for dialysis) or kidney transplant. 
499 
7. A condition that, in the opinion of the investigator, would preclude participation in the study 
500 
(e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic 
501 
control).  
502 
8. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months 
503 
prior to randomization or plans to do so in the next 4 months. 
504 
9. A condition that, in the opinion of the investigator, would preclude participant undergoing 
505 
elective vitrectomy surgery if indicated during the study. 
506 
10. Participation in an investigational trial within 30 days of randomization that involved 
507 
treatment with any drug that has not received regulatory approval for the indication being 
508 
studied. 
509 
• Note: participants cannot receive another investigational drug while participating in the 
510 
study. 
511 
11. Known allergy to any component of the study drug or any drug used in the injection prep 
512 
(including povidone iodine).  
513 
12. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). 
514 
• If blood pressure is brought below 180/110 by anti-hypertensive treatment, potential 
515 
participant can   become eligible.  
516 
13. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization. 
517 
• These drugs cannot be used during the study. 
518 
14. For women of child-bearing potential: pregnant or lactating or intending to become pregnant 
519 
within the next two years. 
520 
• Women who are potential participants should be questioned about the potential for 
521 
pregnancy.  Investigator judgment is used to determine when a pregnancy test is needed. 
522 
15. Potential participant is expecting to move out of the area of the clinical center to an area not 
523 
covered by another clinical center during the two years. 
524 
 
525 
2.2.2 Study Eye Criteria 
526 
The participant must have at least one eye meeting all of the inclusion criteria and none of the 
527 
exclusion criteria listed below.   
528 
 
529 
A participant can have only one study eye.  If both eyes are eligible at the time of randomization, 
530 
the study eye will be selected by the investigator and participant before randomization. 
531 
 
532 
The eligibility criteria for a study eye are as follows: 
533 
 
534 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
2-3 
Inclusion 
535 
a. Vitreous hemorrhage causing vision impairment, presumed to be from proliferative diabetic 
536 
retinopathy, for which intervention is deemed necessary.  
537 
• Note: Prior PRP is neither a requirement nor an exclusion. 
538 
• Subhyaloid hemorrhage alone does not make an eye eligible; however, presence of 
539 
subhyaloid hemorrhage in addition to the criteria above will not preclude participation 
540 
provided the investigator is comfortable with either treatment regimen. 
541 
b. Immediate vitrectomy not required (investigator and participant are willing to wait at least 4 
542 
months to see if hemorrhage clears sufficiently with anti-VEGF without having to proceed to 
543 
vitrectomy). 
544 
c. Visual acuity letter score ≤78 (approximate Snellen equivalent 20/32) and at least light 
545 
perception.  
546 
• Investigators should use particular caution when considering enrollment of an eye with 
547 
visual acuity letter score 69 to 78 (approximate Snellen equivalent 20/32 to 20/40) to 
548 
ensure that the need for vitrectomy and its potential benefits outweigh the potential risks.   
549 
 
550 
Exclusion 
551 
d. Evidence of traction detachment involving or threatening the macula.  
552 
• If the density of the hemorrhage precludes a visual assessment on clinical exam to 
553 
confirm eligibility, then it is recommended that assessment be performed with ultrasound 
554 
as standard care. 
555 
e. Evidence of rhegmatogenous retinal detachment. 
556 
• If the density of the hemorrhage precludes a visual assessment on clinical exam to 
557 
confirm eligibility, then it is recommended that assessment be performed with ultrasound 
558 
as standard care. 
559 
f. Evidence of neovascular glaucoma (iris or angle neovascularization is not an exclusion). 
560 
g. Known diabetic macular edema (DME), defined as either 
561 
i. OCT central subfield thickness (microns): 
562 
1. Zeiss Cirrus: ≥290 in women; ≥305 in men 
563 
2. Heidelberg Spectralis: ≥305 in women; ≥320 in men  
564 
OR 
565 
ii. DME on clinical exam that the investigator believes currently requires treatment.  
566 
h. History of intravitreous anti-VEGF treatment within 2 months prior to current vitreous 
567 
hemorrhage onset or after onset.   
568 
i. History of intraocular corticosteroid treatment within 4 months prior to current vitreous 
569 
hemorrhage onset or after onset.   
570 
j. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular 
571 
surgery, etc.) within prior 4 months or major ocular surgery other than vitrectomy anticipated 
572 
within the next 6 months following randomization.  
573 
k. History of vitrectomy. 
574 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
2-4 
l. History of YAG capsulotomy performed within 2 months prior to randomization.  
575 
m. Aphakia. 
576 
n. Uncontrolled glaucoma (in investigator’s judgment). 
577 
o. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or 
578 
substantial blepharitis. 
579 
 
580 
2.2.3 Non-Study Eye Criteria 
581 
If anti-VEGF treatment is indicated for any condition in the non-study eye at any time during the 
582 
study, the investigator must be willing to use the study anti-VEGF drug (2 mg aflibercept) for the 
583 
non-study eye.  If the non-study eye is currently being treated with a different anti-VEGF drug 
584 
for any condition, then the investigator and patient must be willing to switch to aflibercept.  If 
585 
the investigator or patient is unwilling to change anti-VEGF treatment in the non-study eye, the 
586 
patient should not be enrolled.    
587 
 
588 
2.3 Screening Evaluation and Baseline Testing 
589 
2.3.1 Historical Information 
590 
A history will be elicited from the participant and extracted from available medical records.  
591 
Data to be collected will include:  age, gender, ethnicity and race, diabetes history and current 
592 
management, other medical conditions, medications being used, as well as ocular diseases, 
593 
surgeries, and treatment. 
594 
2.3.2 Baseline Testing Procedures 
595 
The following procedures are needed to assess eligibility and/or to serve as baseline measures for 
596 
the study.   
597 
• If a procedure has been performed (using the study technique and by study certified 
598 
personnel) as part of usual care, it does not need to be repeated specifically for the study 
599 
if it was performed within the defined time windows specified below.  
600 
• The testing procedures are detailed in the DRCR.net Procedures Manuals (Visual Acuity-
601 
Refraction Testing Procedures Manual and Study Procedures Manual).  Visual acuity 
602 
testing and ocular exam will be performed by DRCR.net certified personnel.  
603 
 
604 
1. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 
605 
(including protocol refraction) in each eye. (on day of randomization) 
606 
➢ If the E-ETDRS visual acuity letter score is 0, then counting fingers, hand motion, 
607 
and light perception are assessed. 
608 
2. Workplace Productivity and Activity Impairment Questionnaire (on day of randomization).  
609 
3. OCT on the study eye (within 8 days prior to randomization)  
610 
➢ Unless insufficient view precludes obtaining an accurate measurement  
611 
4. Ocular examination of each eye including slit lamp, measurement of intraocular pressure, 
612 
lens assessment, and dilated ophthalmoscopy (on day of randomization) 
613 
5. B-Scan ultrasound as part of standard care on the study eye if the density of the vitreous 
614 
hemorrhage precludes assessment of traction or rhegmatogenous retinal detachment 
615 
6. Measurement of blood pressure 
616 
7. Laboratory testing- HbA1c 
617 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
2-5 
➢ HbA1c does not need to be repeated if available in the prior 3 months.  If not 
618 
available at the time of randomization, the participant may be enrolled but the test 
619 
must be obtained within 3 weeks after randomization.  
620 
2.4 Enrollment/Randomization of Eligible Participants  
621 
1. Prior to randomization, the participant’s understanding of the trial, willingness to accept the 
622 
assigned treatment group, and commitment to the follow-up schedule should be reconfirmed. 
623 
2. The baseline injection must be given on the day of randomization and vitrectomy must be 
624 
performed within 2 weeks, depending on treatment group; therefore, a participant should not 
625 
be randomized until this is possible.   
626 
3. Randomization is completed on the DRCR.net website.   
627 
• Study eyes will be randomly assigned (stratified by site) with equal probability to one of 
628 
two treatment groups:  
629 
o Group A: Intravitreous 2 mg aflibercept injections 
630 
o Group B: Prompt vitrectomy + PRP 
631 
 
632 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     3-1 
 
633 
CHAPTER 3. FOLLOW-UP VISITS AND TESTING                                                            
634 
3.1 Visit Schedule 
635 
The schedule of protocol-specified follow-up visits is as follows: 
636 
 
637 
➢ Outcome Visits: 
638 
All participants in both groups will have visit at the following time points post-
639 
randomization: 
640 
• Year 1: 4 (±1) weeks, 12 (±4) weeks, 24(±4) weeks, 36 (±4) weeks, 52(±4) weeks 
641 
• Year 2: 68 (±4) weeks, 84  (±4) weeks, 104  (±4) weeks 
642 
 
643 
➢ Vitreous Hemorrhage Treatment Assessment Visits: 
644 
 
645 
Aflibercept Group 
646 
Participants in the aflibercept group, will have treatment assessment visits as often as 
647 
every 4 weeks, depending on treatment administered: 
648 
• Visits every 4±1 weeks for the first 24 weeks and as long as injections are given 
649 
(with a minimum of 21 days between injections). 
650 
• After 24 weeks, if the injection is deferred at the current and previous 2 visits (see 
651 
section 4.3.1 for retreatment criteria), the next study follow-up visit is in twice the 
652 
time since the last visit up to a maximum of 16 weeks between visits.  Otherwise, 
653 
the next study follow-up visit is in 4 weeks. 
654 
 
655 
Vitrectomy Group 
656 
Eyes for which aflibercept is initiated for recurrent hemorrhage post-vitrectomy will 
657 
have treatment assessment visits as often as every 4 weeks until the hemorrhage has 
658 
cleared or repeat vitrectomy is performed (see section 4.5.2). 
659 
 
660 
➢ DME Treatment Visits 
661 
• If aflibercept for DME has been initiated, follow-up visits for DME treatment occur 
662 
every 4 weeks for the first 24 weeks from initial aflibercept treatment for DME. After 
663 
24 weeks, if the injection is deferred at the current and previous 2 visits (see section 
664 
4.7 for retreatment criteria), the next study follow-up visit is in twice the time since 
665 
the last visit up to a maximum of 16 weeks between visits.  Otherwise, the next study 
666 
follow-up visit is in 4 weeks. 
667 
 
668 
➢ Additional Protocol Visits:  
669 
Participants undergoing vitrectomy will have a study visit 1 week (±3 days) post-
670 
vitrectomy for safety evaluation only. Investigators may schedule an initial (e.g. 1 day) 
671 
post-operative visit earlier as standard care.  
672 
 
673 
Additional visits may occur as required for usual care of the study participant. 
674 
3.2 Testing Procedures  
675 
The 1-week post-operative visit will include a safety evaluation only.  Otherwise, the following 
676 
procedures will be performed at each protocol-specified visit on the study eye only, unless 
677 
otherwise specified. A grid in section 1.3 summarizes the testing performed at each visit.  
678 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     3-2 
 
679 
1. E-ETDRS visual acuity testing (best corrected) in each eye. 
680 
• A protocol refraction in the study eye is required at Outcome Visits (listed above) and 
681 
DME treatment visits.  Refraction in the non-study eye is only required at annual visits.  
682 
When a refraction is not performed, the most recently performed refraction is used for the 
683 
testing. 
684 
2. Workplace Productivity and Activity Impairment Questionnaire (WPAIQ) at all outcome 
685 
visits (listed above).  
686 
3. OCT at the 24-week visit, annual visits, and DME treatment visits only. 
687 
➢ Unless insufficient view precludes obtaining an accurate measurement.   
688 
4. Ocular exam, including slit lamp examination (including lens assessment), measurement of 
689 
intraocular pressure, and dilated ophthalmoscopy.  
690 
• Undilated exam of the iris is at the discretion of the investigator; examination of the 
691 
angle is required if neovascularization of the iris is present or increased IOP (defined 
692 
as one of the following: a) IOP ≥ 30mm Hg b) first time IOP has increased at least 
693 
10mm Hg since baseline c) IOP has increased at least 10mm Hg since last visit or d) 
694 
IOP lowering medication initiated since last visit). 
695 
5. B-Scan ultrasound as needed as part of standard care if vitreous hemorrhage precludes ability 
696 
to assess for traction or rhegmatogenous retinal detachment. 
697 
 
698 
6. Laboratory testing of Hemoglobin A1c at the 24-week visit and annual visits only. 
699 
• HbA1c does not need to be repeated if available in the prior 3 months.  
700 
7. Blood pressure at the 24-week visit and annual visits only. 
701 
 
702 
All of the testing procedures do not need to be performed on the same day, provided that they are 
703 
completed within the time window of a visit and prior to initiating any retreatment.  
704 
 
705 
Testing procedures at unscheduled visits are at investigator discretion.  However, it is 
706 
recommended that procedures that are performed should follow the standard DRCR.net protocol 
707 
for each procedure 
708 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     4-1 
CHAPTER 4. TREATMENT REGIMEN     
709 
4.1 Introduction 
710 
All study eyes will be randomly assigned to one of the following two treatment groups:    
711 
• Intravitreous 2 mg aflibercept injections  
712 
• Prompt vitrectomy + PRP 
713 
 
714 
For the intravitreous aflibercept group, the initial injection must be given on the day of 
715 
randomization.  Follow-up injections will be performed as often as every 4 weeks according to 
716 
the retreatment criteria below.  Vitrectomy and PRP can only be performed if protocol criteria 
717 
are met. 
718 
 
719 
For the prompt vitrectomy + PRP group, the vitrectomy must be scheduled within 2 weeks of 
720 
randomization. The vitrectomy procedure and follow-up treatment are described below. 
721 
 
722 
4.2 Intravitreous Injections 
723 
4.2.1 Inravitreous Aflibercept Injection (Eylea®) 
724 
Eylea® (intravitreal aflibercept injection) is made by Regeneron Pharmaceuticals, Inc. and is 
725 
approved by the FDA for the treatment of neovascular age-related macular degeneration, 
726 
macular edema due to central retinal vein occlusion, macular edema due to branch retinal vein 
727 
occlusion, diabetic macular edema, and diabetic retinopathy in eyes with diabetic macular 
728 
edema.   
729 
 
730 
Study eyes that receive anti-VEGF will receive a dose of 2 mg aflibercept in 0.05 cc each time a 
731 
study injection is performed.  The physical, chemical and pharmaceutical properties and 
732 
formulation are provided in the Clinical Investigator Brochure. Aflibercept for the study and 
733 
non-study eye will be distributed by the Network. 
734 
 
735 
4.2.2 Intravitreous Injection Technique 
736 
The injection is preceded by a povidone iodine prep of the conjunctiva.  In general, topical 
737 
antibiotics in the pre-, peri-, or post-injection period should not be used.  
738 
 
739 
The injection will be performed using sterile technique.  The full injection procedure is described 
740 
in the DRCR.net Study Procedures Manual. 
741 
 
742 
4.2.3 Delay in Giving Injections 
743 
If a scheduled injection is not given by the end of the visit window, it can still be given up to 1 
744 
week prior to the next visit window opening.  If it is not given by that time, it will be considered 
745 
missed. 
746 
 
747 
If an injection is given late, the next scheduled injection should occur no sooner than 3 weeks 
748 
after the previous injection. 
749 
 
750 
4.2.4 Deferral of Injections Due to Pregnancy 
751 
Female study participants of child-bearing age must be questioned regarding the possibility of 
752 
pregnancy prior to each injection. In the event of pregnancy, study injections must be 
753 
discontinued during the pregnancy and any post-partum period of breastfeeding.   
754 
 
755 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     4-2 
4.2.5 Non-Study Eye Injections 
756 
If the non-study eye is going to be treated for any condition which requires treatment with an 
757 
anti-VEGF agent, study provided aflibercept must be used.  However, if intravitreous treatment 
758 
is planned on the same day as an intravitreous injection in the study eye, the study eye will be 
759 
injected first, followed by the non-study eye (see Procedures Manual for additional details).  If a 
760 
non-study anti-VEGF medication is desired to be administered by intravitreous injection in the 
761 
non-study eye, a discussion with the Protocol Chair is required first. 
762 
 
763 
4.3 Aflibercept Group Follow-Up Treatment 
764 
4.3.1 Retreatment with Intravitreous Injections of Aflibercept for Vitreous Hemorrhage 
765 
and underlying PDR 
766 
All eyes will receive an injection of aflibercept at the 4-week, 8-week and 12-week visits, unless 
767 
an adverse event precludes treatment. 
768 
 
 
769 
Starting at the 16-week visit, eyes with no contraindication to additional aflibercept injections 
770 
will be evaluated for retreatment based on the status of the hemorrhage and neovascularization.  
771 
In general, the eye will receive an injection at each treatment assessment visit unless one of the 
772 
below criteria is met:  
773 
1. Success: the vitreous hemorrhage has sufficiently cleared such that there is an 
774 
adequate view of the entire fundus and neovascularization is absent 
775 
➢ Injection is deferred. 
776 
2. Stability: it has been at least 24 weeks since the initial injection, the eye has received 
777 
at least 2 prior consecutive injections, and the size and density of the hemorrhage and 
778 
any neovascularization is clinically unchanged since the last visit.   
779 
➢ Injection is deferred. 
780 
3. A vitrectomy has already been performed  
781 
➢ Eyes in the aflibercept group that receive vitrectomy will follow the intra- and 
782 
post-operative anti-VEGF treatment regimen described in sections 4.4 and 
783 
4.5.2 for the Vitrectomy Group. 
784 
 
785 
4.3.2 PRP during Follow-Up 
786 
PRP must not be given unless failure criteria are met (see below for cases that first require 
787 
discussion with the Protocol Chair or Coordinating Center designee).  In addition, if any future 
788 
treatment with aflibercept is contraindicated based on a previous adverse reaction, treatment with 
789 
PRP for PDR is at investigator discretion after discussion with and approval from the Protocol 
790 
Chair or Coordinating Center designee.   
791 
 
792 
• Failure criteria are defined as  
793 
1. growth of NV or new NV of the retina, disc OR iris since the last visit such that 
794 
the NV, including fibrosis, is greater than when first adequately visualized and at 
795 
least 4 study injections have been given over the previous 4 months.  The 
796 
investigator may perform PRP.   
797 
 
798 
OR 
799 
 
800 
2. New or worsened NV of the angle* has developed since the last visit. The 
801 
investigator may perform PRP.   
802 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     4-3 
 
803 
OR  
804 
 
805 
3. definite worsening of NV or fibrous proliferation of the retina, disc OR iris at 
806 
least 1 day after the last injection that the investigator believes is likely to lead to 
807 
substantial vision loss if PRP is not performed within 1 week.  PRP may only be 
808 
performed after discussion with and approval from the Protocol Chair or 
809 
Coordinating Center designee. 
810 
 
811 
4.3.3 Vitrectomy during Follow-Up 
812 
Vitrectomy may be performed in the aflibercept group according to the criteria below.  See 
813 
section 4.4 regarding the vitrectomy procedure. Eyes in the aflibercept group that undergo 
814 
vitrectomy must also receive intraoperative PRP until “complete”.   
815 
 
816 
4.3.3.1 Prior to 16 Weeks 
817 
Vitrectomy prior to 16 weeks should not be performed unless one of the following is present: 
818 
➢ Traction retinal detachment involving (within 1 disc diameter) or actively threatening the 
819 
macula  
820 
➢ Rhegmatogenous retinal detachment  
821 
➢ Neovascular glaucoma resulting in increased intraocular pressure that cannot be 
822 
controlled medically, angle neovascularization, or progressive neovascularization of the 
823 
iris (at least 2 clock hours) 
824 
➢ Ghost cell glaucoma resulting in increased intraocular pressure that cannot be controlled 
825 
medically  
826 
 
827 
If other circumstances develop for which vitrectomy is being considered prior to 16 weeks, the 
828 
Protocol Chair will be contacted for approval. 
829 
 
830 
4.3.3.2 At and After 16 weeks 
831 
After the 16 week visit, vitrectomy may be performed (but is not required) if there is 1) persistent 
832 
vitreous hemorrhage causing vision impairment and 2) the eye has received at least 2 consecutive 
833 
prior injections.  However, if this is the 3rd or more time the hemorrhage recurred after a period 
834 
of clearance during the study, vitrectomy may be performed at investigator discretion without 
835 
first performing 2 additional injections.   
836 
 
837 
If the investigator believes vitrectomy is required for the safety of the participant and the study 
838 
eye does not meet these criteria, protocol chair approval is required to proceed.   
839 
 
840 
4.4 Vitrectomy 
841 
For study eyes receiving vitrectomy, vitrectomy will be performed according to the 
842 
investigator’s usual routine, including pre-operative care, surgical procedure, and post-operative 
843 
care. However, a 23 or smaller gauge vitrectomy system must be used (20 gauge is not 
844 
permitted).   
845 
 
846 
Optional additional procedures at the discretion of the investigator include, but are not limited to: 
847 
• Removal of the internal limiting membrane. 
848 
• Use of agents to improve visualization of membranes, (e.g. triamcinolone acetonide, 
849 
indocyanine green dye, or other staining agents). 
850 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     4-4 
• Use of corticosteroids (intravitreous, sub-tenon’s, sub-conjunctival) at the close of the 
851 
procedure. 
852 
• Cataract extraction. 
853 
 
854 
Study intravitreous aflibercept may be given pre-operatively, but then should not be given 
855 
thereafter unless there is recurrent hemorrhage (see section 4.5.2 below). If pre-op aflibercept is 
856 
given, it is strongly recommended that it be given between 1 day to 1 week prior to the 
857 
procedure, although it can be administered up to 2 weeks prior if necessary.   
858 
     
859 
4.4.1 Vitreous and Aqueous Sample Collection 
860 
Participation in the ancillary sample collection component is not a requirement for participation 
861 
in this study.  It is expected that sites with the capability to obtain and ship intraocular fluids will 
862 
participate.  At the time of consent into the main study, participants will have the option of 
863 
signing the ancillary sample collection portion of the informed consent form to indicate their 
864 
willingness to provide either a vitreous sample only (at least 1 cc of undiluted vitreous collected 
865 
during the vitrectomy procedure) or to provide both vitreous and an additional aqueous sample 
866 
(requiring an additional anterior paracentesis to collect at least 0.1 cc of aqueous fluid).    
867 
 
868 
If consent for vitreous and/or aqueous sampling is obtained, the sample(s) will be collected and 
869 
shipped on dry ice to a central laboratory for storage until analyses are completed. Details 
870 
regarding collection, sample labeling, storage, and shipment can be found in the ancillary study 
871 
procedures manual. 
872 
 
873 
4.4.2 Deferral or Cancellation of Surgery in the Vitrectomy Group 
874 
Surgery may be cancelled if there is substantial improvement in vitreous hemorrhage such that 
875 
visual acuity is no longer affected. 
876 
 
877 
If surgery is postponed for reasons other than substantial vitreous hemorrhage improvement, it 
878 
should be re-scheduled as soon as possible. 
879 
 
880 
Whether surgery is deferred or cancelled, protocol follow-up visits will continue as scheduled 
881 
based on time from randomization.   
882 
 
883 
4.5 Vitrectomy Group Intra- and Post-Operative Treatment 
884 
4.5.1 Panretinal Photocoagulation in the Vitrectomy Group 
885 
PRP should be placed to the extent that it is considered “complete”.  “Complete” PRP is defined 
886 
as 500 micron size burns on the retina placed no further than 1 to 2 burn widths apart beginning 
887 
~3000 microns from the macular center and extending at least to the equator for 12 clock hours. 
888 
See procedures manual for additional details, including use of automated pattern. 
889 
 
890 
If it is determined during surgery that the eye has already received “complete” PRP, further PRP 
891 
treatment is not required.  PRP treatment can be performed using the investigator’s standard 
892 
procedure and may include indirect delivery.     
893 
 
894 
If the size or amount of neovascularization increases following completion of the initial PRP 
895 
session, additional PRP should be given if possible.  Aflibercept may be given for 
896 
neovascularization in the absence of recurrent hemorrhage after discussion with the protocol 
897 
chair (see below for treatment of recurrent hemorrhage from NV).       
898 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     4-5 
 
899 
4.5.2 Treatment for Recurrent Vitreous Hemorrhage in the Vitrectomy Group 
900 
If there is recurrent hemorrhage, no treatment should be given within the first 4 weeks post-
901 
vitrectomy.  After 4 weeks, if the investigator determines there is recurrent hemorrhage from 
902 
neovascularization, two injections of study aflibercept will be given, 4(±1) weeks apart.  
903 
Additional aflibercept may be given every 4(±1) weeks thereafter, at the discretion of the 
904 
investigator.  Repeat vitrectomy (or air/fluid exchange) may only be performed if the recurrent 
905 
hemorrhage has not cleared after at least 2 consecutive 4-week injections.  Otherwise, protocol 
906 
chair approval is required to re-operate.    
907 
 
908 
4.6 Cataract Surgery (Both Groups) 
909 
Investigators should evaluate lens changes throughout the course of follow-up and consider 
910 
cataract surgery (or referral for possible cataract surgery) when a lens change is thought to be 
911 
visually significant based on the investigator’s judgment.  If the visual potential of the study eye 
912 
is unknown, the investigator should assume that there is potential for clinically relevant 
913 
improvement in vision.  Cataract surgery may be performed as part of the surgeon’s usual 
914 
routine.  Limited data will be collected for the study.   
915 
4.7 Treatment for Diabetic Macular Edema (Both Groups) 
916 
No anti-VEGF should be given for DME within 6 weeks of the initial randomized treatment. For 
917 
post-surgical edema, steroid drops or other alternatives may be given at the discretion of the 
918 
investigator.  After 6 weeks, if DME is present (OCT CSF above gender and OCT machine-
919 
specific thresholds and investigator has confirmed thickening is due to diabetic macular edema 
920 
and not post-surgical macular edema or other cause) and vision is 20/32 or worse, treatment with 
921 
intravitreous aflibercept and deferred focal/grid laser will be given, using the DRCR.net 
922 
intravitreous anti-VEGF retreatment protocol (section 4.7.1 below). 
923 
 
924 
For eyes with DME and best-corrected visual acuity better than 20/32, protocol chair approval is 
925 
required to initiate anti-VEGF treatment.  Once initiated, the DRCR.net intravitreous anti-VEGF 
926 
retreatment protocol regimen must be followed.   
927 
 
928 
4.7.1. Intravitreous Injection Retreatment for DME 
929 
Once aflibercept treatment has been initiated for DME, the eye will be evaluated at each visit for 
930 
retreatment. In general, an eye will continue to receive an injection if the eye is improving or 
931 
worsening on OCT or visual acuity. The first time an eye has not improved or worsened the eye 
932 
will receive an injection.  If the eye has not improved or worsened for at least 2 consecutive 4-
933 
week injections and the OCT CSF thickness is less than the gender specific spectral domain OCT 
934 
threshold (see below) and visual acuity is 20/20 or better, then injection will be deferred.  If the 
935 
eye has not improved or worsened for at least 2 consecutive 4-week visits and the OCT CSF 
936 
thickness is ≥ the gender specific spectral domain OCT threshold or visual acuity is worse than 
937 
20/20, the following will be done: 
938 
• If less than 24 weeks from the initial injection for DME, an injection will be given. 
939 
• At and after 24 weeks, the injection will be deferred. 
940 
 
941 
The protocol chair or designee must be contacted prior to deviation from the injection protocol.  
942 
See the DRCR.net Procedure Manual for additional details. 
943 
 
944 
Spectral domain OCT central subfield gender-specific threshold: 
945 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     4-6 
➢ Zeiss Cirrus: 290 microns in women, and 305 microns in men 
946 
➢ Heidelberg Spectralis: 305 microns in women, and 320 microns in men 
947 
 
948 
4.7.2. Focal/Grid Laser Treatment for DME 
949 
In general, focal/grid laser will be initiated at or after 24 weeks from the initial injection for 
950 
DME if 1) the OCT central subfield thickness is greater than the OCT central subfield gender-
951 
specific threshold (above) or there is edema that is threatening the fovea and 2) the eye has not 
952 
improved on OCT or visual acuity from the last two consecutive injections.  Once focal/grid 
953 
laser has been initiated, retreatment with focal/grid laser will be given unless one of the 
954 
following is present: 1) focal/grid laser has been given in the previous 13 weeks, 2) complete 
955 
focal/grid laser has already been given in the investigator’s judgment, 3) the OCT central 
956 
subfield thickness is less than the OCT central subfield gender-specific threshold (above) and 
957 
there is no edema threatening the fovea, 4) the eye has improved since the last laser treatment. 
958 
The protocol chair or designee must be contacted prior to deviating from the focal/grid laser 
959 
protocol.  See the DRCR.net Procedure Manual for additional details. 
960 
 
961 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     5-1 
 
962 
CHAPTER 5.                                                                                               
963 
MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
964 
 
965 
5.1 Endophthalmitis  
966 
Diagnosis of endophthalmitis following intravitreous injections is based on investigator’s 
967 
judgment.  A culture is required prior to initiating antibiotic treatment for presumed 
968 
endophthalmitis.   
969 
5.2 Treatment of Diabetic Retinopathy in Non-study Eye 
970 
Treatment of diabetic retinopathy, including DME, in the non-study eye is at investigator 
971 
discretion. However, if anti-VEGF treatment will be given in the non-study eye, study aflibercept 
972 
must be used. 
973 
5.3 Use of Intravitreal Anti-VEGF for Conditions Other than DME in the Study Eye 
974 
If an ocular condition other than DME or DR develops in the study eye for which aflibercept is 
975 
an FDA approved treatment (e.g. neovascular AMD, macular edema following central retinal 
976 
vein occlusion), the use of study aflibercept is at the discretion of the investigator.  Any off-label 
977 
use of anti-VEGF in the study eye for an ocular condition other than DR, will require discussion 
978 
with and approval by the protocol chair or designee. Study aflibercept must be used for any anti-
979 
VEGF treatment in the study eye.   
980 
5.4 Diabetes Management 
981 
Diabetes management is left to the study participant’s medical care provider. 
982 
5.5 Study Participant Withdrawal and Losses to Follow-up 
983 
A study participant has the right to withdraw from the study at any time.  If a study participant is 
984 
considering withdrawal from the study, the principal investigator should personally speak to the 
985 
individual about the reasons, and every effort should be made to accommodate him or her.   
986 
 
987 
The goal for the study is to have as few losses to follow-up as possible.  The Coordinating Center 
988 
will assist in the tracking of study participants who cannot be contacted by the site.  The 
989 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 
990 
 
991 
Study participants who withdraw will be asked to have a final closeout visit at which the testing 
992 
described for the protocol visits will be performed.  Study participants who have an adverse 
993 
effect attributable to a study treatment or procedure will be asked to continue in follow-up until 
994 
the adverse event has resolved or stabilized. 
995 
 
996 
Study participants who withdraw or are determined to have been ineligible post-randomization 
997 
will not be replaced. 
998 
5.6 Discontinuation of Study 
999 
The study may be discontinued by the Executive Committee (with approval of the Data and 
1000 
Safety Monitoring Committee) prior to the preplanned completion of follow-up for all study 
1001 
participants. 
1002 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     5-2 
5.7 Contact Information Provided to the Coordinating Center 
1003 
The Coordinating Center will be provided with contact information for each study participant.  
1004 
Permission to obtain such information will be included in the Informed Consent Form.  The 
1005 
contact information may be maintained in a secure database and will be maintained separately 
1006 
from the study data. 
1007 
 
1008 
Phone contact from the Coordinating Center will be made with each study participant in the first 
1009 
month after enrollment, and approximately every six months thereafter.  Additional phone 
1010 
contacts from the Coordinating Center will be made if necessary to facilitate the scheduling of 
1011 
the study participant for follow-up visits.  A participant-oriented newsletter may be sent twice a 
1012 
year.  A study logo item may be sent once a year.  
1013 
 
1014 
Study participants will be provided with a summary of the study results in a newsletter format 
1015 
after completion of the study by all participants.   
1016 
5.8 Study Participant Reimbursement 
1017 
The study will be providing the study participant with a $25 merchandise or money card per 
1018 
completed protocol visit.  Additional travel expenses may be paid in cases for participants with 
1019 
higher expenses. In situations of financial hardship supplemental funds for patient expenses may 
1020 
be available on a case by case basis. 
1021 


Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
 
     6-1 
1022 
CHAPTER 6.                                                                                           
1023 
ADVERSE EVENTS 
1024 
 
1025 
6.1 Definition 
1026 
An adverse event is any untoward medical occurrence in a study participant, irrespective of 
1027 
whether or not the event is considered treatment-related. 
1028 
 
1029 
6.2 Recording of Adverse Events 
1030 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
1031 
events or untoward findings.  The first concern will be the safety of the study participant, and 
1032 
appropriate medical intervention will be made. 
1033 
 
1034 
All adverse events whether volunteered by the participant, discovered by study personnel during 
1035 
questioning, or detected through physical examination, laboratory test, or other means will be 
1036 
reported on an adverse event form online.  Each adverse event form is reviewed by the 
1037 
Coordinating Center to verify the coding and the reporting that is required.  
1038 
 
1039 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1040 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1041 
by the treatment (including treatment of the non-study eye with study treatment). 
1042 
 
1043 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1044 
following general guideline when determining whether an adverse event is related: 
1045 
 
1046 
Yes 
1047 
There is a plausible temporal relationship between the onset of the adverse event and 
1048 
administration of the study treatment, and the adverse event cannot be readily explained by the 
1049 
participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event 
1050 
follows a known pattern of response to the study treatment; and/or the adverse event abates or 
1051 
resolves upon discontinuation of the study treatment or dose reduction and, if applicable, 
1052 
reappears upon re-challenge. 
1053 
 
1054 
No 
1055 
Evidence exists that the adverse event has an etiology other than the study treatment (e.g., 
1056 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1057 
medication); and/or the adverse event has no plausible temporal relationship to study treatment 
1058 
administration (e.g., cancer diagnosed 2 days after first dose of study drug).    
1059 
 
1060 
The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3) 
1061 
severe.  It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 
1062 
event is not necessarily serious. For example, itching for several days may be rated as severe, but 
1063 
may not be clinically serious. 
1064 
 
1065 
Adverse events will be coded using the MedDRA dictionary.  
1066 
 
1067 
Definitions of relationship and intensity are listed on the DRCR.net website data entry form.   
1068 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
   
6-2 
 
1069 
Adverse events that continue after the study participant’s discontinuation or completion of the 
1070 
study will be followed until their medical outcome is determined or until no further change in the 
1071 
condition is expected.   
1072 
 
1073 
6.3 Reporting Serious or Unexpected Adverse Events 
1074 
A serious adverse event is any untoward occurrence that: 
1075 
• Results in death. 
1076 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
1077 
become life-threatening, is not necessarily considered a serious adverse event). 
1078 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
1079 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
1080 
to conduct normal life functions (sight threatening). 
1081 
• Is a congenital anomaly or birth defect. 
1082 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
1083 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
1084 
the outcomes listed above). 
1085 
 
1086 
Unexpected adverse events are those that are not identified in nature, severity, or frequency in 
1087 
the current Clinical Investigator’s Brochure.   
1088 
 
1089 
Serious or unexpected adverse events must be reported to the Coordinating Center immediately 
1090 
via completion of the online serious adverse event form. If the study participant required 
1091 
hospitalization, the hospital discharge summary must also be sent to the Coordinating Center.   
1092 
 
1093 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1094 
both serious and unexpected.  Notification will be made within 10 days after the Coordinating 
1095 
Center becomes aware of the event.   
1096 
 
 
1097 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1098 
abiding by any other reporting requirements specific to their Institutional Review Board.  
1099 
 
1100 
6.4 Data and Safety Monitoring Committee Review of Adverse Events 
1101 
A Data and Safety Monitoring Committee (DSMC) will approve the protocol, template informed 
1102 
consent form, and substantive amendments and provide independent monitoring of adverse 
1103 
events.  Cumulative adverse event data are tabulated semi-annually for review by the DSMC.  
1104 
Following each DSMC data review, a summary will be provided to IRBs.  A list of specific 
1105 
adverse events to be reported expeditiously to the DSMC will be compiled and included as part 
1106 
of the DSMC Standard Operating Procedures document.   
1107 
 
1108 
6.5 Risks 
1109 
6.5.1 Potential Adverse Effects of Aflibercept 
1110 
The most common adverse reactions (≥5%) reported in patients receiving aflibercept were 
1111 
conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, 
1112 
vitreous detachment, and vitreous floaters.   
1113 
 
1114 
Serious adverse reactions related to the injection procedure have occurred in <0.1% of 
1115 
intravitreal injections with aflibercept including endophthalmitis and retinal detachment. 
1116 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
   
6-3 
 
1117 
 
1118 
Safety data specific to the diabetes population were published from phase III studies VISTA and 
1119 
VIVID, which included 872 eyes with DME with central involvement that received either 
1120 
intravitreal aﬂibercept every 4 weeks, intravitreal aflibercept every 8 weeks after 5 initial 
1121 
monthly doses, or macular laser photocoagulation.  Overall, the incidences of ocular and non-
1122 
ocular adverse events were similar across treatment groups at 52 weeks.32  The incidence of 
1123 
APTC-defined thromboembolic events was similar across treatment groups.  There were no 
1124 
reported cases of endophthalmitis, and intraocular inflammation occurred in less than 1% of 
1125 
injections.  Through 100 weeks, an integrated safety analysis found that the most frequent 
1126 
serious ocular adverse event was cataract (2.4% and 1.0% in the aflibercept groups compared 
1127 
with 0.3% in the laser group).33   The incidence of APTC ATEs in VISTA and VIVID 
1128 
during the 100 weeks study duration was 6.4% (37out of 578) in the combined EYLEA groups 
1129 
compared with 4.2% (12 out of 287) in the control group.33 
1130 
 
1131 
There may be side effects and discomforts that are not yet known.   
1132 
 
1133 
6.5.2 Potential Adverse Effects of Intravitreous Injection 
1134 
Rarely, the drugs used to anesthetize the eye before the injections (proparacaine, tetracaine, or 
1135 
xylocaine) can cause an allergic reaction, seizures, and an irregular heartbeat less than 1% of 
1136 
the time.   
1137 
 
1138 
Sub-conjunctival hemorrhage or floaters will commonly occur as a result of the intravitreous 
1139 
injection.  Mild discomfort, ocular hyperemia, increased lacrimation, discharge or itching lasting 
1140 
for up to a few days is also likely (more than 10% of the time). 
1141 
 
1142 
Immediately following the injection, there may be elevation of intraocular pressure. It usually 
1143 
returns to normal spontaneously, but may need to be treated with topical drugs or a 
1144 
paracentesis to lower the pressure.  The likelihood of permanent loss of vision from elevated 
1145 
intraocular pressure is less than 1%. 
1146 
 
1147 
As a result of the injection, endophthalmitis (infection in the eye) could develop.  If this occurs, it is 
1148 
treated by intravitreous injection of antibiotics, but there is a risk of permanent loss of vision including 
1149 
blindness. The risk of endophthalmitis is less than 1%. 
1150 
 
1151 
As a result of the injection, a retinal detachment could occur.  If this occurs, surgery may be 
1152 
needed to repair the retina.  The surgery is usually successful at reattaching the retina.  
1153 
However, a retinal detachment can produce permanent loss of vision and even blindness.  The 
1154 
risk of retinal detachment is less than 1%. 
1155 
 
1156 
The injection could cause a vitreous hemorrhage.  Usually the blood will resolve 
1157 
spontaneously, but if not, surgery may be needed to remove the blood.  Although the surgery 
1158 
usually successfully removes the blood, there is a small risk of permanent loss of vision and 
1159 
even blindness.  The risk of having a vitreous hemorrhage due to the injection is less than 1%. 
1160 
6.5.3  Risks of Vitrectomy 
1161 
6.5.3.1 Anesthesia 
1162 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
   
6-4 
Anesthesia may be general endotracheal or local retrobulbar/peribulbar, usually with systemic 
1163 
sedation.  Risks of systemic sedation and general anesthesia include cardiac arrhythmia and 
1164 
death.  The risks of retrobulbar/peribulbar anesthesia include:  retrobulbar hemorrhage; 
1165 
perforation of the eye by the needle; damage to the optic nerve; double vision lasting up to 24 
1166 
hours or more; drooping of the eye lid lasting up to 24 hours or more; difficulty speaking or 
1167 
breathing; lightheadedness/syncope/vasovagal response; allergy to any components of the 
1168 
injection; life threatening response due to the spread of anesthesia to the brain stem, resulting in 
1169 
epileptic fits, drowsiness, confusion, loss of verbalization, convulsions, respiratory arrest, or 
1170 
cardiac arrest.   
1171 
 
1172 
6.5.3.2 Surgical Procedure 
1173 
Risks of the vitrectomy procedure include a retinal tear (5%) and retinal detachment (1%).  
1174 
Uncommon risks include infection (1/5,000) and serious hemorrhage (1/5,000).  Very rare risks 
1175 
include visual field defect, visual loss due to macular toxicity of light or dye (if used) or 
1176 
manipulation, and optic neuropathy.  In phakic eyes, cataract progression is likely.   
1177 
6.5.4  Risks of Panretinal Photocoagulation Treatment 
1178 
Panretinal photocoagulation can reduce peripheral and night vision. In addition, it can reduce 
1179 
transient or permanent central vision loss. Rarely, it can cause transient increase in intraocular 
1180 
pressure, presumably through secondary angle closure as the lens-iris diaphragm shifts forward 
1181 
with transient swelling of the posterior tissues. 
1182 
 
1183 
In some cases retrobulbar or peribulbar injection may be used to anesthetize the eye and to 
1184 
reduce eye movements.  Complications of retrobulbar and peribulbar injections are rare.  They 
1185 
include, but are not limited to, the following: retrobulbar hemorrhage (bleeding behind the 
1186 
eyeball); perforation of the eye by the needle; damage to the optic nerve; diplopia lasting up to 
1187 
24 hours or more; ptosis lasting up to 24 hours or more; difficulty speaking or breathing; 
1188 
lightheadedness/syncope/vasovagal response; allergy to any components of the injection; life 
1189 
threatening response due to the spread of anesthesia to the brain stem, resulting in seizures, 
1190 
drowsiness, confusion, loss of ability to talk, convulsions, stoppage of breathing, or stoppage of 
1191 
heartbeat. All of these complications are rare. 
1192 
 
1193 
6.5.5 Risks of Eye Examination and Tests 
1194 
There is a very rare risk of an allergic response to the topical medications used to anesthetize the 
1195 
eye or dilate the pupil that occurs in less than 1% of eyes. Dilating drops rarely could cause an 
1196 
acute angle closure glaucoma attack (less than 1 in 1000)35, but this is highly unlikely since the 
1197 
participants in the study will have had their pupils dilated many times previously.   
1198 
 
1199 
There are no known risks associated with OCT.  
1200 
 
1201 
 
1202 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
7-1 
CHAPTER 7.                                                                                     
1203 
STATISTICAL METHODS 
1204 
The approach to sample size and statistical analysis is summarized below. 
1205 
7.1 Sample Size 
1206 
The sample size has been chosen for the primary study objective, which is to compare visual 
1207 
acuity outcomes over time of prompt vitrectomy + PRP regimen versus intravitreous aflibercept 
1208 
regimen in eyes with vitreous hemorrhage from PDR for which intervention is deemed 
1209 
necessary. The primary outcome is visual acuity area under the curve (AUC) from baseline to 24 
1210 
weeks. The resulting analysis is a treatment group comparison of mean AUC adjusting for 
1211 
baseline visual acuity and baseline lens status. 
1212 
7.1.1 Sample Size Assumptions 
1213 
Aflibercept Group:  To provide estimates for the aflibercept arm, data from the DRCR.net 
1214 
Protocol N trial (An Evaluation of Intravitreal Ranibizumab for Vitreous Hemorrhage Due to 
1215 
Proliferative Diabetic Retinopathy) were reviewed for eyes with baseline visual acuity 20/32 or 
1216 
worse. Eyes in Protocol N had structured treatment through 16 weeks and visits at 4, 8, and 12 
1217 
weeks. Treatment was at investigator discretion between 16 and 52 weeks, at which time visual 
1218 
acuity was measured. Based on visual acuity data (Table 1), the standard deviation of the AUC at 
1219 
12 weeks was 19.2 (95% CI 17.1, 22.0) and the correlation with baseline visual acuity was -0.39 
1220 
(95% CI -0.53, -0.23). Assuming a true standard deviation of 19.2, this adjustment yields an 
1221 
effective standard deviation of 17.7 (95% CI 16.3 to 18.7). 
1222 
Table 1. Visual acuity data from eyes in the ranibizumab group of Protocol N with baseline 
1223 
visual acuity 20/32 or worse. Visits in common with this protocol are in boldface. 
1224 
Visit 
Mean 
SD 
Baseline 
33 
28 
4-week 
44 
29 
8-week 
50 
29 
12-week 
56 
27 
52-week 
64 
22 
Vitrectomy Group:  For the vitrectomy arm, data from a randomized trial comparing vitrectomy 
1225 
with and without bevacizumab for proliferative diabetic retinopathy were reviewed (Manabe et 
1226 
al., 2015).36 In the sham group, mean baseline visual acuity was 1.14 logMAR (28 letters) and 30 
1227 
of the 34 participants (88%) were enrolled to treat persistent vitreous hemorrhage. At one month 
1228 
after surgery, mean visual acuity improved to 0.43 logMAR (64 letters). Without participant-
1229 
level data, the standard deviation of the AUC cannot be estimated. However, the standard 
1230 
deviation of visual acuity at one month was 0.48 logMAR (24 letters), which is less than the 29 
1231 
letter standard deviation for visual acuity observed in the ranibizumab group at 4 weeks in 
1232 
Protocol N (Table 1). Therefore, assuming the standard deviation of AUC for this group is 
1233 
similar to the anti-VEGF group is likely a conservative approach. 
1234 
Projected Difference:  The estimated treatment group difference in AUC at 24 weeks (6 months) 
1235 
was calculated using the above data, assuming that both groups have baseline visual acuity of 33 
1236 
letters, and the aflibercept arm reaches a visual acuity of 64 letters by 6 months (Figure 1). These 
1237 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
7-2 
calculations projected an AUC difference of +8.3 letters in favor the of the vitrectomy arm. If 
1238 
visual acuity in the aflibercept arm did not reach 64 letters until 1 year, and had a visual acuity of 
1239 
only 60 letters at 6 months, the difference would be +9.3 letters. 
1240 
Figure 1. Projected trajectories of visual acuity in the aflibercept and vitrectomy arms. 
1241 
 
1242 
7.1.2 Sample Size Estimation 
1243 
Table 2 shows sample sizes estimates under several scenarios. The final sample size has been 
1244 
computed with type 1 error rate of 0.049 (0.001 adjustment for DSMC review) and 80% power. 
1245 
Assuming an effective standard deviation of 18 (after adjusting for correlation between baseline 
1246 
and outcome), and a true difference in mean AUC of 8 letters, the required total sample size is 
1247 
162 eyes. This will be increased to 200 eyes to account for uncertainty in our projections and loss 
1248 
to follow-up; if the rate of loss to follow-up is 7.5%, then the power for an effective sample size 
1249 
of 185 would be 85%.   
1250 
Table 2. Sample size estimates for a range of true mean differences and effective standard 
1251 
deviations (after adjustment for correlation between baseline and outcome). Total number of 
1252 
eyes required for 80% / 90% power are shown in cells. The type I error rate is 0.049. 
1253 
Power: 80% / 90% 
Effective Standard Deviation 
True Mean Difference 
17 
18 
19 
7 
190 / 252 
212 / 282 
236 / 314 
8 
146 / 194 
162 / 216 
182 / 242 
9 
116 / 154 
130 / 172 
144 / 192 
 
1254 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
7-3 
7.1.3 Statistical Power 
1255 
As there are several binary variables of interest as secondary outcomes (Section 7.3), confidence 
1256 
interval half-widths (Table 3) and statistical power (Table 4) for the difference of two 
1257 
percentages have been calculated based on an effective total sample size of 186 eyes (200 eyes 
1258 
enrolled with 7% loss to follow-up). In Protocol N, among eyes in the ranibizumab group with 
1259 
baseline visual acuity of 20/32 or worse, 37% achieved 20/32 vision or greater by one year. As 
1260 
power for the difference of two percentages is dependent upon the absolute value of the 
1261 
percentages, this estimate is used as a starting point for the calculations below. 
1262 
Table 3. Expected half-widths of a 95% confidence interval for the difference of two percentages 
1263 
(effective sample size of 186). The width depends upon the true percentages. 
1264 
Outcome Rate 
in Group A 
Difference in Group B 
+10% 
+15% 
+20% 
10% 
10% 
11% 
11% 
30% 
14% 
14% 
14% 
50% 
14% 
14% 
14% 
Table 4. Power for the comparison of two percentages (effective sample size of 186). The power 
1265 
depends upon the true percentages. 
1266 
Outcome Rate 
in Group A 
Difference in Group B 
+10% 
+15% 
+20% 
10% 
41% 
72% 
91% 
30% 
25% 
50% 
76% 
50% 
23% 
49% 
76% 
The expected half-widths for a within-group binary 95% confidence interval (e.g., percentage of 
1267 
eyes in aflibercept group requiring vitrectomy) are shown in Table 5. The expected half-widths 
1268 
for a 95% confidence interval of a difference of means (e.g., visual acuity letter score) are shown 
1269 
in Table 6. 
1270 
Table 5. Expected half-widths of a 95% confidence interval for a within-group binary outcome 
1271 
(effective sample size of 93). The half-width depends upon the true outcome rate. 
1272 
Outcome Rate 
10% 
30% 
50% 
6% 
9% 
10% 
Table 6. Expected half-widths of a 95% confidence interval for a between-group difference of 
1273 
means (effective sample size of 186). The half-width depends upon the common standard 
1274 
deviation. 
1275 
Standard Deviation 
15 
20 
25 
4.3 
5.7 
7.2 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
7-4 
7.2 Primary Analysis Plan 
1276 
7.2.1 Principles for Analysis 
1277 
The primary analysis will consist of a treatment group comparison of mean visual acuity AUC 
1278 
from baseline to 24 weeks between the two treatment groups adjusting for baseline visual acuity 
1279 
and phakic status using analysis of covariance. Only baseline and outcome visits (4, 12, 24, 36, 
1280 
52, 68, 84, and 104 weeks), which are common to both groups, will be used to calculate AUC 
1281 
through the appropriate visit for the primary and secondary outcomes (e.g., 24 weeks for primary 
1282 
outcome). AUC will be calculated for each participant by the trapezoidal rule using the following 
1283 
formula: 
1284 
𝐴𝑈𝐶= ∑(𝑉𝑖+ 𝑉𝑖+1
2
× 𝑑)
𝑛
𝑖=1
  
1285 
Where Vi is the visual acuity from baseline measured at the ith visit, d is the number of days 
1286 
between visits i and i+1, and n is the number of outcome visits included in the analysis. For 
1287 
example, the primary outcome has n = 4 as the analysis will include visits at baseline, 4 weeks, 
1288 
12 weeks, and 24 weeks. For presentation, AUC will be divided by the number of days between 
1289 
baseline and the nth visit so that the value shown will have units of letters rather than letterdays. 
1290 
This statistic can then be interpreted as the average visual acuity over the time period between 
1291 
baseline and the nth visit. 
1292 
The primary analysis will include all randomized eyes according to treatment group assignment 
1293 
at randomization. Rubin’s multiple imputation will be used to handle missing data. A sensitivity 
1294 
analysis using only observed data will also be conducted. If the analyses of imputed and 
1295 
observed data differ substantially, then exploratory analyses will be performed to evaluate 
1296 
factors that may have contributed to the differences. 
1297 
Pre-planned subgroup analyses will be described in the detailed Statistical Analysis Plan and 
1298 
include analyses by history of PRP, treatment for DME, and phakic status. 
1299 
Imbalances between groups in important covariates are not expected to be of sufficient 
1300 
magnitude to produce confounding. However, the presence of confounding will be evaluated in 
1301 
the primary analysis by including factors potentially associated with the outcome for which there 
1302 
is an imbalance between groups. 
1303 
There are no data to suggest that the treatment effect will vary by gender or race/ethnicity. 
1304 
However, both of these factors will be evaluated in exploratory analyses. 
1305 
The primary outcome was primarily selected for sample size considerations. The long-term 
1306 
additional key outcomes and within-group outcomes will be equally important as the area under 
1307 
the curve outcome for evaluating the overall follow-up course for these two treatment 
1308 
approaches. Therefore, publication is not planned until the full 104 week follow-up has closed. 
1309 
7.2.2 Per-Protocol Analysis 
1310 
A per-protocol analysis will be conducted that will include all randomized eyes except those in 
1311 
the prompt vitrectomy + PRP group that never receive vitrectomy and eyes from the aflibercept 
1312 
group that missed an injection. The intent-to-treat analysis is considered the primary analysis. If 
1313 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
7-5 
the results of the primary and per-protocol analyses differ substantially, then exploratory 
1314 
analyses will be performed to evaluate the factors that have contributed to the differences. 
1315 
7.2.3 Interim Analysis Plan 
1316 
There is no formal interim data monitoring for efficacy or futility planned.   
1317 
7.3 Secondary Outcomes 
1318 
Additional analyses of visual acuity and other outcomes are summarized in the table below. 
1319 
Analyses will include adjustments for baseline visual acuity and phakic status. Analyses will be 
1320 
conducted at 24, 52, and 104 weeks (note that visual acuity AUC at 24 weeks is the primary 
1321 
outcome, not a secondary outcome). In addition, mean visual acuity, visual acuity AUC, and 
1322 
percentage of eyes with various visual acuity cutoffs will also be compared at the 4 and 12 week 
1323 
visits as the between-group difference in vision is expected to be greatest during the first months 
1324 
of the trial. 
1325 
Table 3. Analyses of Secondary Outcomes. 
1326 
Outcome 
Analysis Technique 
Mean visual acuity and AUC 
Analysis of covariance 
Percentage of eyes ≥ 20/20, 20/32, or 20/40, ≤ 
20/200 and ≤ 20/800  
Binomial regression 
Percentage of eyes with recurrent vitreous 
hemorrhage on clinical exam 
Binomial regression 
Percentage of eyes with retinal 
neovascularization 
Binomial regression 
OCT central subfield thickness 
Analysis of covariance*† 
*No adjustment for visual acuity.  
1327 
†No adjustment for baseline central subfield thickness as vitreous hemorrhage will prevent 
1328 
obtaining usable scans for many participants. 
1329 
7.3.1 Outcomes within Treatment Groups 
1330 
Within each treatment group, the following outcomes and their 95% confidence intervals will be 
1331 
tabulated: 
1332 
• Percentage of eyes undergoing vitrectomy (initial vitrectomy in aflibercept group and 
1333 
repeat vitrectomy in vitrectomy group) 
1334 
• Number of intravitreous aflibercept injections performed 
1335 
• Percentage of eyes receiving PRP (aflibercept group only) 
1336 
7.3.2 Economic Analysis 
1337 
The purpose of the economic analysis is to compare the treatment groups with respect to cost, 
1338 
cost-effectiveness and workplace productivity loss. The analysis plan is briefly described and 
1339 
will be detailed in a separate document. 
1340 
Data from the clinical trial on number of clinic visits completed, number of procedures 
1341 
performed (e.g. vitrectomy, OCT, exam), and number of study aflibercept injections will be used 
1342 
to estimate an average cost per patient for each treatment arm, using the Medicare Fee Schedule 
1343 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
7-6 
to estimate medical costs. The cost estimates in combination with the percent productivity loss 
1344 
for each treatment arm will be incorporated into the analysis. 
1345 
Scores from the WPAIQ, administered at baseline, 4, 12, 24, 52, and 104 weeks, will be 
1346 
analyzed by treatment group using analysis of covariance to adjust for baseline score and phakic 
1347 
status. Adjusted 95% confidence intervals for treatment group differences will be calculated. 
1348 
Mean change at each visit in the following four scores will be analyzed: 
1349 
• Absenteeism:  percent work time missed due to vision 
1350 
• Presenteeism:  percent impairment while working due to vision  
1351 
• Work Productivity Loss:  percent overall work impairment due to vision  
1352 
o Combination of absenteeism and presenteeism scores 
1353 
• Activity Impairment:  percent activity impairment due to vision 
1354 
In addition, area under the curve analyses will be conducted using data from all available 
1355 
outcome visits for the Work Productivity Loss and Activity Impairment scores. 
1356 
7.4 Safety Analysis Plan 
1357 
Adverse events will be categorized as systemic, study eye, or non-study eye. The events will be 
1358 
tabulated by treatment group. As only one study eye shall be enrolled, there is no group of 
1359 
patients with two study eyes, which would need to be tabulated separately. The frequency of the 
1360 
event occurring at least once will be calculated. Rates of adverse events will be compared 
1361 
between treatment groups using Barnard’s unconditional exact test.  
1362 
The following ocular adverse events will be assessed: 
1363 
o Endophthalmitis 
1364 
o Any retinal detachment 
1365 
o Rhegmatogenous retinal detachment 
1366 
o Tractional retinal detachment 
1367 
o Retinal tear 
1368 
o Ocular inflammation (defined as anterior chamber cell, anterior chamber flare, 
1369 
choroiditis, episcleritis, uveitis, iritis, or vitreal cells) 
1370 
o Adverse intraocular pressure (IOP) events 
1371 
▪ Increase in IOP ≥ 10 mmHg from baseline 
1372 
▪ IOP ≥ 30 mmHg 
1373 
▪ Initiation of medication to lower IOP that was not in use at baseline 
1374 
▪ Glaucoma surgery 
1375 
o Neovascularization of the iris 
1376 
o Cataract extraction in eyes phakic at baseline 
1377 
o Visually significant cataract on clinical exam 
1378 
The following serious systemic adverse events will be assessed: 
1379 
o Primary: 
1380 
▪ Death 
1381 
▪ Serious adverse event (at least one) 
1382 
▪ Hospitalization (at least one) 
1383 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
7-7 
▪ Cardiovascular/cerebrovascular events according to Antiplatelet Trialists’ 
1384 
Collaboration (excerpted from BMJ Jan 8, 1994): 
1385 
• Non-fatal myocardial infarction 
1386 
• Non-fatal stroke (counted only if symptoms lasted at least 24 hours) 
1387 
• Death attributed to cardiac, cerebral, hemorrhagic, embolic, other 
1388 
vascular (does not need to be ischemic in origin), or unknown cause 
1389 
• At least one event (non-fatal myocardial infarction, non-fatal stroke, or 
1390 
death attributed to potential vascular or unknown cause) 
1391 
APTC Notes:  Transient ischemic attacks, angina, and possible myocardial 
1392 
infarction or stroke are not counted. ‘Nonfatal’ myocardial infarction or 
1393 
stroke required that the participant was alive at the end of the study. If not, 
1394 
only the death is counted. 
1395 
o Secondary: 
1396 
▪ Frequency of at least one event per participant in each Medical Dictionary for 
1397 
Regulatory Activities (MedDRA) system organ class 
1398 
 
1399 
An additional tabulation will be made for adverse events possibly related to study treatment. 
1400 
7.5 Additional Tabulations and Analyses 
1401 
The following will be tabulated according to treatment group: 
1402 
• Baseline demographic and clinical characteristics 
1403 
• Visit completion rate 
1404 
• Treatment completion 
1405 
7.6 Statistical Modeling Techniques 
1406 
All model assumptions, including linearity, normality of residuals, and homoscedasticity will be 
1407 
verified where applicable. If model assumptions are not reasonably satisfied, then a 
1408 
transformation, nonparametric analysis, or other appropriate approach will be considered. 
1409 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
8-1 
CHAPTER 8. REFERENCES 
1410 
 
1411 
 
1412 
1. Vision disorders in diabetes.Available at: 
1413 
http://diabetes.niddk.nih.gov/dm/pubs/america/pdf/chapter14.pdf. Accessed August 21, 2009 
1414 
2. Bourne RR, Stevens GA, White RA, et al. Causes of vision loss worldwide, 1990-2010: a 
1415 
systematic analysis. Lancet Glob Health 2013;1:e339-49. 
1416 
3. Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal 
1417 
photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: A 
1418 
randomized clinical trial. JAMA 2015;314:2137-46. 
1419 
4. Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy among 
1420 
adults in the United States. Arch Ophthalmol 2004;122:552-63. 
1421 
5. Ferris FL, 3rd. How effective are treatments for diabetic retinopathy? JAMA 1993;269:1290-
1422 
1. 
1423 
6. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the 
1424 
treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695 e1-15. 
1425 
7. Ho T, Smiddy W, Flynn Jr H. Vitrectomy in the Management of Diabetic Eye Disease. Surv 
1426 
Ophthalmol 1992;37:190-202. 
1427 
8. Misra A, Ho-Yen G, Burton RL. 23-gauge sutureless vitrectomy and 20-gauge vitrectomy: a 
1428 
case series comparison. Eye (Lond) 2009;23:1187-91. 
1429 
9. Khuthaila MK, Hsu J, Chiang A, et al. Postoperative vitreous hemorrhage after diabetic 23-
1430 
gauge pars plana vitrectomy. Am J Ophthalmol 2013;155:757-63, 63 e1-2. 
1431 
10. Castellarin A, Grigorian R, Bhagat N, et al. Vitrectomy with silicone oil infusion in severe 
1432 
diabetic retinopathy. Br J Ophthalmol 2003;87:318-21. 
1433 
11. Ostri C, La Cour M, Lund-Andersen H. Diabetic vitrectomy in a large type 1 diabetes patient 
1434 
population: long-term incidence and risk factors. Acta Ophthalmol 2014;92:439-43. 
1435 
12. Ostri C, Lux A, Lund-Andersen H, et al. Long-term results, prognostic factors and cataract 
1436 
surgery after diabetic vitrectomy: a 10-year follow-up study. Acta Ophthalmol 2014;92:571-
1437 
6. 
1438 
13. Gupta B, Sivaprasad S, Wong R, et al. Visual and anatomical outcomes following vitrectomy 
1439 
for complications of diabetic retinopathy: the DRIVE UK study. Eye (Lond) 2012;26:510-6. 
1440 
14. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe 
1441 
vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic 
1442 
Retinopathy Vitrectomy Study report 2 Arch Ophthalmol 1985;103:1644-52. 
1443 
15. Fassbender JM, Ozkok A, Canter H, et al. A Comparison of Immediate and Delayed 
1444 
Vitrectomy for the Management of Vitreous Hemorrhage due to Proliferative Diabetic 
1445 
Retinopathy. Ophthalmic Surg Lasers Imaging Retina 2016;47:35-41. 
1446 
16. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels 
1447 
in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 
1448 
1994;118:445-50. 
1449 
17. Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor 
1450 
prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch 
1451 
Ophthalmol 1996;114. 
1452 
18. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of 
1453 
patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480-
1454 
7. 
1455 
19. Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by 
1456 
inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor 
1457 
chimeric proteins. Proc Natl Acad Sci USA 1995;92:10457-61. 
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Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
8-2 
20. Amano S, Rohan R, Kuroki M, et al. Requirement for vascular endothelial growth factor in 
1459 
wound- and inflammation-related corneal neovascularization. Invest Ophthalmol Vis Sci 
1460 
1998;39:18-22. 
1461 
21. Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal 
1462 
neovascularization with intravitreal anti-vascular endothelial growth factor antibody 
1463 
fragment. Arch Ophthalmol 2002;120:338-46. 
1464 
22. Malecaze F, Clamens S, Simorre-Pinatel V, et al. Detection of vascular endothelial growth 
1465 
factor messenger RNA and vascular endothelial growth factor-like activity in proliferative 
1466 
diabetic retinopathy. Arch Ophthalmol 1994;112:1476-82. 
1467 
23. Schwesinger C, Yee C, Rohan RM, et al. Intrachoroidal neovascularization in transgenic 
1468 
mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. 
1469 
Am J Pathol 2001;158:1161-72. 
1470 
24. Tolentino MJ, Miller JW, Gragoudas ES, et al. Vascular endothelial growth factor is 
1471 
sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman 
1472 
primate. Arch Ophthalmol 1996;114:964-70. 
1473 
25. Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal 
1474 
permeability is mediated by protein kinase C in vivo and suppressed by an orally effective 
1475 
beta-isoform-selective inhibitor. Diabetes 1997;46:1473-80. 
1476 
26. Diabetic Retinopathy Clinical Research N. Randomized clinical trial evaluating intravitreal 
1477 
ranibizumab or saline for vitreous hemorrhage from proliferative diabetic retinopathy. JAMA 
1478 
Ophthalmol 2013;131:283-93. 
1479 
27. Sinawat S, Rattanapakorn T, Sanquansak T, et al. Intravitreal bevacizumab for proliferative 
1480 
diabetic retinopathy with new dense vitreous hemorrhage after full panretinal 
1481 
photocoagulation. Eye (Lond) 2013;27:1391-6. 
1482 
28. US FDA approves EYLEA (aflibercept) injection for the treatment of we age-related macular 
1483 
degeneration.Available at: 
1484 
http://www.press.bayer.com/baynews/baynews.nsf/0/EB1AAB6D8405A0BDC125794A0056
1485 
C856. accessed January 1, 2012 
1486 
29. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central 
1487 
retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol 
1488 
2013;97:278-84. 
1489 
30. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema 
1490 
secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS 
1491 
study edema secondary to central retinal vein occlusion: 1-year results from the phase 3 
1492 
COPERNICUS study. Am J Ophthalmol 2013;155:429-37. 
1493 
31. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular 
1494 
edema secondary to central retinal vein occlusion: six-month results of the phase 3 
1495 
COPERNICUS study. Ophthalmology 2012;119:1024-32. 
1496 
32. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular 
1497 
edema. Ophthalmology 2014;121:2247-54. 
1498 
33. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal Aflibercept for Diabetic Macular 
1499 
Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology 2015. 
1500 
34. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for 
1501 
diabetic macular edema. N Engl J Med 2015;372:1193-203. 
1502 
35. Wolfs RC, Grobbee DE, Hofman A, et al. Risk of acute angle-closure glaucoma after 
1503 
diagnostic mydriasis in nonselected subjects: the Rotterdam Study. Invest Ophthalmol Vis 
1504 
Sci 1997;38:2683-7. 
1505 


 
Vx for Vitreous Hemorrhage Protocol 1.0 7-28-16 
8-3 
36. Manabe A, Shimada H, Hattori T, et al. Randomized controlled study of intravitreal 
1506 
bevacizumab 0.16 mg injected one day before surgery for proliferative diabetic retinopathy. 
1507 
Retina 2015;35:1800-7. 
1508 
 
1509 

SAP_001.pdf: 
Diabetic Retinopathy Clinical Research Network 
Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous 
Hemorrhage from Proliferative Diabetic Retinopathy  
(Protocol AB) 
Statistical Analysis Plan 
NCT 02858076 
Document date 27 April 2020 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0 
Wesley Beaulieu 
Michele Melia 
17 October 2017 
Initial version for Protocol version 1.0. 
1.1 
Wesley Beaulieu 
Michele Melia 
12 February 2019 
Revisions for consistency across 
DRCR.net SAPs following DSMC review. 
Still applies to Protocol version 1.0. 
Changes made prior to initial data 
analysis. 
1.2 
Wesley Beaulieu 
Maureen Maguire 
27 April 2020 
Updated significance threshold for 
primary outcome from .05 to .049 for 
consistency with protocol. Added post hoc 
visual acuity subgroup analysis. Changed 
measure of treatment group effect for 
binary outcomes to risk difference instead 
of odds ratio. Other minor changes and 
clarifications. Changes were made after 
the initial analysis. Still applies to Protocol 
version 1.0. 
 
SIGNATURES 
AUTHOR 
 
 
 
 
 
APPROVER 
 
 
 
 


 
Protocol V Statistical Analysis Plan 
 
 
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Protocol AB Statistical Analysis Plan 
 
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1.0 Introduction 
1 
This document outlines the statistical analysis plan for the Diabetic Retinopathy Clinical 
2 
Research Network (DRCR.net) Protocol AB comparing prompt vitrectomy with panretinal 
3 
photocoagulation (PRP) versus an intravitreous anti-vascular endothelial growth factor (VEGF) 
4 
regimen for treatment of vitreous hemorrhage from proliferative diabetic retinopathy (PDR) for 
5 
which intervention is deemed necessary. The anti-VEGF agent used in this trial is aflibercept 
6 
(Eylea®, Regeneron Pharmaceuticals, Tarrytown, New York, USA). 
7 
The primary objective of the protocol is to determine if there is a difference between the two 
8 
treatment groups in visual acuity area under the curve (AUC) over 24 weeks. Participants will 
9 
have outcome visits at 4, 12, 24, 36, 52, 68, 84, and 104 weeks. The long-term outcomes (e.g., 2-
10 
year visual acuity AUC, other secondary outcomes, safety) are considered equally important as 
11 
the primary outcome. Therefore, results from this trial will not be published until the 104-week 
12 
follow-up has closed. 
13 
Study eyes will be assigned randomly to the two treatment groups in a 1:1 ratio stratified by site. 
14 
Participants may have only one study eye enrolled in the randomized trial. 
15 
2.0 Efficacy Analysis Plan 
16 
2.1 Primary Outcome Analysis 
17 
The primary analysis will consist of a treatment group comparison of mean visual acuity AUC 
18 
from baseline to 24 weeks adjusting for baseline visual acuity and phakic status using a general 
19 
linear model with robust variance estimation. The primary analysis is an intention-to-treat 
20 
analysis. All randomized eyes will be included in the primary analysis according to treatment 
21 
group assignment at randomization. Only baseline and outcome visits (4, 12, 24, 36, 52, 68, 84, 
22 
and 104 weeks), which are common to both groups, will be used to calculate AUC through the 
23 
appropriate visit for the primary and secondary outcomes (e.g., 24 weeks for the primary 
24 
outcome). AUC will be calculated for each participant by the trapezoidal rule using the following 
25 
formula: 
26 
𝐴𝑈𝐶= ∑(𝑉𝑖+ 𝑉𝑖+1
2
× 𝑑)
𝑛
𝑖=1
  
27 
Where Vi is the visual acuity measured at the ith visit, d is the number of days between visits i and 
28 
i+1, and n is the number of outcome visits included in the analysis. For example, the primary 
29 
outcome has n = 4 as the analysis will include visits at baseline, 4, 12, and 24 weeks. For 
30 
presentation, AUC will be divided by the number of days between baseline and the nth visit so 
31 
that the value shown will have units of letters rather than letterdays (e.g., 168 days for the 
32 
primary outcome at 24 weeks). This statistic can then be interpreted as the average visual acuity 
33 
over the time between baseline and the nth visit. If the P value for the test of the treatment effect 
34 
is less than or equal to .049, then it will be concluded that there is a significant difference in 
35 
visual acuity AUC between the two groups. 
36 


 
 
Protocol AB Statistical Analysis Plan 
 
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Markov chain Monte Carlo (MCMC) multiple imputation will be used to impute missing data. 
37 
The imputation model will include the visual acuities measured at baseline and at all outcome 
38 
visits (4, 12, 24, 36, 52, 68, 84, and 104 weeks) along with treatment group and phakic status. If 
39 
the data are judged to be substantially non-normal, then predictive mean matching with a match 
40 
set of k = 5 may be used for imputation instead of MCMC. Due to the nature of vitreous 
41 
hemorrhage, there is a higher than usual chance of the data following a non-normal distribution. 
42 
To limit the influence of extreme data points, visual acuity will be truncated to ± 3 standard 
43 
deviations based on observed 24-week data (see Section 7.4) prior to the AUC calculation but 
44 
after imputation. Imputed data implying a nonbiologic value for visual acuity (< 0 or > 100) will 
45 
be truncated at the closest biologic value (i.e., 0 or 100). 
46 
A plot showing the mean level of visual acuity by group over time will be constructed using 
47 
observed data. In general, summary statistics (e.g., within-group means and standard deviations), 
48 
will be based on observed data while numbers from statistical models (e.g., treatment group 
49 
differences, confidence intervals, and P values) will be based on imputed data. 
50 
2.1.1 Sensitivity Analyses 
51 
A sensitivity analysis including observed data from participants completing the 24-week visit (no 
52 
imputation of missing data) will be conducted (i.e., complete-case analysis). If the analyses of 
53 
imputed and observed data differ substantially, then exploratory analyses will be performed to 
54 
evaluate factors that may have contributed to the differences. An additional sensitivity analysis 
55 
using observed visual acuity data without truncation or imputation of missing data will also be 
56 
performed. 
57 
A sensitivity analyses using nonparametric methods will be conducted using observed data from 
58 
participants completing the 24-week visit. The primary outcome will be converted to van der 
59 
Waerden (Normal) scores and analyzed similarly as above with a general linear model adjusting 
60 
for baseline visual acuity and phakic status. 
61 
Multiple imputation assumes that data are missing at random (MAR). In the present study, this 
62 
would mean that whether follow-up visual acuity data are missing or observed may be a function 
63 
of observed baseline characteristics included in the imputation model (e.g., baseline visual 
64 
acuity, follow-up visual acuity, treatment group, or phakic status), but not a function of the 
65 
unobserved follow-up visual acuities that are being imputed. This assumption cannot be tested 
66 
since these unobserved data are unknown. However, a tipping point analysis will be conducted to 
67 
adjust the imputed values using a shift parameter and thereby determine how severe the 
68 
departure from MAR must be to change outcome of the analysis with respect to rejecting or 
69 
failing to reject the null hypothesis. 
70 
A shift parameter will be applied to the imputed values in the aflibercept group to determine the 
71 
tipping point at which the conclusion of the primary hypothesis test changes. That is, if one 
72 
group is found to be superior, the tipping point will identify the shift parameter necessary to 
73 
nullify the result. Conversely, if the null hypothesis is not rejected, two tipping points will be 
74 
identified – one that would make aflibercept superior and one that would make vitrectomy 
75 


 
 
Protocol AB Statistical Analysis Plan 
 
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superior. In either case, the tipping point(s) will be evaluated to determine plausibility. If not 
76 
plausible, then the MAR assumption is likely reasonable. For example, if the tipping point were 
77 
100 letters, then this would be evidence that the MAR assumption is reasonable for this analysis. 
78 
2.1.2 Per-Protocol Analysis 
 
79 
A per-protocol analysis will be conducted to estimate the treatment effect for each treatment 
80 
among those who complied with the treatment. This analysis will include observed data (no 
81 
imputation) from all randomized eyes that complete the 4-, 12-, and 24-week visits except those 
82 
in the prompt vitrectomy group that never receive vitrectomy and eyes in the aflibercept group 
83 
that missed at least one injection before the 24-week visit. The intention-to-treat analysis is 
84 
considered the primary analysis. If the results of the primary and per-protocol analyses differ 
85 
substantially, then exploratory analyses will be performed to evaluate the factors that may have 
86 
contributed to the differences. The per-protocol analysis will only be performed if more than 
87 
10% of randomized participants would be excluded by these criteria. 
88 
 
2.1.3 Confounding 
89 
Imbalances between groups in important covariates are not expected to be of sufficient 
90 
magnitude to produce confounding in the primary analysis. However, the presence of 
91 
confounding in the primary analysis will be evaluated in additional regression models using 
92 
observed data (no imputation) by including baseline participant and study eye covariates 
93 
including but not limited to the following:  
94 
• Age 
95 
• Duration of diabetes 
96 
• Mean arterial blood pressure 
97 
• Duration of vitreous hemorrhage 
98 
• HbA1c 
99 
• Prior PRP 
100 
• Prior treatment for diabetic macular edema (DME) 
101 
Additional variables associated with the outcome will be included in regression models if there is 
102 
an imbalance in the variables between treatment groups. Imbalance by treatment group will not 
103 
be judged using statistical testing. Instead, imbalance will be judged by whether the size of the 
104 
imbalance is clinically important, i.e., whether the imbalance is large enough to have a clinically 
105 
important effect on the primary outcome.  
106 
 
2.1.4 Subgroup Analyses 
107 
Pre-planned subgroup analyses will repeat the primary analysis while including an interaction 
108 
term for the baseline subgroup factor by treatment. Only observed data (no imputation) will be 
109 
used for these analyses. Unless the imputation process is done separately for each treatment 
110 
group and the subgroup factor is included in the imputation model, the analysis will be biased 
111 
towards the null hypothesis of no interaction (Sullivan et al., 2016). It is recognized that 
112 


 
 
Protocol AB Statistical Analysis Plan 
 
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analyzing only observed data may be biased, but unlike the imputed analysis, it is not 
113 
automatically biased in the presence of interaction. 
114 
A significant type III test of the interaction term will be taken as an indication that subgroup 
115 
effects need to be explored for full interpretation of the trial results. It is recognized that the 
116 
study is not powered to detect subgroup effects and that lack of significance is not necessarily an 
117 
indication that subgroup effects do not exist.  
118 
Interpretation of subgroup analyses will depend on whether the overall analysis demonstrates a 
119 
significant treatment effect. In the absence of a significant treatment effect in the primary 
120 
analysis, finding a significant treatment effect in a subgroup will be regarded as likely due to 
121 
chance. 
122 
Baseline variables to be evaluated for subgroup effects include the following: 
123 
• History of PRP: yes vs. no 
124 
• Phakic status: phakic vs. pseudophakic 
125 
• Age: continuous and < 60 vs ≥ 60 years 
126 
The above subgroups are considered those of primary interest for which a rationale for a 
127 
subgroup effect is hypothesized. For each factor, the rationale for performing the analysis is 
128 
listed in Table 1 below. 
129 
Table 1. Subgroup analyses. 
130 
Factor 
Rationale 
History of PRP 
Eyes with prior PRP may have less active disease, which 
could be impacted differently by treatment. Alternatively, 
eyes with prior PRP that subsequently have a vitreous 
hemorrhage could have more severe underlying disease, 
which could be impacted differently by treatment. 
Phakic status 
Phakic eyes may have more cataract progression in the 
vitrectomy group than in the aflibercept group, which would 
reduce visual acuity. 
Age 
Eyes from older individuals may have a longer recovery time 
from surgery and be at a higher risk of cataract, which could 
be exacerbated in the vitrectomy group. 


 
 
Protocol AB Statistical Analysis Plan 
 
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The following subgroup factors will be evaluated in exploratory analyses. The finding of a 
131 
significant subgroup effect for any of these factors will be interpreted as hypothesis generating 
132 
only and in need of confirmation from further studies. 
133 
• Prior DME treatment: yes vs. no 
134 
• Prior focal/grid laser for DME: yes vs. no 
135 
• Prior anti-VEGF for DME: yes vs. no  
136 
• HbA1c: continuous and < 7.5% vs. ≥ 7.5% 
137 
• Duration of vitreous hemorrhage: below vs. at or above median 
138 
• Sex: female vs. male 
139 
• Race/Ethnicity: White vs. Black/African American vs. Hispanic (exclude all other groups 
140 
due to anticipated small sample size) and White vs. non-White 
141 
• Baseline visual acuity: 20/32 to 20/800 (78 to 4 letters) vs. worse than 20/800 (< 3 letters) 
142 
o The subgroup analysis by baseline visual acuity was added after reviewing the 
143 
data (i.e., post hoc) 
144 
To increase the accuracy of estimates, subgroups will only be analyzed if there are at least 20 
145 
eyes in each treatment group for each subgroup. Cutoffs of continuous and ordinal outcomes 
146 
may be modified to achieve a reasonable number of eyes in each group. Interaction P values will 
147 
be calculated using the continuous and ordinal variables, where possible, in addition to the 
148 
categorizations described above. 
149 
2.1.5 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 
2.2 Secondary Outcome Analyses 
156 
 
2.2.1 Visual Acuity 
157 
Additional analyses of visual acuity will use the imputed data sets created for the primary 
158 
outcome. These analyses are summarized in Table 2. The analysis models will include 
159 
adjustments for baseline visual acuity and phakic status. Analyses will be conducted at 4, 12, 24, 
160 
52, and 104 weeks unless otherwise noted. Note that visual acuity AUC at 24 weeks is the 
161 
primary outcome and not a secondary outcome.  
162 


 
 
Protocol AB Statistical Analysis Plan 
 
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For all outcomes analyzed with logistic regression, the percentage of eyes meeting the outcome 
163 
at the visit will be reported for each treatment group. The treatment group comparison will be 
164 
summarized with a risk difference and 95% confidence interval (estimated using the delta 
165 
method, see Localio et al. 2007) and a P value. For binary change in visual acuity outcomes, 
166 
only eyes at risk of the outcome will be included in the analysis. For example, because the 
167 
minimum visual acuity letter score is 0 letters, only eyes with baseline visual acuity ≥ 15 letters 
168 
will be included in the analysis ≥ 15-letter loss. All eyes will be included in the analyses of 
169 
binary visual acuity letter score (e.g., ≥ 69 letters) since visual acuity may increase or decrease 
170 
following randomization, which makes all eyes at risk for the outcome. 
171 
Table 2. Visual Acuity Secondary Outcome Analyses. 
172 
Outcome 
Analysis Technique 
Visual acuity letter score AUC (104 weeks only) 
General linear model 
Visual acuity letter score 
General linear model 
Success proportion: visual acuity ≥ 84 letters (~20/20) 
Tabulation only 
Success proportion: visual acuity ≥ 74 letters (~20/32) 
Logistic regression 
Success proportion: visual acuity ≥ 69 letters (~20/40) 
Tabulation only 
Failure proportion: visual acuity ≤ 38 letters (~20/200) 
Logistic regression 
Failure proportion: visual acuity ≤ 8 letters (~20/800) 
Tabulation only 
Success proportion: visual acuity gain ≥ 15 letters * 
Logistic regression 
Success proportion: visual acuity gain ≥ 30 letters * 
Tabulation only 
Failure proportion: visual acuity loss ≥ 15 letters * 
Logistic regression 
Failure proportion: visual acuity loss ≥ 30 letters * 
Tabulation only 
* These outcomes are considered exploratory because they were added after the protocol was finalized. 
173 
2.2.2 PDR and DME 
174 
Additional secondary outcomes will be evaluated at 24, 52, and 104 weeks. Analyses will use 
175 
observed data (no imputation) and adjust for phakic status. 
176 
Table 3. Additional Secondary Outcomes. 
177 
Outcome 
Analysis Technique 
Percentage of eyes with recurrent vitreous hemorrhage on clinical 
exam at any time during follow-up* 
Logistic regression 
Percentage of eyes with retinal neovascularization on clinical 
exam (neovascularization of the disc or elsewhere) 
Logistic regression 
OCT central subfield thickness† 
General linear model 
*A subgroup analysis similar to what is described in section 2.1.4 will be conducted for this outcome by whether the 
178 
participant was on anticoagulants or antiplatelet medication at baseline. This outcome will be evaluated through 104 
179 
weeks only. 
180 
†No adjustment for baseline central subfield thickness because vitreous hemorrhage will prevent obtaining usable 
181 
OCT scans for many participants. 
182 


 
 
Protocol AB Statistical Analysis Plan 
 
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A plot of mean OCT central subfield thickness over time by group will be constructed using 
183 
observed data.  
184 
2.2.3 Workplace Productivity and Activity Impairment Questionnaire 
185 
Outcomes from the Workplace Productivity and Activity Impairment Questionnaire (WPAIQ) 
186 
will be compared between treatment groups at 4, 12, 24, 52 and 104 weeks unless otherwise 
187 
indicated in the bulleted list below. Analyses will be conducted with a general linear model that 
188 
is adjusted for the baseline level of the score being analyzed and phakic status. Only participants 
189 
completing the corresponding visit will be included in the analysis. There will be no imputation 
190 
of missing data. The following outcomes will be evaluated: 
191 
• Change in Absenteeism score (tabulated without statistical comparison) 
192 
• Change in Presenteeism score (tabulated without statistical comparison) 
193 
• Change in Work Productivity Loss score 
194 
• Change in Work Productivity Loss score AUC (24 and 104 weeks only) 
195 
• Change in Activity Impairment score 
196 
• Change in Activity Impairment score AUC (24 and 104 weeks only) 
197 
WPAIQ AUC scores will be calculated similarly to visual acuity AUC (described in Section 2.1). 
198 
The Work Productivity Loss score (a composite of the Absenteeism and Presenteeism scores) 
199 
will be considered the scale of primary interest from the WPAIQ. It is anticipated that the 
200 
vitrectomy group will be superior to the anti-VEGF group due to a faster recovery of visual 
201 
acuity. Plots showing the mean levels of the Work Productivity Loss and Activity Impairment 
202 
scores by treatment group over time will be constructed. 
203 
2.3 Exploratory Outcomes 
204 
The following outcomes were not outlined in the protocol. However, they are considered of 
205 
interest. These analyses will adjust for baseline phakic status and use observed data only.  
206 
Table 4. Exploratory Outcomes. 
207 
Outcome 
Analysis Technique 
Presence of DME* 
Logistic regression 
Time to initiation of DME treatment through 104 weeks† 
Cox Proportional Hazards 
Regression 
*Defined as OCT central subfield thickness ≥ 305 µm for women and ≥ 320 µm for men (Heidelberg Spectralis) or 
208 
≥ 290 for women and ≥ 305 for men (Zeiss Cirrus). Evaluated at 24, 52, and 104 weeks for eyes completing the visit. 
209 
†Defined as anti-VEGF injection, corticosteroid injection, administration of focal/grid laser, or vitrectomy for DME. 
210 
Includes all randomized eyes. The hazard ratio with 95% confidence interval and P value will be reported for the 
211 
full 104-week follow-up. A Kaplan-Meier plot will be constructed and the cumulative probabilities with 95% 
212 
confidence intervals will be presented for each treatment group at 104 weeks.  
213 


 
 
Protocol AB Statistical Analysis Plan 
 
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The ability to obtain an OCT scan may be related to the treatment if the hemorrhage clears more 
214 
quickly in one arm, potentially introducing bias into the treatment comparison for these two 
215 
outcomes. Therefore, the proportion of eyes in which an OCT scan cannot be obtained will be 
216 
tabulated for each group at 24, 52, and 104 weeks. 
217 
 
2.3.1 Development of DME 
218 
Development of DME in eyes with OCT assessment at baseline with be evaluated as an 
219 
exploratory outcome over the full 2-year follow-up. Having DME on OCT at baseline is an 
220 
exclusion criterion for randomization. It is recognized that OCT will be unavailable for many 
221 
eyes due to dense vitreous hemorrhage at baseline; however, since OCT is obtained prior to 
222 
randomization, the treatment comparison is still valid. The analysis will adjust for baseline OCT 
223 
central subfield thickness and phakic status. Therefore, only eyes with available baseline OCT 
224 
data will be included. Cox proportional hazards regression will be used to estimate the hazard 
225 
ratio and associated 95% confidence interval for developing DME with vitrectomy versus 
226 
aflibercept. Data from eyes not developing DME within the 2-year follow-up period will be 
227 
considered censored on the day of their final completed visit, without regard for interim missed 
228 
visits. To increase the accuracy of estimates, this analysis will be conducted only if at least 20 
229 
eyes in each treatment group meet the outcome criteria. 
230 
A Kaplan-Meier curve showing time-to-development of DME by treatment group will be 
231 
constructed. Within each treatment group, the Kaplan-Meier estimate of the survival function 
232 
and 95% confidence interval at the final available time point will be calculated.  
233 
3.0 Outcomes within Treatment Groups 
234 
Within each treatment group, the following outcomes will be tabulated at 24, 52, and 104 weeks 
235 
(for 24-, 52-, and 104-week completers, respectively), both cumulatively from baseline, and for 
236 
the intervening periods between those visits. There will be no formal statistical comparisons. 
237 
• Proportion of eyes undergoing vitrectomy (initial vitrectomy in aflibercept group and 
238 
repeat vitrectomy in vitrectomy group) 
239 
• Distribution and mean (standard deviation) number of intravitreous aflibercept injections 
240 
performed 
241 
• Proportion of eyes receiving PRP during follow-up 
242 
For the vitrectomy group, the following components of the surgical treatment will be 
243 
characterized with data tabulations and descriptive statistics: 
244 
• Surgery time in minutes 
245 
• Vitrectomy system gauge 
246 
• Intraoperative use of anti-VEGF or steroid 
247 
o Drugs used 
248 


 
 
Protocol AB Statistical Analysis Plan 
 
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• Administration of PRP 
249 
o For those undergoing PRP, also tabulate the average power (mW), exposure time 
250 
(seconds), total number of spots, estimated number of quadrants treated, estimated 
251 
total number of burns that had a visible effect on the retina, and if the PRP is 
252 
considered “complete” as defined by the protocol 
253 
• Surgical complications (e.g., choroidal detachment, rhegmatogenous retinal detachment, 
254 
retinal dialysis, retinal tear, etc.) 
255 
• Use of staining agents to visualize epiretinal proliferation or internal limiting membrane 
256 
o Agent used 
257 
• Placement of gas in the eye (C3F8, SF6, or filtered air) 
258 
• Additional procedure(s) performed during vitrectomy surgery (e.g., cataract extraction, 
259 
cryopexy, fluid-gas exchange, epiretinal membrane peeling, internal limiting membrane 
260 
peel, intraocular lens implantation, laser retinopexy, removal of fibrous proliferation, 
261 
scleral buckle, etc.) 
262 
4.0 Economic Analysis 
263 
The purpose of the economic analysis is to compare the treatment groups with respect to cost, 
264 
cost effectiveness, and workplace productivity loss. Resource utilization data will be calculated 
265 
using the number of clinic visits along with the number and types of diagnostic and therapeutic 
266 
ocular procedures performed on each group. To capture patient resource utilization, cost data for 
267 
all diagnostic and therapeutic procedures performed will tabulated to obtain a total cost for eye 
268 
care services over 2 years of follow-up. 
269 
To capture the health-related quality-of-life associated with receipt of the two interventions over 
270 
the course of the trial, two methods will be used. The first method will be to convert the visual 
271 
acuities from the better-seeing eye over the two years of the trial into Quality-Adjusted Life-
272 
Years (QALYs) using the methods of Brown et al (2003). This method has been used widely in 
273 
prior cost-effectiveness analyses of ophthalmologic interventions. The second method will use 
274 
the best-corrected visual acuities from the treated eye, regardless of whether it is the better or 
275 
worse-seeing eye. Resource use, costs, and QALYs will be aggregated over the two years of the 
276 
trial. The incremental cost-effectiveness ratio (ICER) will calculated by taking the incremental 
277 
cost of intravitreous aflibercept over vitrectomy and dividing it by the incremental QALYs of 
278 
aflibercept over vitrectomy. A probabilistic sensitivity analysis will be conducted to better 
279 
characterize overall uncertainty in the results. 
280 
5.0 Safety Analysis 
281 
Adverse events will be categorized as study eye, fellow eye, or systemic. A full listing of adverse 
282 
events will be tabulated by treatment group for systemic, study-eye ocular, and fellow-eye ocular 
283 
adverse events. An additional tabulation will be made for adverse events possibly related to 
284 
study treatment.  
285 


 
 
Protocol AB Statistical Analysis Plan 
 
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All randomized eyes will be included in the safety analysis and analyzed according to the 
286 
treatment group they were assigned to at randomization. For the 104-week primary safety 
287 
analysis, any adverse event that occurred at least once prior to the 104-week visit (or 728 days if 
288 
the participant did not complete the 104-week visit) will be reported. 
289 
Due to the different visit schedules among the treatment groups, the mean ratio of adverse events 
290 
divided by the number of visits will be provided in addition to the number of eyes with an 
291 
adverse event and the total number of adverse events for each treatment group. This will attempt 
292 
to account for a potential disproportion of reported adverse events observed in the aflibercept 
293 
group because of having more visits. 
294 
5.1 Study Eye Ocular Adverse Events 
295 
The proportion of eyes experiencing each event listed below will be reported for study eyes by 
296 
treatment group. Proportions will be compared between treatment groups using Barnard’s 
297 
unconditional exact test, considering the number of eyes randomized to each group as fixed. 
298 
The following ocular adverse events will be assessed: 
299 
• Endophthalmitis 
300 
• Any retinal detachment (rhegmatogenous, traction, combined rhegmatogenous and 
301 
traction, or not otherwise specified) 
302 
o Rhegmatogenous retinal detachment (tabulated without statistical comparison) 
303 
o Traction retinal detachment (tabulated without statistical comparison)  
304 
• Retinal tear 
305 
• Cataract extraction in eyes phakic at baseline or visually significant cataract on clinical 
306 
exam as defined on the case report form 
307 
o Cataract extraction in eyes phakic at baseline (tabulated without statistical 
308 
comparison) 
309 
o Visually significant cataract on clinical exam as defined on the case report form 
310 
(tabulated without statistical comparison) 
311 
• Ocular inflammation 
312 
• Intraocular pressure (IOP) elevation (any of the following) 
313 
o Increase in IOP ≥ 10 mmHg from baseline (at a follow-up visit) 
314 
o IOP ≥ 30 mmHg (at a follow-up visit) 
315 
o Initiation of medication to lower IOP that was not in use at baseline 
316 
o Glaucoma procedure 
317 
• Neovascular glaucoma  
318 


 
 
Protocol AB Statistical Analysis Plan 
 
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• Neovascularization of the iris 
319 
5.2 Systemic Adverse Events 
320 
The proportion of randomized participants experiencing each event listed below will be reported 
321 
by treatment group. Proportions will be reported and compared using Barnard’s unconditional 
322 
exact test, considering the number of eyes randomized to each group as fixed. The following 
323 
serious systemic adverse events will be assessed: 
324 
• Primary: 
325 
o Death 
326 
o Serious adverse event (at least one) 
327 
o Hospitalization (at least one) 
328 
o Cardiovascular and cerebrovascular events according to the Antiplatelet Trialists’ 
329 
Collaboration (excerpted from BMJ Jan 8, 1994): 
330 
▪ Nonfatal myocardial infarction 
331 
▪ Nonfatal stroke (counted only if symptoms lasted at least 24 hours) 
332 
▪ Death attributed to cardiac, cerebral, hemorrhagic, embolic, other vascular 
333 
(does not need to be ischemic in origin), or unknown cause 
334 
▪ At least one event (nonfatal myocardial infarction, nonfatal stroke, or death 
335 
attributed to potential vascular or unknown cause) 
336 
Note that transient ischemic attack, angina, possible myocardial infarction, and possible stroke 
337 
are not counted. Nonfatal myocardial infarction and nonfatal stroke require that the patient is 
338 
alive at the end of the study. If not, then only the death is counted. 
339 
• Secondary (tabulated without statistical comparison): 
340 
o Frequency of at least one event per participant in each Medical Dictionary for 
341 
Regulatory Activities (MedDRA) system organ class 
342 
6.0 Additional Tabulations 
343 
The following will be tabulated according to treatment group: 
344 
• Baseline demographic and clinical characteristics 
345 
• Visit completion rate for each outcome visit (4, 12, 24, 36, 52, 68, 84, and 104 weeks) 
346 
• Treatment completion 
347 


 
 
Protocol AB Statistical Analysis Plan 
 
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7.0 General Principles for Analysis 
348 
7.1 Analysis Cohort 
349 
Unless otherwise stated, all treatment comparison analyses will follow the intention-to-treat 
350 
principle with all randomized eyes included and each eye analyzed according to the randomized 
351 
treatment assignment, regardless of treatment actually received.  
352 
7.2 Visit Windows for Analysis 
353 
For common visits, the analysis windows will be defined according to Table 5. For visits falling 
354 
in more than 1 window, priority will be given to the 104-, 52-, and 24-week visits. Otherwise, the 
355 
visit will be assigned to the earlier window (e.g., a visit on day 42 would be assigned as the 4-
356 
week visit). 
357 
Table 5. Analysis Windows for Outcome Visits 
358 
Visit (Protocol Window) 
Target 
Analysis Window 
4 (±1) weeks 
28 days 
14 – 42 days     
(4 ± 2 weeks) 
12 (±4) weeks 
84 days 
42 – 126 days    
(12 ± 6 weeks) 
24 (±4) weeks 
168 days 
126 – 210 days 
(24 ± 6 weeks) 
36 (±4) weeks 
252 days 
210 – 308 days 
(36 +8 weeks) 
52 (±4) weeks 
364 days 
308 – 420 days 
(52 ± 8 weeks) 
68 (±4) weeks 
476 days 
420 – 532 days 
(68 ± 8 weeks) 
84 (±4) weeks 
588 days 
532 – 644 days 
(84 ± 8 weeks) 
104 (±4) weeks 
728 days 
644 – 812 days 
(104 ± 12 weeks) 
7.3 Missing Data 
359 
The strategy for handling missing data generally is included with the description of each 
360 
individual analysis. Where not otherwise specified, only participants with non-missing data are 
361 
included in the analysis. 
362 
7.4 Outliers 
363 
To help ensure that statistical outliers do not have undue impact on analyses of continuous visual 
364 
acuity and OCT central subfield thickness outcomes (including the primary outcome), outcomes 
365 
will be truncated to ± 3 standard deviations based on the mean and standard deviation at 24 
366 
weeks for 24-week completers, irrespective of treatment group. Visual acuity letter score, change 
367 
in visual acuity from baseline, and OCT central subfield thickness will be truncated. Truncation 
368 
will be performed after imputation of missing data, where applicable (i.e., raw data will be used 
369 
for imputation). For the primary outcome, AUC will be calculated based on the imputed values 
370 
after truncation. There will be no truncation of the AUC outcome itself. 
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Protocol AB Statistical Analysis Plan 
 
Page 15 of 15 
7.5 Model Assumptions 
372 
All model assumptions, including linearity, normality of residuals, and heteroscedasticity, will be 
373 
verified. If model assumptions are not reasonably satisfied, then covariates may be categorized 
374 
or excluded, and a nonparametric approach, robust estimation method, or transformation may be 
375 
considered. The possibility of using a transformation, robust method, or nonparametric approach 
376 
is higher than usual in this study due to the nature of the cohort as vitreous hemorrhage severity 
377 
can vary greatly, potentially leading to atypical (non-Gaussian) distributions of outcome data. 
378 
7.6 Type I Error Rate 
379 
There is no formal adjustment for multiplicity to compensate for the large number of outcomes 
380 
being compared. All comparisons are conducted at alpha level 0.05 unless otherwise noted (e.g., 
381 
the primary outcome is conducted at alpha level 0.049). In some cases, select secondary 
382 
outcomes have been designated as being of “primary interest” along with a hypothesized 
383 
direction of effect to place more weight on these outcomes over others. 
384 
References 
385 
Brown NM, Brown GC, Sharma S, Landy J. Health care economic analyses and value-based 
386 
medicine. Surv Ophthalmol. 2003;48(2):204-23. 
387 
Localio AR, Margolis DJ, Berlin JA. Relative risks and confidence intervals were easily 
388 
computed indirectly from multivariable logistic regression. J Clin Epidemiol. 2007;60(9):874-82. 
389 
Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the method of 
390 
choice for handling missing data in randomized trials? Stat Methods Med Res. 2016. DOI: 
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https://doi.org/10.1177/0962280216683570. 
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