Conditions: Retinopathy of Prematurity
Keywords: Retinopathy of Prematurity Bevacizumab ROP
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 120
Healthy volunteers: no

Brief summary:
The purpose of this study is to find a dose of intravitreal bevacizumab that is lower than currently used for severe retinopathy of prematurity (ROP), is effective in this study, and can be tested in future larger studies.

Detailed description:
Despite promising initial results using empirical doses of bevacizumab based on half the adult dose for treatment of acute severe ROP, little is known about lower doses of bevacizumab for ROP. An increasing number of ophthalmologists are treating premature infants with severe ROP using bevacizumab. Given the potential systemic and ocular adverse effects of intravitreal bevacizumab injections, determining a lower effective dose of bevacizumab is an important next step. The proposed study will test progressively lower doses to find a dose to take forward to a future larger study.

Arms:
arm 1: Dosage of injected Bevacizumab to be studied arm 2: Dosage of injected Bevacizumab to be studied arm 3: Dosage of injected Bevacizumab to be studied arm 4: Dosage of injected Bevacizumab to be studied arm 5: Dosage of injected Bevacizumab to be studied arm 6: Dosage of injected Bevacizumab to be studied arm 7: Dosage of injected Bevacizumab to be studied arm 8: Dosage of injected Bevacizumab to be studied

Interventions: intervention 1: Bevacizumab
Intervention descriptions: intervention 1: Varying dosages in 10µl

Protocol document:
ICF_000.pdf: 
 
 
 
Phase 1 Trial of Bevacizumab Treatment for 
Severe Retinopathy of Prematurity 
 
Informed Consent Form 
April 13, 2018 
 
NCT02390531 


RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 1 of 10 
1. Introduction 
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We are asking you to consider having your infant take part in a research study. The study is being 
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conducted by the Pediatric Eye Disease Investigator Group. Your infant’s eye doctor is a member of this 
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group. The Jaeb Center for Health Research in Tampa, FL is the coordinating center which is organizing 
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the study. The National Eye Institute is paying for the study. The institute is part of the federal 
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government. This form is part of the process to inform you about the research study. Research is a 
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scientific way to learn about medical conditions and/or treatments. 
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First, we want you to know that participation is voluntary. Refusal to participate will involve no penalty 
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or loss of benefits to which your infant is otherwise entitled. Also, you may stop your infant’s 
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participation at any time without penalty or loss of benefits to which your infant is otherwise entitled. 
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Before you decide whether to have your infant take part in the study, please take as much time as you 
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need to ask any questions. You may discuss this study with your infant’s doctors, the medical staff, 
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family, and/or friends. For your infant to be in the study, you will need to sign this form.  
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2. Information about the Study 
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Your infant has a condition called retinopathy of prematurity (ROP), which is a disease in which the 
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blood vessels inside the eye do not grow the way they should. ROP can occur when an infant is born too 
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early. In some cases, ROP may lead to vision loss or blindness. Your infant’s ROP is bad enough that it 
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needs to be treated, and treatment will lower the chance that vision loss will occur. 
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There are different ways to treat ROP. It is often treated using a laser. The laser stops the blood vessels 
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from growing the wrong way and usually prevents vision loss. Until recently, laser was used for almost all 
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cases of severe ROP. A newer way to treat severe ROP is with a drug called bevacizumab, commonly 
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known as Avastin® (Genentech, South San Francisco, CA). It is the same drug that is used to treat some 
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eye diseases in adults, and, in much higher doses, some cancers in adults. Avastin is injected into the eye 
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with a fine needle, and it works by stopping the blood vessels from growing the wrong way. In some 
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cases, Avastin seems to work even better than laser. However, for some infants, it is possible that it does 
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not work better than laser, or that it does not work as well. 
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Avastin has been used for several years to treat ROP, but it has not been approved by the United States 
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Food and Drug Administration (FDA) for this purpose. Therefore, it is considered an experimental drug 
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when used to treat ROP.  Avastin appears to treat ROP well and to be safe. Some Avastin gets into the 
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blood when it is injected into the eye. It is possible that this could cause some side effects in the body, 
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such as affecting how organs develop. Injecting a lower amount of Avastin into the eye may be safer for 
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an infant, but it is not known how little Avastin can be injected and still treat the ROP. The purpose of this 
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study is to find a lower amount of Avastin that treats ROP well.  
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In this study, 10-14 infants will receive a low dose of Avastin in one eye, which is about one-half of the 
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dose that is most commonly used. If that dose works well, then one-half of that dose will be used for 
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another 10-14 infants. An expert committee will review the results before approving the testing of each 
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lower dose. Up to 9 doses (the starting dose plus 8 lower doses, each one-half of the previous dose) will 
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be used in this study. 
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You are being asked to have your infant take part in the study because he/she has severe ROP that needs 
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treatment. The study will include up to 201 infants with ROP at pediatric hospitals throughout North 
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RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 2 of 10 
America. Your infant would be in the study for one year after your original due date. 
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3. Study Procedures 
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If your infant is in the study, he/she will have one injection of Avastin into one or both eyes. If both of 
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your infant’s eyes need treatment for ROP, a computer program will be used to decide which eye will 
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receive the study dose of Avastin. This is like flipping a coin. If only one of your infant’s eyes needs 
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treatment, then that eye will receive the study dose of Avastin. The study dose of Avastin is the amount of 
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medication that is currently being tested in the study. You and your infant’s doctor will not be told this 
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amount. If both eyes need treatment, then your infant’s eye doctor may choose to treat the other eye with 
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laser or with the last dose that worked well in the study.  
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Injection of Avastin 
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The injection into the eye will be performed by an ophthalmologist (eye surgeon) and will be done 
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through a small needle after your infant receives anesthesia (numbing) to the area of the injection. 
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Your infant may require sedation in accordance with your neonatologist’s usual routine. 
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Amount of Avastin 
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The lowest amount of Avastin needed to treat ROP is not known. The purpose of this study is to find out a 
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lower amount of Avastin that works well for ROP. The amount of Avastin used in this study will start at 
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about half the amount that is commonly used to treat ROP. This lower amount is used by some doctors 
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and has worked well. The amount of Avastin will continue to be lowered as long as it works well for at 
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least 8 of 10 infants who receive each amount. Also, an expert committee will review the results from 
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each dose before approving the testing of a lower dose. If the lower amount of Avastin does not work well 
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for your infant, then your doctor may use another treatment as soon as 3 days after the injection of 
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Avastin. 
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Your infant will only receive one study injection of Avastin as part of this protocol. The amount of 
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Avastin your infant receives will depend on how other infants in the study have responded to treatment. 
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You and your doctor will not be told the amount and will not be able to choose the amount of Avastin that 
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your infant receives. If this is unacceptable to you, you should not enroll your infant in the study. 
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Any additional Avastin injections would be for treatment purposes at the discretion of your eye doctor 
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and not part of the study protocol.  However, information about your child’s response to any additional 
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injections will be gathered. 
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Follow-up Visits 
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After the injection, your infant’s eye doctor will examine your infant the next day, and if needed, 3 to 5 
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days after that. Your infant will be examined at least once each week for 4 weeks after the injection. Your 
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infant’s eye doctor may decide that more examinations are needed for your infant, just as if your infant 
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were not part of this study. If your infant’s eyes do not respond to the Avastin, then your infant’s doctor 
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may choose to use additional treatment, such as a higher dose of Avastin or laser. Your infant’s eye doctor 
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will decide which type of additional treatment would be best for your infant. 
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At each exam, the eye doctor will check your infant’s eyes to make sure that the ROP has responded to 
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treatment. It is possible that ROP can seem to get better but then come back, even several weeks after 
92 


RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 3 of 10 
treatment. At each exam, the eye doctor will also check to make sure the rest of your infant’s eye is 
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healthy. 
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After the 4 week exam, your infant will have a study visit 12 months after your original due date. 
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Additional examinations between 4 weeks and 12 months will be as per usual care of your infant’s eye 
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doctor. You may contact your doctor at any time to report any problems your infant is having.  
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Six months after your original due date we will collect information from eye exams that your child 
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received since the 4-week visit.  We will collect this information again at the 12-month visit.  You may be 
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asked to sign a medical records release form if he/she has been followed by another physician. 
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4. Risks 
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Risks of Injection 
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The risks of injection are the same whether your infant receives Avastin as part of a study or not. There is 
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a very small chance that the drugs used to numb the eye before the injection could cause an allergic 
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reaction. Some bleeding on the white of the eye at the place where the needle enters the eye may occur. 
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There may be some mild discomfort, tearing, and itching that may last a few days. Right after the 
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injection, the pressure in the eye may go up, but this usually goes away on its own. Rarely this increase in 
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pressure needs to be treated with eye drops or by removing some of the fluid within the eye. It is very 
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unlikely, but possible, that the Avastin injection will cause or lead to bleeding inside the eye, cataract, 
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retinal detachment, need for additional surgery, blindness, or loss of the eye. However, these 
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complications could also occur after laser treatment or as a result of severe ROP. A rare complication of 
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injection is infection inside the eye, which may cause loss of vision. Infections inside the eye are treated 
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with antibiotics injected into the eye.  While preparing your child for the injection, your infant’s heart or 
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breathing rate could slow.  This might decrease their blood oxygen level. This also could happen during 
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the injection or after the injection.  In almost all cases, these effects are temporary and cause no 
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permanent harm.  But permanent damage to the brain or other organs could happen in rare cases.  Death is 
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even possible although not expected to occur related to an injection in any infant in the study. 
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Risks of Avastin 
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Tests have shown that low levels of Avastin can reach an infant’s blood after injection into the eye. It is 
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unknown how much Avastin leaves the eye or its risk of side effects in the body. Less Avastin injected 
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into the eye may lead to less Avastin leaving the eye, which may lower the risk of problems. Doctors do 
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not think it is likely that the amount of Avastin leaving the eye will have any harmful side effects to an 
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infant’s organs as they develop, but the risk is unknown. We want to minimize this risk by giving a 
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smaller amount of Avastin that works well, which is why this study is being done. Your infant will be 
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watched for side effects. Examples of possible side effects involving the body are slowed healing or more 
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bleeding of a wound.  
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Risks for Infants with ROP in Both Eyes 
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Infants with ROP in both eyes will have Avastin treatment in one eye and laser or Avastin treatment in the 
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other eye. Eyes treated with laser may end up being more nearsighted than the eye that is treated with 
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Avastin.  
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Risks of Eye Examinations 
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The risks and discomforts of the eye examinations are the same whether or not your infant takes part in 
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RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 4 of 10 
the study.  There may be some redness or, rarely, bleeding on the surface of the eye after the eye is 
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examined.  Some infants have a drop in the blood oxygen level or a slowing of the heart rate during or 
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after the eye exams. 
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Unknown Risks  
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Although we have tried to list all possible risks and discomforts with this study, there may be others that 
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we do not know about at this time. These unknown risks of the treatment would be the same whether your 
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infant was receiving Avastin as part of this study or not. 
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5. Benefits of Participation 
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Your infant needs treatment for ROP. As part of the study, your infant will receive treatment. Your 
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infant’s ROP is likely to improve during the study, but it is possible that it will not improve and could 
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worsen. Your infant may not directly benefit from taking part in the study. However, the information will 
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help doctors treat infants with ROP in the future.  
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6. Alternative Procedures or Treatment 
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The alternative to taking part in the study is to not take part. Your infant does not have to be in this study 
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in order to get treatment for severe ROP.  
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7. Other Considerations 
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We will send the information about your infant’s eyes to a central computer. The computer is located at 
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the Jaeb Center for Health Research in Tampa, Florida. 
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In addition, the Jaeb Center for Health Research in Tampa will be provided with information on how to 
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contact you. This contact information will be kept separate from your infant’s research data.  
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• During the study, you may receive calls from the coordinating center to help schedule an office visit for 
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your child.  If we are not able to reach you when we try to schedule your child’s follow-up visit, we will 
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try to contact you through the other information you have given us.  If this is not successful, we may use 
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the information you have given us to try to locate you through the use of a third-party search service. 
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• You will be given a toll-free number (888-797-3344) to call the coordinating center any time you have 
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questions.  
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• You will also receive updates and information about the study in the mail.  
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We will report the results of the study in medical journals and at scientific meetings. We will not identify any 
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of the infants who take part in the study. In addition, after the study is completed, a dataset will be made 
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available to the public that will not include any information that might identify your infant. Your infant’s 
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records will be confidential.  
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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
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law. This Web site will not include information that can identify your infant. At most, the Web site will 
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include a summary of the results. You can search this Web site at any time.  
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8. Costs 
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• The National Eye Institute will provide funds for services specific to the research study. It will not 
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cover patient services considered to be usual patient care.  
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• All exams in this study are considered to be part of usual care. These exams would be needed whether 
183 


RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 5 of 10 
your infant was in the study or not. The costs of the exams will be your or your insurance company's 
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responsibility. 
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• The cost of the Avastin itself will be covered by the study. 
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• You or your insurance company will be responsible for the cost of procedures, complications, or 
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additional treatment, since treatment for ROP is needed whether or not your infant is in the study.  
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9. Compensation 
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You will be given a $50 debit card for completion of the 12-month visit required by the study after your 
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infant has been released from the hospital. This is meant to cover your time involved in the study and any 
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travel expenses involved.  If your expenses are more than $50 and you will be unable to complete the 
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study visit without additional funds, you may discuss this with the study staff, and additional funds may 
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be available to pay for your costs. 
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10. Research-Related Injuries  
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Medical care is available if your infant has a research-related injury. If your infant has an emergency, 
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your infant can get emergency care. If possible, you should tell the emergency care medical staff that your 
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infant is in a research study. You should also tell your infant’s eye doctor about the emergency as soon as 
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possible.  
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The costs of care will be your or your insurance company’s responsibility. The study will not pay for lost 
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wages or for direct or indirect losses. The [name of institution] will not pay for medical expenses or any 
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other expenses for injuries related to the research. You can get more information about research-related 
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injuries from the Office of the Institutional Review Board [phone number]. 
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You can get more information about research-related injuries from your infant’s eye doctor (see contact 
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information on the last page) or from the coordinating center staff at the Jaeb Center (toll-free at 888-797-
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3344). 
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11. Withdrawal from the Study 
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It is up to you whether your infant takes part in this study. You can withdraw your infant from the study at 
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any time by contacting your infant’s eye doctor and by letting him/her know in writing that you are 
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withdrawing your infant (see contact information on the last page).  
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You will be told of any relevant new scientific findings during the study. These findings might affect your 
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willingness to have your infant continue in this study. 
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Your infant’s doctor or individuals in charge of this study may stop your infant’s participation in the 
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study. Some possible reasons for this include: 
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• Your doctor decides that continued participation would be harmful to your infant. 
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• The study is stopped. 
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• There are unanticipated circumstances. 
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If your infant leaves the study early, the study will still use the data which were already collected.  
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RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 6 of 10 
If you have any questions about the study at any time, you should speak with Dr. [name of investigator] 
228 
or one of his/her staff [phone number]. If you have questions about your infant’s rights as a research 
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subject, you should contact the Institutional Review Board administrator [name and phone number]. You 
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may also call the coordinating center staff toll-free at 888-797-3344 should you have any questions at any 
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time. 
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RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 7 of 10 
12. How will my child’s information be protected and kept confidential? 
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Note:  ~customize sections A- E for your IRB here or as separate document per IRB 
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requirements~ 
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Below is Jaeb Center for Health Research IRB’s HIPAA language for ICF as an 
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example for you:  
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As required by law, study related records with identifying information will be kept confidential. 
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Safeguards for authorized access, security, and privacy of your child’s information have been put in place 
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by the Federal Privacy Regulations.  Unless the law requires it, your child’s name, address, social security 
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number, telephone number, or any other direct identifying information will not be used to identify you or 
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your child.  
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A. Purpose of Authorization 
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We have rules to protect information about your child. Federal and state laws and the federal medical 
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Privacy Rule also protect your child’s information.  By signing this form you provide your permission, 
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called your “authorization,” for the use and disclosure of information protected by the Privacy Rule.  
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You must sign the Protected Health Information Authorization at the end of this form if you want your 
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child to be in the study.  When you sign the form, you give permission for the use and disclosure of your 
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child’s Protected Health Information (PHI) for the study. PHI is health information that identifies your 
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child for this study.  Your authorization is beneficial and important for the study. Without your 
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authorization, your child will not be able to be in it.  
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B. Use and Disclosure of the PHI 
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Your child’s study doctor will collect information about your child. This information includes things 
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learned from procedures listed and described in this form as well as his or her name, address, date of birth, 
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and information from medical records. Your child’s name, address, telephone number, and social security 
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number are examples of identifiable information. 
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A code number will go with the study results instead of your child’s name, address, telephone number, or 
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social security number.  Your child’s study results will be given to the Jaeb Center for Health Research.  
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The Jaeb Center is the coordinating center for the study.  It is located in Tampa, Florida.  
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This doctor’s office will not disclose study results that have identifiable information except as explained 
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in Section C. or when required by law.  The Jaeb Center and this doctor’s office will guard the privacy of 
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your child’s study PHI.   
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Study results without the protected information may appear in medical journals and be shared at scientific 
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meetings.  Your child’s records will be confidential.  No one will disclose the identity of your child in a 
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medical journal or at a scientific meeting.   
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C. Authorized Recipients and Users 
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People outside of this doctor’s office and the Jaeb Center may need to see or receive your child’s 
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information for this study.  Some examples include: government agencies (such as the Food and 
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RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 8 of 10 
Drug Administration), safety monitors, other sites in the study, and companies that sponsor the study.   
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In most cases the information will have a code number with it instead of your child’s name, address, 
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telephone number, or social security number.  
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There are some situations where the information will not have a code number with it.  If so, people 
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outside this doctor’s office who assist in your child’s care may see your child’s study PHI. They may not 
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be covered by the federal Privacy Rule.  We try to make sure that everyone who needs to see your child’s 
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information keeps it confidential – but we cannot guarantee that your child’s information will not be 
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disclosed.  
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D. Cancellation of Authorization 
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Over the course of the study, you will be told of any new scientific findings that might affect your 
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willingness to have your child stay in this study.   
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You may cancel your permission for the use and disclosure of your child’s study PHI at any time.  You 
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need to contact your child’s study doctor and give him/her a notice of cancellation in writing.  When you 
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cancel your permission or when you withdraw your child from the study directly, your child is no longer 
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part of the study.  No new information about your child will be gathered for the study except when it is on 
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an adverse (unfavorable) event that is related or potentially related to the study.  If one happens, your 
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child’s entire medical record may need to be reviewed.   
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E. 50 Year Expiration Date and Indefinite Expiration Date  
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Some of your child’s study PHI does not have a code number with it.  Your permission for the use and 
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disclosure of this PHI lasts 50 years from the date of your signature or until the end of the study, 
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whichever is sooner.  
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The rest of your child’s study PHI does have a code number with it.  When it is collected, it becomes a 
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research report.  Your permission for the use and disclosure of these coded data will never end.  These 
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coded data do not have your child’s name, address, telephone number, or social security number. The 
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above supports the HIPAA Privacy Rule – 45 CFR 164.508 
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RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 9 of 10 
Subject's Name printed   
 
 
 
 
 
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Description of Representative’s Authority to Act for the Subject____________  
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Protected Health Information Authorization 
315 
 
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Study Enrollment 
317 
 
318 
 
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You will be given a signed copy of this document in case you want to read it again.
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By signing, you authorize the use and disclosure of your (infant’s) protected 
health information. This information is collected as part of your (infant’s) 
participation in this study. 
 
 
 
 
 
 
Signature 
 
Date 
By signing, you agree to (have your infant) 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 (have your infant) participate. 
 
Name of Study:  Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy 
of Prematurity 
 
 
 
 
 
 
Signature 
 
Date 
 
I certify that to the best of my knowledge the subject (parent/guardian) 
understands the nature, demands, risks, and benefits involved in his/her 
(infant’s) participation in this study.  
 
 
 
 
 
 
Investigator’s Signature  
 
Date 


RETINOPATHY OF PREMATURITY 1 (ROP1) 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity  
(Protocol Version 3.1) 
Template Informed Consent Form 
 
ROP1 v3.1 ICF NonJaeb Template 11-28-16 clean4-13-18 
Page 10 of 10 
Investigator Contact Information 
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Name of Investigators: [list all investigators at site] 
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_____________________________ 
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_____________________________ 
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_____________________________ 
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_____________________________ 
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Address: __________________________________________ 
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___________________________________________________ 
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Telephone: ________________________________________ 
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SAP_002.pdf: 
ROP Phase1 SAP v3.0 - 16Mar2020 [clean]   
 
Page 1 of 7 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity 
1 
(ROP1) 
2 
 
3 
Statistical Analysis Plan  
4 
Version 3.0  
5 
 
6 
Statistical Analysis Plan Version: 3.0, 16Mar2020  
7 
Protocol Version: 3.1, 17Apr2013 
8 
 
9 
 
10 
 
VERSION HISTORY 
 
The following table outlines changes for the analysis plan: 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION* 
2.0a 
T. Dean 
M. Melia 
08Sep2016 
· 
The primary analysis was updated to incorporate 
GEE to adjust for the correlation between eyes 
within a patient. 
· 
Clarified which eyes would be used in analyses 
· 
Added a secondary analysis that will repeat the 
primary analysis but look at the total dose received at 
baseline in lieu of the dose injected into the eye. 
· 
Secondary, safety, and exploratory analyses will be 
performed stratified by the total dose received at 
baseline and the total dose received by week 4, 
where applicable, as well as the dose injected in the 
eye at baseline. 
3.0b 
 
 
16Mar2020 
After reviewing the data, it was clear that a dose response 
curve, the primary analysis, could not be constructed 
using the proposed methods. Section 8.0 was added to 
describe the newly proposed primary analysis.  
a Changes made after patient listings for first 4 doses reviewed with the Data and Safety Monitoring Committee, but 
11 
prior to data analysis.  
12 
b Changes made during the data analysis phase.  
13 
 
14 
 
15 
 
16 
 
17 
Trevano Dean
I am the author of this 
document
2020-03-16 16:59-04:00
Michele Melia
I am approving this 
document
2020-03-16 17:41-04:00


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1.0 Study Design 
18 
The goal of the study is to identify an effective dose of bevacizumab lower than the current 
19 
standard (0.625 mg in 25 µL) that can be used in future studies to test the efficacy of 
20 
bevacizumab in treating retinopathy of prematurity (ROP).  
21 
 
22 
In brief, the study will begin by evaluating the efficacy of 0.25 mg of bevacizumab and if there is 
23 
evidence of efficacy, the dose will be reduced by half. This process will continue until a dosage 
24 
provides insufficient evidence of efficacy or until the ninth dose (0.001 mg) is deemed 
25 
efficacious. For the purposes of this study, efficacy is defined as an 80% success rate (defined in 
26 
section 3.1 of the protocol). 
27 
 
28 
2.0 Primary Analysis 
29 
A dose response curve will be used to identify the lowest effective dose of bevacizumab. 
30 
Logistic regression will be used to obtain estimates of the predicted success rate and 
31 
corresponding 95% confidence intervals for each dosage level. The estimates obtained from the 
32 
regression will be used to construct a dose response curve (predicted probability of success vs. 
33 
dose of bevacizumab administered). Doses corresponding to success rates with a lower 95% 
34 
bound greater than 80% will be identified, and the smallest dose will be selected as the lowest 
35 
effective dose.  
36 
 
37 
This analysis will make use of data from all study eyes. Eyes will be excluded if censoring 
38 
occurred due to death but will be considered a failure if non-protocol treatment is received after 
39 
enrollment but prior to the determination of success at the 4-week exam. The dosage level (in 
40 
mg) will be included as a continuous covariate and may be transformed (using the log2 scale for 
41 
example) to facilitate interpretation.  
42 
 
43 
At least 3 doses will need to be tested in order for a dose response curve to be fit. If only 2 doses 
44 
are tested, the data and safety monitoring committee will have decided that the second dose was 
45 
not effective. In this case, the first dose evaluated will be considered the lowest effective dose. 
46 
 
47 
 
48 
2.1 Model Specification 
49 
A plot of the observed vs. fitted values will be compared to assess the appropriateness of the 
50 
logistic regression model. If the logistic regression model is not appropriate, probit and 
51 
cumulative log-log regressions will be explored to identify the model that best fits the data. 
52 
 
53 
3.0 Secondary Analyses 
54 
3.1 Effect of Bevacizumab on Successful Treatment of Type I ROP 
55 
The primary analysis will be repeated using data from study eyes and non-study eyes that were 
56 
diagnosed with type I ROP at enrollment and received an injection of bevacizumab at the time 
57 
the study eye was injected. Eyes receiving an injection of 0.625mg of bevacizumab will not be 
58 
included because this dose is not of interest in this study.  
59 
 
60 
Logistic regression using generalized estimating equations to account for correlation between 
61 
eyes within an individual will be used to obtain estimates of the predicted success rate and 
62 
corresponding 95% confidence intervals for each dosage level. Estimates obtained from the 
63 


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Page 3 of 7 
regression will be used to construct a dose response curve (predicted probability of success 
64 
versus dose of bevacizumab administered) which will be compared with the curve created in the 
65 
primary analysis. 
66 
 
67 
As specified in the primary analysis, eyes will be excluded if censored due to death but will be 
68 
considered a failure if non-protocol treatment was received after enrollment but prior to the 
69 
determination of success at the 4-week exam. The dosage level (in mg) will be included as a 
70 
continuous covariate and may be transformed to facilitate interpretation. 
71 
 
72 
3.2 Effect of Total Bevacizumab Received on Successful Treatment of Type I ROP 
73 
Even though injections are localized, bevacizumab is expected to diffuse into the circulatory 
74 
system, giving rise to the possibility of the study eye receiving an additional benefit if the non-
75 
study eye was injected. 
76 
 
77 
In order to evaluate the effect of the total dose of bevacizumab administered on the successful 
78 
treatment of type I ROP in study eyes, the primary analysis will be repeated, controlling for the 
79 
dose of bevacizumab received in the fellow eye. The dose response curve constructed from the 
80 
model controlling for the dose of bevacizumab injected into the fellow eye will be compared 
81 
with the curve created for the primary analysis. If clinicians are unable to determine if a 
82 
significant shift has occurred, a likelihood ratio test will be used to determine if the inclusion of 
83 
the dose of bevacizumab injected into the fellow eye significantly improves the model fit.  
84 
 
85 
3.3 Potential Confounders  
86 
Depending upon sample size and the number of dosage levels studied, a secondary analysis may 
87 
explore if the following factors confound the relationship between dosage level and success: 
88 
· Location of disease (Zone I vs. Zone II) 
89 
· Severity of disease (Zone I with plus disease vs. Zone I stage 3 without plus disease vs. 
90 
Zone II stage 2 or 3 ROP with plus disease) 
91 
 
92 
The success rate for each dosage studied will be tabulated, stratified by each of the factors listed 
93 
above. In addition, the primary analysis will be rerun adjusting for each of the factors above 
94 
(models will adjust for one factor at a time as the factors are co-linear). The dose response curve 
95 
derived from the model including the confounder will be compared with the curve constructed 
96 
for the primary analysis. If clinicians are unable to determine if the difference between the curves 
97 
is clinically significant, a likelihood ratio test will be used to determine if the addition of the 
98 
confounder has a significant improvement on the model fit.  
99 
 
100 
 
101 
4.0 Exploratory Analyses 
102 
Depending upon sample size and the number of dosage levels studied, interaction terms for each 
103 
potential confounder (section 3.2) and dosage will be added to the multiple logistic regression to 
104 
evaluate whether the relationship between dosage and success is modified by the factor.  In 
105 
accordance with NIH guidelines, an analysis of treatment effect according to gender, as well as 
106 
race/ethnicity, will be conducted. We recognize that these analyses are exploratory and may not 
107 
have sufficient power to detect an interaction. 
108 
 
109 


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5.0 Safety 
110 
5.1 Adverse Events 
111 
Adverse events reported at any time during the study will be coded using the MedRA system and 
112 
tabulated including all enrolled infants. The number and proportion of infants will be calculated 
113 
for each of the following, stratified by the total dose of bevacizumab received prior to the time 
114 
the event was reported: 
115 
 
116 
· Infants for whom at least one event was reported 
117 
· Infants with an adverse event thought by the investigator to be related to study drug 
118 
· Infants for whom at least one serious adverse event was reported 
119 
· Infant deaths 
120 
 
121 
Additionally, adverse events will be categorized as systemic or ocular. Ocular adverse events 
122 
will be further subdivided into those related to the study eye injected at baseline, non-study eye 
123 
injected after baseline, or non-study eye receiving no injection.  
124 
 
125 
The Clopper-Pearson interval will be used to obtain 95% confidence intervals for the 
126 
proportions. 
127 
 
128 
The tabulations above will be repeated 1) limited to events reported through the 4-week post-
129 
injection examination to evaluate the safety of the initial study eye injection (treatment was at 
130 
investigator discretion after the 4-week post-injection examination), and 2) limited to events 
131 
reported after the 4-week post-injection examination but prior to the adjusted 12-month corrected 
132 
age examination.   
133 
 
134 
5.2 Physical exam data at each visit 
135 
The distribution (median, quartiles, and range) of head circumference (in centimeters) and 
136 
weight (in grams) will be tabulated at pre-injection and at each follow-up visit. The mean change 
137 
in head circumference and mean change in weight from pre-injection to each examination will 
138 
also be calculated, and a 95% confidence interval will be calculated for each.  
139 
 
140 
This analysis will be stratified by the total dose of bevacizumab received prior to the visit. If this 
141 
data is not available, the analysis will be stratified by the total dose of bevacizumab received at 
142 
enrollment. 
143 
 
144 
6.0 Plasma Concentrations of VEGF and Bevacizumab 
145 
A separate analysis plan will be written to define analyses involving the relationship between 
146 
VEGF and bevacizumab serum concentrations, as well as change in bevacizumab and VEGF 
147 
concentration over time. 
148 
 
149 
7.0 Additional Analyses and Tabulations 
150 
 
151 
7.1.1 Description of cohort at Baseline 
152 
Subject-level and eye-level characteristics will be summarized for the entire cohort and stratified 
153 
by dose level and total dose received at time of study eye injection. The following will be 
154 
tabulated: gender, race, gestational age, birth weight, gestational age at time of study-eye 
155 


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injection, and examination findings in the study eye and non-study eye at the time of study eye 
156 
injection. 
157 
 
158 
 
159 
7.1.2 Description of Cohort at 6-Month Corrected Age 
160 
The following data will be tabulated to describe the cohort at the 6-month corrected age data 
161 
collection: 
162 
· Infants requiring additional treatment for ROP in either eye since the 4-week post-
163 
injection examination 
164 
· Infants developing stage 4 or 5 ROP or vitreous hemorrhage in either eye since the 4-
165 
week post-injection examination 
166 
· Infants having retinal surgery since the 4-week post-injection examination 
167 
 
168 
Marginal proportions will be reported, but data will also be tabulated and stratified by 1) dose of 
169 
bevacizumab injected in the eye at baseline, 2) total dose of bevacizumab injected in eye by 4 
170 
weeks, and 3) total dose of bevacizumab received (in both eyes) by week 4. 
171 
 
172 
7.1.3 Description at 12-month Corrected Age  
173 
Descriptive statistics will be calculated to describe the cohort at 12-month corrected age. The 
174 
statistics below will be computed for the entire cohort but will also be stratified by 1) total dose 
175 
of bevacizumab received at baseline and 2) total dose of bevacizumab received by 4 weeks. 
176 
 
177 
The median, quartiles, and range will be calculated for the following data which are not expected 
178 
to be normally distributed: 
179 
· Time since initial hospital discharge 
180 
· Number of times re-hospitalized since initial study eye injection 
181 
· Magnitude of alignment at near (horizontal and vertical) 
182 
· Magnitude of alignment at distance (horizontal and vertical) 
183 
 
184 
The mean and standard deviation will be computed for the following data which are expected to 
185 
be approximately normally distributed: 
186 
· Spherical equivalent refractive error in the study eye 
187 
· Spherical equivalent refractive error in the non-study eye 
188 
 
189 
The distribution of the following will be tabulated: 
190 
· Number and proportion of infants requiring supplemental oxygen (current or past, current 
191 
only) 
192 
· Number and proportion of infants with periventricular leukomalacia 
193 
· Number and proportion of infants with hydrocephalus (with shunt placement) 
194 
· Number and proportion of infants requiring additional treatment for ROP in the study eye 
195 
(and the number of retreatments) if treated 
196 
· Number and proportion of infants requiring treatment for ROP in the fellow eye (and the 
197 
number of treatments) if treated 
198 
· Distribution of most severe abnormality in study eye:  
199 
o Essentially normal 
200 
o Abnormal angle of temporal vessels 
201 


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o Macular ectopia 
202 
o Stage 4A retinal detachment 
203 
o Stage 4B retinal detachment 
204 
o View of macula blocked 
205 
o Total retinal detachment 
206 
o All view of posterior pole and near periphery is blocked due to anterior segment 
207 
opacity 
208 
o Enucleation due to ROP 
209 
o Enucleation due to causes other than ROP 
210 
o Unable to determine 
211 
· Distribution of most severe abnormality in fellow eye:   
212 
o Essentially normal 
213 
o Abnormal angle of temporal vessels 
214 
o Macular ectopia 
215 
o Stage 4A retinal detachment 
216 
o Stage 4B retinal detachment 
217 
o View of macula blocked 
218 
o Total retinal detachment 
219 
o All view of posterior pole and near periphery is blocked due to anterior segment 
220 
opacity 
221 
o Enucleation due to ROP 
222 
o Enucleation due to causes other than ROP 
223 
o Unable to determine 
224 
·  Number and proportion of infants with assessment of study eye 
225 
o Cornea normal/abnormal 
226 
o Anterior segment normal/abnormal 
227 
o Lens normal/abnormal 
228 
o Macular Ectopia absent, questionable, present, view obscured 
229 
o Optic Nerve Atrophy absent, questionable, present, view obscured 
230 
o Retinal Fold absent, present, view obscured 
231 
o Retinal detachment absent, present, view obscured 
232 
· Number and proportion of infants with assessment of fellow eye 
233 
o Cornea normal/abnormal 
234 
o Anterior segment normal/abnormal 
235 
o Lens normal/abnormal 
236 
o Macular Ectopia absent, questionable, present, view obscured 
237 
o Optic Nerve Atrophy absent, questionable, present, view obscured 
238 
o Retinal Fold absent, present, view obscured 
239 
o Retinal detachment absent, present, view obscured 
240 
· Number and proportion of infants with visual fixation in study eye of central, steady, or 
241 
maintained  
242 
· Number and proportion of infants with visual fixation in fellow eye of central, steady, or 
243 
maintained 
244 
· Number and proportion of infants with amblyopia present in study eye 
245 
· Number and proportion of infants with amblyopia present in fellow eye 
246 
· Number of infants on treatment for amblyopia and types of treatment  
247 


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· Number and proportion of infants with alignment at distance of orthophoria, phoria, 
248 
intermittent tropia, or constant tropia 
249 
· Number and proportion of infants with alignment at near of orthophoria, phoria, 
250 
intermittent tropia, or constant tropia 
251 
· Number and proportion of infants with nystagmus 
252 
 
253 
8.0 Post-hoc Analyses 
254 
8.1 Primary Outcome 
255 
After data were collected and reviewed, it was clear that the data did not lend itself to analysis 
256 
via dose response curve (see section 2.0). Similar success rates were observed for the 7 highest 
257 
doses, 5 of which resulted in the same observed success rate. Of the 8 doses evaluated, the 6 
258 
highest doses appeared to fall within the plateau phase of the dose response curve, the region in 
259 
which the maximum effect has been achieved. Given that the success rate for only 2 doses did 
260 
not fall within the plateau phase, there was insufficient data to construct a curve.  
261 
 
262 
Nevertheless, logistic, probit, and cumulative log-log regressions were performed to comply with 
263 
the analysis plan, but goodness of fit statistics indicated that these models were a poor fit to the 
264 
data.  
265 
 
266 
Instead of reporting results based on these regressions, the number and proportion of study eyes 
267 
that met success criteria were tabulated for each dose. For each dose, the number and proportion 
268 
of study eyes that met success criteria was also tabulated by severity of disease (Zone I with plus 
269 
disease vs. Zone I stage 3 without plus disease vs. Zone II stage 2 or 3 ROP with plus disease). 
270 
These tabulations were also performed for fellow eyes.  
271 
 
272 
In addition to tabulations, Bayesian approaches were explored to identify the dose of 
273 
bevacizumab that will be used in a future randomized trial designed to compare the efficacy of 
274 
bevacizumab with that of laser photocoagulation for the treatment of type I ROP. 
275 
 
276 
 
277 
 
278 
 
279 

Prot_001.pdf: 
 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
1-1 
 
1 
 
2 
 
3 
 
4 
Phase 1 Trial of Bevacizumab Treatment for 
5 
Severe Retinopathy of Prematurity 
6 
 
7 
 
8 
 
9 
PROTOCOL 
10 
 
11 
IND # 122552 
12 
 
13 
 
14 
 
15 
Version 3.1 
16 
17 April 2018 
17 
 
 
18 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
1-2 
RETINOPATHY OF PREMATURITY STUDY 1 (ROP1) 
19 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity 
20 
 
21 
PROTOCOL AMENDMENT III (17Apr2018) 
22 
 
23 
Protocol Change # 1 
24 
Original Protocol 
25 
Unless the study eye meets failure criteria, the fellow eye should not be given more than one 
26 
injection of bevacizumab within 4 weeks of injection of the study eye (because of crossover 
27 
effects).   
28 
 
29 
Protocol Change 
30 
To add a sentence allowing investigators to call the Protocol Chair to discuss cases where 
31 
alternative treatment in the fellow eye may be necessary in the best interest of the infant.  
32 
 
33 
The following sentence has been added in Chapter 3.  
34 
 
35 
If there is a strong rationale for treating the fellow eye with more than one injection of 
36 
bevacizumab, the Protocol Chair or his/her designee should be called to discuss it before 
37 
treatment is given.     
38 
 
39 
Rationale for Change 
40 
Investigators should be allowed to consider non-protocol treatment that is in the best interest of 
41 
the infant; but are asked to call the Protocol Chair to discuss the case first to come to consensus.  
42 
 
43 
Other Changes 
44 
The contact information for the protocol chair has been changed to reflect his move from Duke 
45 
University to Indiana University.  
46 
 
47 
 
48 
 
49 
 
50 
 
51 
 
52 
 
53 
 
54 
 
55 
 
56 
 
57 
 
58 
 
59 
 
 
60 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
1-3 
RETINOPATHY OF PREMATURITY STUDY 1 (ROP1) 
61 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity 
62 
 
63 
PROTOCOL AMENDMENT II (11-1-16) 
64 
 
65 
Protocol Change # 1 
66 
Original Protocol 
67 
If a very high success rate is achieved at every dose tested, then consideration may be given to 
68 
amending the protocol with DSMC and IRB approval to evaluate doses of 0.016 mg, 0.008 mg, 
69 
0.004 mg, 0.002 mg, and 0.001 mg. 
70 
 
71 
Protocol Change 
72 
To evaluate a dose of 0.016mg and if success criteria are met, consecutively evaluate the 
73 
following smaller doses as long as success criteria are met: 0.008mg, 0.004mg, 0.002mg, and 
74 
0.001mg.  
75 
   
76 
Rationale for Change 
77 
A successful 4-week outcome was achieved for all four dose levels studies under the current 
78 
protocol (11 of 11 eyes receiving 0.25 mg, 14 of 14 eyes receiving 0.125 mg, 21 of 24 eyes 
79 
(88%) receiving 0.0625 mg, and 9 of 9 eyes receiving 0.03125 mg).  The PEDIG DSMC has 
80 
reviewed the safety and efficacy data and has approved continuation of the study to evaluate up 
81 
to five additional lower doses of bevacizumab.  
82 
 
83 
Protocol Change # 2 
84 
Original Protocol:  
85 
The maximum number of study participants is 112, but it is expected to be approximately 50-60. 
86 
 
87 
Protocol Change 
88 
The maximum number of study participants is 201.   
89 
 
90 
Rationale for Change 
91 
Sixty-one infants were enrolled to evaluate the first four dose levels of bevacizumab.  If as high 
92 
as 14 infants are enrolled into each of two series of infants for up to an additional five lower 
93 
dose levels, then the maximum number of infants that will be enrolled is 201 (61 plus 140).   
94 
 
95 
Protocol Change # 3 
96 
 
97 
Original Protocol:  
98 
If adverse events occur, they will be recorded and reported throughout the study. 
99 
 
100 
Protocol Change 
101 
All adverse events between the time of study eye injection and the 4-week ocular exam or 
102 
hospital discharge (whichever is later) will be recorded.   After the 4-week ocular exam or 
103 
hospital discharge (whichever is later), only serious adverse events (see section 5.3), ocular 
104 
adverse events, and any events judged by the investigator to be related to injection and/or study 
105 
treatment will be recorded.  
106 
   
107 
Rationale for Change 
108 
Non-serious non-ocular events occur very commonly in premature infants.  It is extremely time-
109 
consuming to record all of these events, and those occurring after the 4-week ocular exam or 
110 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
1-4 
hospital discharge (whichever is later) are not expected to be related to the study injection or 
111 
treatment, and thus not useful for data analyses, particularly since there is no control arm.   
112 
 
113 
This amendment also provides for the following clarification to the success/failure 
114 
definition:   
115 
 
116 
The success/failure definition as defined in section 3.4 was edited to provide a more realistic 
117 
definition of improvement by 3-5 days for infants with pre-treatment zone I, stage 3 without 
118 
plus disease.  
119 
 
120 
Rationale for Change 
121 
Previously, all study eyes with I, stage 3 without plus disease had to demonstrate a significant 
122 
reduction in the severity and/or extent of neovascularization by 3-5 days, or they were 
123 
considered failures.  However, some eyes show improvement in the posterior pole from pre-plus 
124 
to normal, and no worsening of neovascularization by 3-5 days, with improvement of 
125 
neovascularization noted by 1-2 weeks.  These eyes will not be considered failures.  
126 
 
127 
 
 
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1-5 
RETINOPATHY OF PREMATURITY STUDY 1 (ROP1) 
129 
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity 
130 
 
131 
PROTOCOL AMENDMENT I (1-27-16) 
132 
 
133 
Proposed Change # 1 
134 
 
135 
Current Protocol 
136 
Other than for adverse events, there is no data collection between the 4-week post-injection 
137 
exam and the visit at 12 months corrected age. 
138 
 
139 
Proposed Change 
140 
After the 4-week post-injection exam, sites will report any study infants who develop stage 4 or 
141 
5 ROP, or require additional bevacizumab injection, laser treatment, or retinal surgery (vitrectomy 
142 
or scleral buckle).  In addition, at 6 months corrected age (calculated as the estimated date of 
143 
confinement (EDC), or due date, plus 6 months), medical records will be reviewed to collect data 
144 
from non-study exams after 4 weeks post-injection.  
145 
 
146 
Rationale for Change 
147 
Some cases of ROP that are successfully treated with bevacizumab have recurrence of severe 
148 
ROP that requires treatment.  It is possible that the incidence of ROP recurrence requiring 
149 
treatment will increase with lower doses of bevacizumab.  It is also possible that some of these 
150 
cases will have sub-optimal outcomes, whether or not additional treatment was required.     
151 
 
152 
These data may be useful to the DSMC when deciding to reduce dosages.  It is not feasible to 
153 
have 6-month data on all infants during DSMC deliberations, because that would require 
154 
waiting several months after each dosage level is tested before moving to the next dosage level.  
155 
The primary outcome of successful treatment can be determined after 4 weeks, and late 
156 
recurrence with suboptimal outcome is expected to be uncommon. 
157 
 
158 
 
159 
Protocol Change #2 
160 
 
161 
Current Protocol 
162 
The visit window for the 2, 3, and 4 week post-injection exams is the target date +/- 2 days.  
163 
 
164 
Proposed Change 
165 
Extend the window one day on each side such that the visit window for the 2, 3, and 4 week 
166 
post-injection exams is the target date +/-3 days.    
167 
 
168 
Rationale for Change 
169 
This 7-day window will better match clinical exam schedules, since most centers do ROP 
170 
rounds once per week.   It will help to eliminate extra examinations for infants, which can be 
171 
stressful. 
172 
 
173 
 
174 
 
175 
 
176 
 
177 
 
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ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
1-6 
Protocol Change #3 
179 
Current Protocol 
180 
The treating investigator and a second person will review the Bevacizumab Study Syringe 
181 
Preparation Form to confirm which eye will receive the intravitreal injection and will place a 
182 
mark (with a sticker or marking pen) above the brow of the eye before injection. 
183 
 
184 
Proposed Change 
185 
The sentence will be changed to: “For each eye to be treated, the treating investigator and 
186 
second person will review the Bevacizumab Study Syringe Label to confirm which eye will 
187 
receive the intravitreal injection.” The reference to marking the infant with sticker or pen will be 
188 
removed.  
189 
 
190 
Rationale for Change 
191 
To maintain masking investigators will review the syringe label rather than the prescription 
192 
form as the label does not contain the study dosage.  Investigators will operate under their own 
193 
surgical routine with respect to marking or not marking the eye. 
194 
 
195 
 
 
196 


 
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CONTACT INFORMATION  
197 
 
198 
 
199 
 
200 
 
201 
COORDINATING CENTER 
202 
Raymond T. Kraker, M.S.P.H. (Director) 
203 
Jaeb Center for Health Research 
204 
15310 Amberly Drive, Suite 350 
205 
Tampa, FL 33647 
206 
Phone (888) 79PEDIG or (813) 975-8690 
207 
Fax (888) 69PEDIG or (813) 975-8761 
208 
Email: rkraker@jaeb.org 
209 
 
210 
 
211 
 
212 
 
213 
PROTOCOL CHAIR 
214 
 
215 
David K. Wallace, M.D., M.P.H. 
216 
Indiana University Department of Ophthalmology 
217 
Indianapolis, IN 
218 
Phone:  317-278-2651 
219 
Email: dwallac@iu.edu 
220 
 
221 
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1-8 
TABLE OF CONTENTS 
223 
 
224 
CHAPTER 1: BACKGROUND AND SUMMARY ..................................................................................................... 1-9 
225 
1.1 
Background............................................................................................................................................ 1-9 
226 
1.2 
Anti-VEGF Treatments for Other Retinal Disorders ........................................................................... 1-10 
227 
1.3 
Safety ................................................................................................................................................... 1-10 
228 
1.4 
Rationale for the Study ........................................................................................................................ 1-11 
229 
1.5 
Study Objective ................................................................................................................................... 1-12 
230 
1.6 
Synopsis of Study Design .................................................................................................................... 1-12 
231 
CHAPTER 2: STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT ....................................................... 2-1 
232 
2.1 
Eligibility Assessment and Informed Consent ....................................................................................... 2-1 
233 
2.2 
Eligibility Criteria .................................................................................................................................. 2-1 
234 
2.2.1 
Participant-level Inclusion Criteria ................................................................................................... 2-1 
235 
2.2.2 
Study Eye Inclusion and Exclusion Criteria ..................................................................................... 2-1 
236 
Inclusion Criteria: ........................................................................................................................................ 2-1 
237 
Exclusion Criteria for the Study Eye: .......................................................................................................... 2-1 
238 
2.3 
Historical Information ........................................................................................................................... 2-1 
239 
2.4 
Enrollment Examination ........................................................................................................................ 2-2 
240 
CHAPTER 3: TREATMENT AND FOLLOW-UP ..................................................................................................... 3-1 
241 
3.1 
Bevacizumab Dose and Injection .......................................................................................................... 3-1 
242 
3.1.1 
Injection Technique .......................................................................................................................... 3-2 
243 
3.2 
Exam Schedule ...................................................................................................................................... 3-3 
244 
3.3 
Follow-up Exam Procedures ................................................................................................................. 3-3 
245 
3.4 
Definition of Success / Failure .............................................................................................................. 3-4 
246 
3.5 
Side Effects of Bevacizumab ................................................................................................................. 3-4 
247 
3.6 
Additional Examinations ....................................................................................................................... 3-5 
248 
3.7 
Additional Treatment ............................................................................................................................. 3-5 
249 
3.8 
Plasma levels of VEGF and Avastin ..................................................................................................... 3-5 
250 
CHAPTER 4: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP ........................................................... 4-1 
251 
4.1 
Patient Withdrawals ............................................................................................................................... 4-1 
252 
4.2 
Discontinuation of Study ....................................................................................................................... 4-1 
253 
4.3 
Participant Payments ............................................................................................................................. 4-1 
254 
4.4 
Study Costs ............................................................................................................................................ 4-1 
255 
4.5 
Contacts by the Jaeb Center for Health Research .................................................................................. 4-1 
256 
4.6 
General Considerations.......................................................................................................................... 4-1 
257 
CHAPTER 5: ADVERSE EVENTS AND RISKS ........................................................................................................ 5-1 
258 
5.1 
Definition ............................................................................................................................................... 5-1 
259 
5.2 
Recording of Adverse Events ................................................................................................................ 5-1 
260 
5.3 
Reporting Serious or Unexpected Adverse Events ................................................................................ 5-2 
261 
5.4 
Data and Safety Monitoring Committee Review of Adverse Events .................................................... 5-2 
262 
5.5 
Risks ...................................................................................................................................................... 5-3 
263 
5.5.1 
Potential Adverse Effects of Bevacizumab ....................................................................................... 5-3 
264 
5.5.2 
Potential Adverse Effects of Intravitreal Injection ............................................................................ 5-3 
265 
CHAPTER 6: STATISTICAL CONSIDERATIONS AND ANALYSES ................................................................... 6-1 
266 
6.1 
Study Design ......................................................................................................................................... 6-1 
267 
6.2 
Classification of Success/Failure and Decision to Increase, Repeat, or Decrease Dosage .................... 6-1 
268 
6.3 
Additional Analyses .............................................................................................................................. 6-1 
269 
6.3.1 
Description of Cohort ....................................................................................................................... 6-1 
270 
6.3.2 
Safety ................................................................................................................................................ 6-1 
271 
6.3.3 
Power for Analysis of Adverse Effects ............................................................................................. 6-2 
272 
6.3.4 
Plasma levels of VEGF and Avastin ................................................................................................. 6-2 
273 
6.3.5 
Twelve-month Corrected Age........................................................................................................... 6-2 
274 
CHAPTER 7: REFERENCES ....................................................................................................................................... 7-1 
275 
 
276 
 
 
277 


 
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CHAPTER 1: BACKGROUND AND SUMMARY 
278 
 
279 
This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and is 
280 
funded through a cooperative agreement from the National Eye Institute.   
281 
 
282 
1.1 
Background 
283 
Retinopathy of prematurity (ROP) is a significant cause of childhood vision loss in the United 
284 
States,1 characterized by preretinal neovascularization and fibrosis that may ultimately lead to 
285 
retinal traction and detachment.  Low birth weight, gestational age, and supplemental oxygen 
286 
are important risk factors for ROP, but despite the judicious use of supplemental oxygen and 
287 
effective screening and management of ROP in most developed countries, it continues to be a 
288 
significant cause of visual impairment.  Severe visual loss is particularly common in middle 
289 
income countries such as China and India.1, 2 Treatment for severe ROP has focused on ablation 
290 
of the peripheral avascular retina with laser photocoagulation.3 More recently, treatments have 
291 
targeted blockade of pro-angiogenic growth factors, such as vascular endothelial growth factor 
292 
(VEGF), or their receptors.4-6 
293 
 
294 
Examination findings in ROP are classified according to the international classification of ROP 
295 
(ICROP).7  Zone refers to location of disease, from zone I (most posterior) to zone III (most 
296 
anterior). Stage refers to activity at the vascular/avascular border.  Stage 1 is a line, stage 2 is a 
297 
ridge, stage 3 is neovascular tissue, stage 4 is a partial retinal detachment, and stage 5 is a total 
298 
retinal detachment.  Plus disease is dilation and tortuosity of the posterior retinal vessels 
299 
meeting or exceeding the amount seen in a standard photograph that has been used in many 
300 
clinical trials.  The Early Treatment for ROP (ETROP) study established “type 1 ROP” as the 
301 
degree of disease severity for which treatment with laser is indicated.  Type 1 ROP is defined as 
302 
any stage ROP in zone I with plus disease, stage 2 or 3 ROP in zone II with plus disease, or 
303 
stage 3 ROP in zone I without plus disease.8 
304 
 
305 
Bevacizumab (trade name Avastin®; Genentech, Inc., South San Francisco, CA) is a humanized 
306 
monoclonal antibody which binds to VEGF, prevents coupling of VEGF to its receptor, and 
307 
inhibits angiogenesis.  Initially approved by the FDA for anti-angiogenic treatment of metastatic 
308 
colorectal cancer, bevacizumab is used increasingly in the US and abroad as an off-label 
309 
treatment for severe (type 1) ROP, given by intravitreal injection at a small fraction of the 
310 
systemic dose for cancer.  The BEAT-ROP trial (Bevacizumab Eliminates the Angiogenic 
311 
Threat of Retinopathy of Prematurity), was a randomized trial of bevacizumab monotherapy 
312 
versus conventional laser therapy for zone I and posterior zone II, stage 3+ ROP.5  Results of 
313 
the BEAT-ROP trial suggested a benefit of bevacizumab treatment over conventional laser 
314 
therapy for zone I ROP but not for zone II ROP. In addition, high myopia was much less 
315 
common after bevacizumab compared with laser.  However, the BEAT-ROP study had 
316 
important limitations.  The primary outcome was “recurrence of ROP requiring retreatment,” 
317 
and the decisions about retreatment were made by unmasked examiners.  The study lacked a 
318 
functional outcome measure such as visual acuity.  The recurrence of ROP requiring retreatment 
319 
was relatively high (22%). Therefore, additional studies are needed to determine the relative 
320 
effectiveness of Avastin and laser. 
321 
 
322 
Little is known about the safety of using bevacizumab for ROP,9 as the BEAT-ROP study 
323 
provided little short-term and no long-term safety data.  In the BEAT-ROP study, 5 infants 
324 
undergoing bevacizumab injection and 2 infants undergoing laser treatment died before the age 
325 
of 54 weeks, but the study was not powered to evaluate whether the death rate was any higher 
326 


 
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following bevacizumab injection.5  At 2 ½ years of age the death rate was similar between 
327 
groups, with a total of 6 infants treated with bevacizumab and 7 infants in the laser treated 
328 
group dying prior to age 2 ½ years.10  Angiogenesis is an important process in the normal 
329 
development of other organ systems such as the lungs, kidneys, brain, and bones. Intravitreal 
330 
bevacizumab reaches the systemic circulation, so there is significant potential for negative 
331 
systemic side effects.  The dose of bevacizumab used in the BEAT-ROP study (0.625 mg in 25 
332 
µl) was chosen empirically as one-half the adult dose used for macular degeneration.5  Studies 
333 
looking at dose of intravitreal bevacizumab for treatment of proliferative diabetic retinopathy in 
334 
adults found consistent biological effects with doses as high as 1.25 mg to as low as 0.00625 
335 
mg,11 suggesting that bevacizumab may be effective at much lower doses than the dose used in 
336 
the BEAT-ROP study.  Ideally, future treatment with bevacizumab would utilize the lowest 
337 
effective dose, reducing the systemic drug exposure.  Nevertheless, the lowest effective dose of 
338 
bevacizumab for the treatment of severe ROP is unknown.  A phase 1 study is needed to find a 
339 
lower dose of intravitreal bevacizumab injection for the treatment of severe ROP that can be 
340 
evaluated in future larger studies.  
341 
 
342 
1.2 
Anti-VEGF Treatments for Other Retinal Disorders 
343 
Intravitreal injection of anti-VEGF agents has become increasingly common for treatment of 
344 
retinal disorders in adult patients.  Macugen (pegaptanib sodium, manufactured by Pfizer) was 
345 
the first of the anti-VEGF agents for ocular use, approved by the FDA in 2004 for treatment of 
346 
choroidal neovascularization secondary to wet age-related macular degeneration.  Macugen is a 
347 
pegylated aptamer that works by binding to VEGF165 and preventing its binding to VEGF target 
348 
receptors.  In 2006, Lucentis (ranibizumab, manufactured by Genentech) was approved by the 
349 
FDA for treatment of wet age-related macular degeneration.  Lucentis is a monoclonal antibody 
350 
fragment which binds all forms of VEGF, much like Avastin, preventing binding to target 
351 
receptors.  In 2010, Lucentis became the first FDA-approved anti-VEGF agent for treatment of 
352 
macular edema resulting from retinal vein occlusion. In 2012, Lucentis became the first and 
353 
only FDA approved anti-VEGF agent for treatment of diabetic macular edema. Eylea 
354 
(afibercept, manufactured by Regeneron) was first approved by the FDA in 2011 for treatment 
355 
of wet AMD and then later in 2012 as a treatment for macular edema following retinal vein 
356 
occlusion. Eylea is a recombinant fusion protein containing the extracellular domains of human 
357 
VEGF receptors 1 and 2 fused to a portion of human IgG1, which competes with native VEGF 
358 
receptors for binding of free VEGF.  Despite wide usage of anti-VEGF agents for treatment of 
359 
retinal disorders in adults, no approval exists for their use in pediatric populations. 
360 
 
361 
1.3 
Safety 
362 
In a meta-analysis performed by Genentech, Inc. on all clinical trial results using intravenously 
363 
administered bevacizumab (usually dosed as 5 mg/kg every 14 days) in adults, it was found that 
364 
adult study participants were at an increased risk for certain adverse events, some of which were 
365 
potentially fatal.  These included wound healing complications, bowel perforation, hemorrhage, 
366 
stroke, myocardial infarction, hypertension, congestive heart failure, and proteinuria.  Warnings 
367 
and precautions included in the bevacizumab package insert for intravenously administered 
368 
drugs fall under the categories of gastrointestinal perforations, surgery and wound healing 
369 
complications, hemorrhage, non-gastrointestinal fistula formation, arterial thromboembolic 
370 
events, hypertension, reversible posterior leukoencephalopathy syndrome, proteinuria, infusion 
371 
reactions, ovarian failure, and infertility in females with reproductive potential.12 Data regarding 
372 
the safety and pharmacokinetics of bevacizumab in pediatric patients have not been 
373 
established,12 although there is potential for similar adverse events in infants as in adults.   
374 
 
375 


 
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Doses administered to infants for treatment of ROP (typically 0.3 mg to 0.625 mg) are lower 
376 
than those administered to adults for treatment of ocular conditions, and much less than 
377 
intravenous doses used for cancer treatments. A study by Sato et al13 found serum 
378 
concentrations of bevacizumab following a 0.5mg intravitreal injection for ROP were well 
379 
above concentrations required to completely block in vitro VEGF activities in human umbilical 
380 
vein endothelial cells.14  There was an inverse relationship between the serum bevacizumab and 
381 
serum VEGF concentrations. Sato et al concluded that bevacizumab has the ability to cross the 
382 
blood retinal barrier and enter the systemic circulation in relatively high concentrations.13  
383 
Others have reported similar effects with an even lower dose (0.375mg) of bevacizumab.15  
384 
Because of the vasculoproliferative role that VEGF plays in the normal development of organs, 
385 
systemic bevacizumab presents a potential risk to the developing organs of the premature 
386 
neonate.   
387 
 
388 
Ocular side effects have been reported after intravitreal injections of bevacizumab. In some 
389 
cases, retinal traction may be worsened by injection of bevacizumab, leading to retinal 
390 
detachment,16 particularly if membranes have already begun to form.17  Regression of ROP 
391 
following bevacizumab treatment may in some cases be transient, with recurrence of ROP 
392 
occurring later than what is observed with laser treatment.18  Other complications observed 
393 
following bevacizumab treatment for ROP include retinal hemorrhage,19, 20 transient vascular 
394 
sheathing,20 choroidal ischemia,21 abnormalities of the retinal periphery (large avascular areas, 
395 
abnormal branching, shunts) and of the posterior pole (hyperfluorescent areas, absence of the 
396 
foveal avascular zone).  It is possible but unknown if these changes will have an effect on 
397 
vision.22   
398 
 
399 
It is unclear whether the mortality rate of premature infants receiving intravitreal bevacizumab 
400 
is any higher than those treated with laser. In the BEAT-ROP study, 7 of 150 infants died prior 
401 
to the 54-week post-menstrual age outcome examination (5 after intravitreal bevacizumab, 2 
402 
after laser).5  While the mortality was higher in infants receiving bevacizumab, this result was 
403 
statistically non-significant, although it was acknowledged that the study was grossly 
404 
underpowered to detect a difference (a sample of 2800 infants would be required to assess a 
405 
death rate 1.5 times the 5.4% mortality rate observed in the ET-ROP study by 9 months8 at an 
406 
alpha of 0.05 and 80% power).5  Additional follow-up of children enrolled into the BEAT-ROP 
407 
study showed similar rates of mortality in both groups, with 6 infants treated with bevacizumab 
408 
and 7 infants in the laser treated group dying prior to age 2 ½ years.10  Another study reported 
409 
death of 2 of 7 infants with ROP following a 0.75 mg bevacizumab injection, but attributed the 
410 
mortality to complications of their previous systemic conditions.23  However, it is unclear 
411 
whether systemic bevacizumab may have exacerbated the existing conditions, particularly in 
412 
cases of multiple organ failure or lung failure.  Dosing studies and long-term follow-up studies 
413 
with a large number of infants are required to determine the safety of intravitreal bevacizumab 
414 
injection for the treatment of ROP.5, 9, 24, 25 
415 
 
416 
1.4 
Rationale for the Study 
417 
Despite promising initial results using empirical doses of bevacizumab based on half the adult 
418 
dose for treatment of acute severe ROP, little is known about lower doses of bevacizumab for 
419 
ROP.  An increasing number of ophthalmologists are treating premature infants with severe 
420 
ROP using bevacizumab.  Given the potential systemic and ocular adverse effects of intravitreal 
421 
bevacizumab injections, determining a lower effective dose of bevacizumab is an important next 
422 
step.  The proposed study will test progressively lower doses to find a dose to take forward to a 
423 
future larger study. 
424 


 
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1.5 
Study Objective 
425 
To find a dose of intravitreal bevacizumab that is lower than currently used for severe ROP, is 
426 
effective in this study, and can be tested in future larger studies.  
427 
 
428 
1.6 
Synopsis of Study Design 
429 
Major eligibility criteria: (See section 2.2 for a complete listing) 
 
430 
1. Type 1 ROP (as defined in section 2.4) in one or both eyes 
431 
2. No previous treatment for ROP (except previous treatment of the fellow eye with laser is 
432 
allowed) 
433 
 
434 
Treatment Paradigm: 
435 
A dosage of 0.625 mg in 25 µl is commonly used in practice by clinicians.  This study will 
436 
evaluate the effectiveness of 0.25 mg and, if there is evidence of effectiveness, will reduce the 
437 
dose by half until a dosage is found where the evidence suggests insufficient effectiveness.  If 
438 
all doses meet the study effectiveness criteria, then up to 9 different dosages will be evaluated in 
439 
this study.  Effectiveness for the purpose of this study is defined as at least 80% of eyes meeting 
440 
the study’s definition of success (as defined in section 3.4).   
441 
 
442 
Approach to Study Design: 
443 
Not all outcomes for every enrolled subject will be obtainable at the 4-week outcome 
444 
examination for various reasons, including instability of the infant's medical condition, non-
445 
drug-related mortality, need to transfer to another medical institution, hospital discharge with 
446 
poor outpatient follow-up, or obstructed view of the retina.  Therefore, additional infants will be 
447 
enrolled until an outcome has been established for 10 subjects, up to a maximum of 14 subjects 
448 
per dose.  
449 
 
450 
1. A minimum of 10 subjects, and a maximum of 14 subjects, will be injected with an 
451 
initial dose of 0.25 mg bevacizumab in 10 µl.  For infants with bilateral type 1 ROP 
452 
requiring treatment, one randomly selected eye will be injected with bevacizumab. The 
453 
other eye will be treated with laser photocoagulation or with the last effective dose level 
454 
of bevacizumab (one level higher than the level currently being studied).  
455 
a. Recruitment of subjects at each dose will continue until any one of the following 
456 
occurs: 
457 
a. There are 4 failures, declared 3 days to 4 weeks post-injection 
458 
b. There are 8 successes, declared 4 weeks post-injection 
459 
c. 14 infants receive injections 
460 
d. The 10th subject for whom an outcome can be assessed is 3 weeks post-
461 
injection 
462 
b. After recruitment for a dosage ends based on the above criteria, the Data Safety and 
463 
Monitoring Committee (DSMC) will review outcomes from the first 10 infants 
464 
injected as well as preliminary outcomes from any additional (1-4) infants injected, 
465 
and the committee will make a recommendation to reduce the dosage and test 
466 
another 10-14 subjects, repeat the same dosage for another 10-14 subjects, wait for 
467 
outcomes of 1-4 additional infants injected, or stop the study. The DSMC will apply 
468 
the following guidelines, but may make a different decision based on the specific 
469 
study data: 
470 
a. If the success rate is 80% or greater, then the study will continue to the next 
471 
lower dose. Up to 4 different doses will be evaluated. 
472 


 
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b. If the success rate is greater than 70% but less than 80%, then 10-14 
473 
additional infants will be treated at the same dose. 
474 
c. If the success rate is less than 70%, then another 10-14 infants will be 
475 
evaluated at the next higher dose to confirm efficacy, unless the first dose 
476 
(0.25 mg) is unsuccessful, or the previous successful dose was already tested 
477 
on 2 sets of 10-14 infants. 
478 
2. The maximum number of study participants is 201.  
479 
 
480 
Exam Schedule 
481 
Data will be collected on the day of injection (day 0).   
482 
 
483 
The exam schedule is as follows: 
484 
• 
1 day post-injection 
485 
• 
If type 1 is still present at day 1, then an exam will occur at 4 days (3 to 5 days) post-
486 
injection  
487 
• 
1 week (6 to 8 days) post-injection 
488 
• 
2 weeks (11 to 17 days) post-injection 
489 
• 
3 weeks (18 to 24 days) post-injection 
490 
• 
4 weeks (25 to 31 days) post-injection  
491 
 
492 
• 
After 4 weeks, follow-up and treatment will be at investigator discretion, except for the 
493 
following:  
494 
o If at any time after 4 weeks post-injection an infant develops stage 4 or 5 ROP, or 
495 
requires additional bevacizumab injection, laser treatment, or retinal surgery 
496 
(vitrectomy or scleral buckle), medical records will be reviewed to collect data 
497 
from non-study exams since the 4 week post-injection exam.       
498 
 
499 
o For all infants: 
500 
▪ At 6 months (+/-2 weeks) corrected age calculated as the estimated date of 
501 
confinement (EDC), or due date, plus 6 months, medical records will be 
502 
reviewed to collect data from non-study exams since the 4 week post-
503 
injection exam.  
504 
▪ At 12 months (+/-2 weeks) corrected age, an examination will be done and 
505 
medical records will be reviewed to collect data from non-study exams not 
506 
already collected.     
507 
 
508 
• 
All adverse events between the time of study eye injection and the 4-week ocular exam 
509 
or hospital discharge (whichever is later) will be recorded.   After the 4-week ocular 
510 
exam or hospital discharge (whichever is later), only serious adverse events (see section 
511 
5.3), ocular adverse events, and any events judged by the investigator to be related to 
512 
injection and/or treatment will be recorded.  
513 
 
514 
Primary Outcome 
515 
The outcome for each subject will be defined as successfully treated or not successfully treated 
516 
after 4 weeks (see section 3.4).  Success is defined as improvement* by the 4-day exam and no 
517 
recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 
518 
weeks of injection.   
519 
 
520 
* For infants with pre-treatment plus disease, improvement by the 4-day post-injection exam is 
521 
defined as plus disease no longer being present. For infants with pre-treatment zone I, stage 3, 
522 


 
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with pre-plus disease, improvement by the 4-day post-injection exam is defined as: (1) pre-plus 
523 
no longer present (neither plus nor pre-plus disease), or (2) a reduction in severity and/or extent 
524 
of extraretinal neovascularization.  For infants with pre-treatment zone I, stage 3, with neither 
525 
plus nor pre-plus disease, improvement by the 4-day post-injection exam is defined as a 
526 
reduction in severity and/or extent of extraretinal neovascularization.    
527 
 
528 
A dose will be considered effective if it successfully treats at least 80% of subjects.
529 


 
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2-1 
CHAPTER 2: STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 
530 
 
531 
2.1 
Eligibility Assessment and Informed Consent 
532 
A subject is considered for the study after undergoing a routine examination (as part of standard 
533 
care) that identifies type 1 ROP that meets the eligibility criteria.  The study will be discussed with 
534 
the infant’s parent(s) or guardian(s) (referred to subsequently as parent(s)).  Parent(s) who express 
535 
an interest in the study will be given a copy of the informed consent form to read.  Written informed 
536 
consent must be obtained from the parent prior to performing any study-specific procedures that are 
537 
not part of the patient’s routine care.   
538 
 
539 
2.2 
Eligibility Criteria 
540 
2.2.1 
Participant-level Inclusion Criteria 
541 
Study participants are eligible for the study if the following are true:  
542 
1. Parent understands the protocol and is willing to provide consent. 
543 
2. If hospital discharge is anticipated within the next 4 weeks, parents are able and willing to 
544 
return to the PEDIG site for outpatient follow-up visits. 
545 
3. Transfer to another hospital not covered by study-certified examiners is not anticipated 
546 
within the next 4 weeks. 
547 
 
548 
2.2.2 
Study Eye Inclusion and Exclusion Criteria 
549 
The study participant must have at least one eye meeting all of the inclusion criteria and none of the 
550 
exclusion criteria listed below.  Study participants can have only one study eye.  If both eyes are 
551 
eligible at the time of enrollment, then one eye will be randomly selected for injection at the time of 
552 
enrollment (on the PEDIG website), and the fellow eye will be treated with laser photocoagulation 
553 
or with the last effective dose level of bevacizumab (one level higher than the level currently being 
554 
studied).  Data will be collected for both the study and non-study eyes.    
555 
 
556 
Inclusion Criteria:  
557 
1. Type 1 ROP; defined as: 
558 
o Zone I, any stage ROP with plus disease, or 
559 
o Zone I, stage 3 ROP without plus disease, or 
560 
o Zone II, stage 2 or 3 ROP with plus disease  
561 
2. No previous treatment for ROP in the study eye; no previous bevacizumab treatment in 
562 
the non-study eye 
563 
 
564 
Exclusion Criteria for the Study Eye:  
565 
The following exclusions apply to the study eye:  
566 
1. Nasolacrimal duct obstruction 
567 
2. Major ocular anomalies (e.g., cataract, coloboma) 
568 
3. Any opacity that precludes an adequate view of the retina 
569 
 
570 
If purulent ocular discharge is present in either eye, then the infant is ineligible. 
571 
 
572 
2.3 
Historical Information 
573 
Historical information recorded at enrollment will include any prior treatment for ROP (i.e. laser 
574 
treatment in the non-study eye), gestational age at birth, birth weight, current weight, head 
575 
circumference, gender, race, ethnicity, concurrent medical conditions (e.g. IVH, PVL, 
576 
hydrocephalus), and current medications.   
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578 
2.4 
Enrollment Examination 
579 
Classification of ROP on day of examination when type 1 ROP is diagnosed: 
580 
ROP will be classified by the investigator using the revised International Classification of 
581 
Retinopathy of Prematurity (ICROP) criteria.7, 26   
582 
 
583 
Location, extent, and stage of disease, as well as presence of pre-plus, plus disease, or 
584 
aggressive posterior ROP, will be recorded as follows: 
585 
 
586 
Location: Location will be recorded as follows: 
587 
• Zone I: circle centered on the optic nerve with a radius of twice the distance from the 
588 
center of the optic nerve to the center of the macula 
589 
• Zone II: extends centrifugally from the edge of Zone I to the nasal ora serrata and is 
590 
concentric to zone I 
591 
 
592 
Stage: Disease stage will be recorded as stages 1-5 as defined: 
593 
• Stage 1: Demarcation line 
594 
• Stage 2: Ridge 
595 
• Stage 3: Extraretinal fibrovascular proliferation 
596 
• Stage 4: Partial retinal detachment. Stage 4 will be further classified based on location of 
597 
the partial retinal detachment: 
598 
o Stage 4A: Extrafoveal 
599 
o Stage 4B: Foveal 
600 
• Stage 5: Total retinal detachment 
601 
 
602 
Extent of Disease (clock hours): Extent of the highest stage will be recorded in 30◦ increments, 
603 
or clock hours. 
604 
 
605 
Plus Disease: A diagnosis of plus disease will be made if at least 2 quadrants have abnormal 
606 
dilation and tortuosity meeting or exceeding the amount shown in the standard photograph of 
607 
plus disease.26, 27  
608 
 
609 
Pre-plus Disease: A diagnosis of pre-plus disease will be made when there is abnormal dilation 
610 
and tortuosity, but it is insufficient to diagnose plus disease. 
611 
 
612 
Type 1 ROP is the degree of disease severity for which treatment is indicated. It is defined as: 
613 
• Zone I, any stage ROP with plus disease, or 
614 
• Zone I, stage 3 ROP without plus disease, or 
615 
• Zone II, stage 2 or 3 ROP with plus disease 
616 
 
617 
The above classification of ROP in the non-study eye will also be made and data collected at the 
618 
time of enrollment.  
619 
 
620 
   
621 
 
622 


 
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3-1 
CHAPTER 3: TREATMENT AND FOLLOW-UP 
623 
 
624 
Bevacizumab (Avastin) is made by Genentech, Inc. and is approved for metastatic colorectal 
625 
cancer, nonsquamous, non-small cell lung cancer, recurrent glioblastoma, and metastatic renal cell 
626 
carcinoma. The study is being conducted under an Investigational New Drug Application (IND) as 
627 
intravitreal injection of bevacizumab for ROP in children is an off-label use. 
628 
 
629 
All participants will receive a single intravitreal injection of bevacizumab (see section 3.1 for dose) 
630 
following enrollment into the study.  The injection should be given as soon as possible but no later 
631 
than 72 hours after the diagnosis of type 1 ROP.  If there is type 1 ROP in one eye only, then that 
632 
eye will be injected.  If the fellow eye reaches type 1 ROP at a later date within 4 weeks of injection 
633 
in the study eye, then that eye will be treated with laser photocoagulation or the last effective dose 
634 
level of bevacizumab (one level higher than the level currently being studied).  If there is type 1 
635 
ROP in both eyes, then one eye will be randomly selected for injection at the time of enrollment, 
636 
and the fellow eye will be treated with laser or the last effective dose level of bevacizumab (one 
637 
level higher than the level currently being studied). If the study eye meets failure criteria, then either 
638 
eye can be treated at investigator discretion.  Unless the study eye meets failure criteria, the fellow 
639 
eye should not be given more than one injection of bevacizumab within 4 weeks of injection of the 
640 
study eye (because of crossover effects).  If there is a strong rationale for treating the fellow eye 
641 
with more than one injection of bevacizumab, the Protocol Chair or his/her designee should be 
642 
called to discuss it before treatment is given.  The fellow eye can be treated or re-treated with laser 
643 
at investigator discretion.  
644 
 
645 
3.1 
Bevacizumab Dose and Injection 
646 
Study eyes will receive a single dose of bevacizumab provided by the pharmacy at the investigator’s 
647 
institution.  A coordinator at each site will be unmasked to dosage as he/she will be required to 
648 
process the prescription/s to the pharmacy per their usual institutional ordering mechanism.  The 
649 
pharmacy will prepare the bevacizumab in a sterile manner, adhering to USP 797 standards.  Syringes 
650 
containing bevacizumab at the appropriate study concentration will be prepared.  If one eye is injected, 
651 
then two syringes will be prepared.  If two eyes are injected, then four syringes will be prepared.  One 
652 
syringe will serve as a backup and will only be used if the other syringe is compromised for any reason; 
653 
otherwise, the backup syringe will be discarded if unused.  The investigator and all other personnel at 
654 
the site will be masked to the dosage level.    
655 
 
656 
The dosages of injected bevacizumab to be studied are listed in Table 1.  The decision of whether to 
657 
increase, repeat, or decease the dose of bevacizumab will be determined as follows: 
658 
 
659 
1. A minimum of 10 subjects, and a maximum of 14 subjects, will be injected with an initial dose 
660 
of 0.25 mg bevacizumab in 10 µl.  For infants with bilateral type 1 ROP requiring treatment, 
661 
one randomly selected eye will be injected with bevacizumab. The other eye will be treated with 
662 
laser photocoagulation or with last effective dose level of bevacizumab (one level higher than 
663 
the level currently being studied). If the study eye is treated with 0.25 mg, and bevacizumab is 
664 
used for the non-study eye, then the dose for the non-study eye will be 0.625 mg. 
665 
a. Recruitment of subjects at each dose will continue until any one of the following occurs: 
666 
a. There are 4 failures, declared 3 days to 4 weeks post-injection 
667 
b. There are 8 successes, declared 4 weeks post-injection 
668 
c. 14 infants receive injections 
669 
d. The 10th subject for whom an outcome can be assessed is 3 weeks post-injection. 
670 
b. After recruitment for a dosage ends based on the above criteria, the DSMC will review 
671 
outcomes from the first 10 infants injected as well as preliminary outcomes from any 
672 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
3-2 
additional (1-4) infants injected, and the committee will make a recommendation to 
673 
reduce the dosage and test another 10-14 subjects, repeat the same dosage for another 
674 
10-14 subjects, wait for 4-week outcomes of 1-4 additional infants injected, or stop the 
675 
study. The DSMC will apply the following guidelines, but may make a different decision 
676 
based on the specific study data: 
677 
a. If the success rate is 80% or greater, then the study will continue to the next 
678 
lower dose. Up to 4 different doses will be evaluated. 
679 
b. If the success rate is greater than 70% but less than 80%, then an additional 10-
680 
14 infants will be evaluated at the same dose. 
681 
c. If the success rate is less than 70%, then another 10-14 infants will be evaluated 
682 
at the next higher dose to confirm efficacy, unless the first dose (0.25 mg) is 
683 
unsuccessful, or the previous successful dose was already tested on 2 sets of 10-
684 
14 infants. 
685 
2. The maximum number of study participants is 201.   
686 
 
687 
 
688 
Table 1:  Dosages of Injected Bevacizumab to be Studied:  
689 
Dose 
Volume Injected 
Concentration 
0.25mg (start) 
10µl 
25 mg/ml  
0.125mg 
10µl 
12.5 mg/ml  
0.0625mg 
10µl 
6.25 mg/ml 
0.03125mg 
10µl 
3.125 mg/ml 
0.016mg  
10µl 
1.6 mg/ml 
0.008mg  
10µl 
0.8mg/ml 
0.004mg 
10µl 
0.4mg/ml 
0.002mg 
10µl 
0.2mg/ml 
0.001mg 
10µl 
0.1mg/ml 
 
690 
It may not be necessary to enroll 10 subjects for each dose evaluated, because if 8 have success or 4 
691 
have failure before 10 are enrolled and treated, then success or failure of that dosage can be 
692 
declared at that point (and failure may be declared earlier than the 4-week outcome).   
693 
 
694 
3.1.1 
Injection Technique 
695 
The bevacizumab injection will be given preferably within 24 hours, but no later than 72 hours, 
696 
after the diagnosis of type 1 ROP.  The ophthalmologist may choose to give the intravitreal 
697 
injection in the operating room or at the bedside, with or without anesthesia given after consultation 
698 
with the institutional neonatologist.  A binocular indirect ophthalmoscope with an appropriate 
699 
condensing lens should be available, and the pupils should be dilated. 
700 
 
701 
For each eye to be treated, the treating investigator and a second person will review the 
702 
Bevacizumab Study Syringe Label to confirm which eye will receive the intravitreal injection. 
703 
 
704 
Two individuals must confirm the label information on the study syringe to be used for injection 
705 
matches the information on the Bevacizumab Study Syringe Preparation Form prior to injection to 
706 
ensure accuracy.  
707 
 
708 
The investigator who gives the injection must have previous experience giving intravitreal 
709 
injections.  If the injection is the first given by the investigator for ROP, then it must be given with 
710 
the assistance of an ophthalmologist who has previously given intravitreal injections for ROP. 
711 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
3-3 
 
712 
The injection will be done as outlined in the ROP Injection Procedure Manual. 
713 
 
714 
3.2 
Exam Schedule 
715 
The exam schedule is as follows: 
716 
• 
1 day post-injection 
717 
• 
If improvement (defined in sections 1.6 and 3.4) has not occurred at day 1, then an exam is 
718 
done at 4 days (3 to 5 days) post-injection  
719 
• 
1 week (6 to 8 days) post-injection 
720 
• 
2 weeks (11 to 17 days) post-injection 
721 
• 
3 weeks (18 to 24 days) post-injection 
722 
• 
4 weeks (25 to 31 days) post-injection (primary outcome) 
723 
 
724 
• 
After 4 weeks, follow-up and treatment will be at investigator discretion, except for the 
725 
following:  
726 
o If at any time after 4 weeks post-injection an infant develops stage 4 or 5 ROP, or 
727 
requires additional bevacizumab injection, laser treatment, or retinal surgery 
728 
(vitrectomy or scleral buckle), medical records will be reviewed to collect data from 
729 
non-study exams since the 4 week post-injection exam.       
730 
 
731 
o For all infants: 
732 
▪ At 6 months (+/-2 weeks) corrected age calculated as the estimated date of 
733 
confinement (EDC), or due date, plus 6 months, medical records will be 
734 
reviewed to collect data from non-study exams since the 4 week post-injection 
735 
exam.  
736 
▪ At 12 months (+/-2 weeks) corrected age, a study-mandated examination will 
737 
be done and medical records will be reviewed to collect data from non-study 
738 
exams not already collected.        
739 
 
740 
• 
All adverse events between the time of study eye injection and the 4-week ocular exam or 
741 
hospital discharge (whichever is later) will be recorded.   After the 4-week ocular exam or 
742 
hospital discharge (whichever is later), only serious adverse events (see section 5.3), ocular 
743 
adverse events, and any events judged by the investigator to be related to injection and/or 
744 
treatment will be recorded.  
745 
 
746 
• 
If any study-mandated examination is deferred because of an infant’s unstable medical status, 
747 
then that examination will be done as soon as possible. 
748 
 
749 
• 
Additional (non-study) examinations may be done at investigator discretion. 
750 
 
751 
3.3 
Follow-up Exam Procedures 
752 
Classification of ROP will be determined at each follow-up exam as described in section 2.4.  Data 
753 
will be collected for both the study and non-study eye.  
754 
 
755 
Additional data collected at 6 and 12 months will include the following: 
756 
 
757 
• Additional treatment/s for ROP  since the 4-week exam (for both the study and non-study 
758 
eye) 
759 
• Complications since the 4-week exam 
760 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
3-4 
 
761 
 
762 
Additional data collected at 12-months will include the following:  
763 
 
764 
• Date of initial hospital discharge 
765 
• Number of times re-hospitalized by 12 months 
766 
• Most recent head circumference (in centimeters) and date obtained 
767 
• Most recent weight (in grams) and date obtained 
768 
• Current supplemental oxygen requirement, or date supplemental oxygen discontinued 
769 
• Date and cause of death (if applicable) 
770 
• Presence or history of systemic co-morbidities including:  
771 
o Periventricular leukomalacia 
772 
o Hydrocephalus (with shunt placement) 
773 
• Assessment of vision, amblyopia, strabismus, retinal structure, and refractive error   
774 
 
775 
Some data collected at 6 and 12 months will be collected retrospectively from chart review.   
776 
 
777 
3.4 
Definition of Success / Failure 
778 
Assessment of success/failure will be standardized by certifying investigators as knowledgeable 
779 
with respect to the revised International Classification of Retinopathy of Prematurity (ICROP) 
780 
criteria7, upon which exam findings and failure criteria will be based. 
781 
 
782 
Success is defined as improvement* by the 4-day exam (3 to 5 days), and no recurrence of type 1 
783 
ROP or severe neovascularization requiring additional treatment within 4 weeks of injection.  If 
784 
either or both of these criteria are not met, then a second examination will be done by a study-
785 
certified examiner.  If the second examiner confirms that any success criteria are not met, then 
786 
treatment for this eye will be considered a failure, and the investigator may give any additional 
787 
treatment he/she deems necessary.  Failure can be declared as early as the 4-day post-injection 
788 
examination (3 to 5 days), and treatment can then be started at investigator discretion.   
789 
 
790 
If the second examiner does not confirm failure, then they will examine together and reach 
791 
consensus.  
792 
 
793 
* For infants with pre-treatment plus disease, improvement by the 4-day post-injection exam is 
794 
defined as plus disease no longer being present. For infants with pre-treatment zone I, stage 3, with 
795 
pre-plus disease, improvement by the 4-day post-injection exam is defined as: (1) pre-plus no longer 
796 
present (neither plus nor pre-plus disease), or (2) a reduction in severity and/or extent of extraretinal 
797 
neovascularization.  For infants with pre-treatment zone I, stage 3, with neither plus nor pre-plus 
798 
disease, improvement by the 4-day post-injection exam is defined as a reduction in severity and/or 
799 
extent of extraretinal neovascularization.     
800 
 
801 
The investigator will be masked to dosage.   
802 
 
803 
3.5 
Side Effects of Bevacizumab 
804 
Data will be collected at each follow-up visit to evaluate potential adverse effects of injection as 
805 
described in section 5.1.   
806 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
3-5 
3.6 
Additional Examinations 
807 
Investigators may perform additional examinations at their discretion.  Failure may occur at any 
808 
exam prior to 4 weeks starting with the 4-day post-injection exam.  Success cannot be declared until 
809 
the 4-week exam. 
810 
 
811 
3.7 
Additional Treatment 
812 
Treatment for the study eye or the fellow eye is at investigator discretion after the 4-week outcome 
813 
examination, or sooner if the study eye meets criteria for failure and it is confirmed by a second 
814 
examiner. Investigators should not treat the study eye with laser or additional injections prior to the 
815 
4-week outcome examination, unless failure criteria are met and confirmed. If there is a strong 
816 
rationale for earlier treatment in the study eye in the absence of meeting failure criteria, the Protocol 
817 
Chair or his/her designee should be called to discuss it before treatment is given.  
818 
 
819 
The fellow eye may be treated with laser photocoagulation or the last effective dose level of 
820 
bevacizumab (one level higher than the level currently being studied).  Unless the study eye meets 
821 
failure criteria, the fellow eye should not be given more than one injection of bevacizumab within 4 
822 
weeks of injection of the study eye (because of crossover effects).  If there is a strong rationale for 
823 
treating the fellow eye with more than one injection of bevacizumab, the Protocol Chair or his/her 
824 
designee should be called to discuss it before treatment is given.  The fellow eye may be treated or 
825 
re-treated with laser at investigator discretion. 
826 
 
827 
3.8 
Plasma levels of VEGF and Avastin 
828 
The parents of each infant enrolled in the study will be given the option to participate in a study to 
829 
measure levels of VEGF and Avastin in the plasma. Participants in this optional study will have 
830 
blood collected for analysis as described in a separate procedures manual.  Scavenged blood may be 
831 
used if feasible.  VEGF and Avastin levels will be determined before injection, and at 2 weeks and 
832 
4 weeks post-injection. (The Avastin level before injection will serve as a control.) 
833 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
4-1 
CHAPTER 4: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
834 
 
835 
4.1 
Patient Withdrawals 
836 
Parents may withdraw their infant from the study at any time. 
837 
4.2 
Discontinuation of Study 
838 
The study may be discontinued by the Steering Committee or by the Data Safety and Monitoring 
839 
Committee (with approval of the National Eye Institute) prior to the completion of enrollment and 
840 
follow-up for all participants. 
841 
 
842 
4.3 
Participant Payments 
843 
The parent/guardian of each participant will be given a $50 merchandise or money card for 
844 
completion of each protocol-specified outpatient follow-up visit to cover travel and other expenses 
845 
related to completing the visit.  No payment will be made for visits completed while the infant is in 
846 
the hospital before discharge.  If there are extenuating circumstances, and the participant is unable 
847 
to complete outpatient study visits without additional funds due to travel costs, additional funds may 
848 
be provided. 
849 
 
850 
4.4 
Study Costs  
851 
The study will cover the cost of the bevacizumab, but will not cover physician fees and any facility 
852 
fees associated with the injection, as this is part of standard care of severe ROP.  All visits 
853 
(including study exams and additional exams at the discretion of the investigator) and/or other 
854 
required treatments that are part of routine care will be the participant’s or his/her insurance 
855 
company’s responsibility.  Treatment required for complications of the injection itself will also be 
856 
the participant’s or his/her insurance company’s responsibility. 
857 
 
858 
4.5 
Contacts by the Jaeb Center for Health Research 
859 
The Jaeb Center serves as the PEDIG Coordinating Center.  The Jaeb Center will be provided with 
860 
the parent’s contact information.  The Jaeb Center will contact the parents of the participants only 
861 
when necessary.  Permission for such contacts will be included in the Informed Consent Form.  The 
862 
principal purpose of the contacts will be to help coordinate scheduling of the 12-month 
863 
examination.   
864 
  
865 
4.6 
General Considerations 
866 
The study is being conducted in compliance with the policies described in the study policies 
867 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with the 
868 
protocol described herein, and with the standards of Good Clinical Practice. 
869 
 
870 
There is no restriction on the number of subjects to be enrolled by each site towards the overall 
871 
recruitment goal.  A risk-based monitoring approach will be followed, consistent with the FDA 
872 
“Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to 
873 
Monitoring” (August 2013). 
874 
 
875 
It is the investigators’ opinion that the protocol’s level of risk falls under DHHS 46.406, which is 
876 
research involving greater than minimal risk and no prospect of direct benefit to individual subjects, 
877 
but likely to yield generalizable knowledge about the subject's disorder or condition. 
878 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
5-1 
CHAPTER 5: ADVERSE EVENTS AND RISKS 
879 
 
880 
5.1 
Definition 
881 
An adverse event is any untoward medical occurrence in a study participant, irrespective of whether 
882 
or not the event is considered treatment-related. 
883 
 
884 
5.2 
Recording of Adverse Events 
885 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
886 
events or untoward findings.  The first concern will be the safety of the study participant, and 
887 
appropriate medical intervention will be made. 
888 
 
889 
All adverse events between the time of study eye injection and the 4-week ocular exam or hospital 
890 
discharge (whichever is later), whether discovered by study personnel during questioning or 
891 
parents, or detected through physical examination, laboratory test, or other means will be reported 
892 
on an adverse event form online.  Each adverse event form is reviewed by the Coordinating Center 
893 
to verify the coding and the reporting that is required.   
894 
The study investigator will assess the relationship of any adverse event to be related or unrelated by 
895 
determining if there is a reasonable possibility that the adverse event may have been caused by the 
896 
treatment. 
897 
 
898 
After the 4-week ocular exam or hospital discharge (whichever is later), only serious adverse events 
899 
(see section 5.3), ocular adverse events, and any adverse event judged by the investigator to be 
900 
related to injection and/or treatment will be recorded.  
901 
 
902 
To ensure consistency of adverse event causality assessments, investigators should apply the 
903 
following general guideline when determining whether an adverse event is related: 
904 
 
905 
Yes 
906 
There is a plausible temporal relationship between the onset of the adverse event and administration 
907 
of the study treatment and the adverse event cannot be readily explained by the subject’s clinical 
908 
state, intercurrent illness, or concomitant therapies; and/or the adverse event follows a known 
909 
pattern of response to the study treatment. 
910 
 
911 
No 
912 
Evidence exists that the adverse event has an etiology other than the study treatment (e.g., 
913 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); 
914 
and/or the adverse event has no plausible temporal relationship to study treatment administration.    
915 
 
916 
The maximum intensity that occurred since the onset of an adverse event will be rated on a three-
917 
point scale: (1) mild, (2) moderate, or (3) severe, categorized as follows:  
918 
 
919 
Mild - Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
920 
not influence performance or functioning; prescription drug not ordinarily needed for relief of 
921 
symptom(s). 
922 
 
923 
Moderate - Symptom(s) of sufficient severity to make subject uncomfortable; performance of 
924 
daily activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
925 
be needed. 
926 
 
927 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
5-2 
Severe - Symptom(s) cause severe discomfort; severity may cause cessation of treatment with 
928 
study medication or device; treatment for symptom(s) may be given and/or subject hospitalized 
929 
 
930 
It is emphasized that the term severe is a measure of intensity: thus, a severe adverse event is not 
931 
necessarily serious. For example, itching for several days may be rated as severe, but may not be 
932 
clinically serious. 
933 
 
934 
Adverse events that continue after the study participant’s discontinuation or completion of the study 
935 
will be followed until their medical outcome is determined or until no further change in the 
936 
condition is expected.   
937 
 
938 
5.3 
Reporting Serious or Unexpected Adverse Events 
939 
A serious adverse event is any untoward occurrence that: 
940 
• Results in death. 
941 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
942 
become life-threatening, is not necessarily considered a serious adverse event). 
943 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
944 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
945 
conduct normal life functions (sight-threatening). 
946 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
947 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
948 
the outcomes listed above). 
949 
 
950 
Unexpected adverse events are those that are not identified in the current Clinical Investigator’s 
951 
Brochures.   
952 
 
953 
Serious or unexpected adverse events must be reported to the Coordinating Center immediately via 
954 
completion of the online serious adverse event form.   
955 
 
956 
The Coordinating Center will notify all participating investigators of any adverse event that is both 
957 
serious and unexpected.  Notification will be made within 10 days after the Coordinating Center 
958 
becomes aware of the event.   
959 
 
 
960 
Each principal investigator is responsible for reporting serious study-related adverse events and 
961 
abiding by any other reporting requirements specific to their Institutional Review Board.  
962 
5.4 
Data and Safety Monitoring Committee Review of Adverse Events 
963 
A Data and Safety Monitoring Committee will approve the protocol, template informed consent 
964 
form, and substantive amendments, and provide independent monitoring of adverse events.  
965 
Cumulative adverse event data will be tabulated for review by the DSMC at intervals determined by 
966 
the coordinating center and the DSMC.  Following each DSMC data review, a summary will be 
967 
made available for submission to Institutional Review Boards.  A list of specific adverse events to 
968 
be reported to the DSMC expeditiously will be compiled and included as part of the DSMC 
969 
Standard Operating Procedures.   
970 
 
971 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
5-3 
5.5 
Risks 
972 
5.5.1 
Potential Adverse Effects of Bevacizumab 
973 
As noted in section 1.3, the risks of using bevacizumab in infants are largely unknown, but may be 
974 
similar to risks in adults.  Because bevacizumab works by inhibiting vascular growth, any organ 
975 
system or bodily function that relies on vascular growth or maintenance of vasculature is 
976 
susceptible to experiencing complications.  Administration of bevacizumab during the period of 
977 
organ development may have negative long-term implications.  The systemic risks of bevacizumab 
978 
when used intravenously include wound healing complications, bowel perforation, hemorrhage, 
979 
stroke, myocardial infarction, hypertension, congestive heart failure, proteinuria, gastrointestinal 
980 
perforations, non-gastrointestinal fistula formation, arterial thromboembolic events, reversible 
981 
posterior leukoencephalopathy syndrome, infusion reactions, and ovarian failure. After intravitreal 
982 
injection, bevacizumab is present in the blood in low concentrations, and it is unknown if these 
983 
amounts are sufficient to cause any of the systemic complications listed above.  The ocular risks of 
984 
intravitreal injection include worsened retinal traction, recurrent ROP, retinal hemorrhage, transient 
985 
vascular sheathing, abnormalities of the retinal periphery (large avascular areas, abnormal 
986 
branching, shunts) and of the posterior pole (hyperfluorescent areas, absence of the foveal avascular 
987 
zone).  It is possible but unknown if these changes will have an effect on vision.12, 16-20, 22 
988 
 
989 
Children with severe ROP often have high myopia (nearsightedness) and astigmatism, and it is 
990 
common for one eye to have more myopia and/or astigmatism than the other (anisometropia).  This 
991 
can lead to the brain favoring one eye over the other (amblyopia), which is usually treated with 
992 
patching of the preferred eye to force the brain to use the non-preferred eye.  Preliminary studies 
993 
indicate that use of bevacizumab for ROP seems to result in less myopia (nearsightedness) than 
994 
laser treatment, especially for zone I eyes.  If one eye is treated with laser and the other eye with 
995 
bevacizumab, it may increase the chances of anisometropia and amblyopia. 
996 
 
997 
5.5.2 
Potential Adverse Effects of Intravitreal Injection 
998 
Rarely, the topical drugs used to anesthetize the eye before the injections (proparacaine, tetracaine, 
999 
or xylocaine) can cause an allergic reaction, seizures, and an irregular heartbeat.  Generally, infants 
1000 
will have already been exposed to topical anesthetic during diagnostic examinations. 
1001 
 
1002 
Temporary stinging, burning and conjunctival redness may occur with the use of proparacaine. A 
1003 
rare, severe, immediate-type, apparently hyperallergic corneal reaction characterized by acute, 
1004 
intense and diffuse epithelial keratitis, a gray, ground glass appearance, sloughing of large areas of 
1005 
necrotic epithelium, corneal filaments and iritis with descemetitis has also been reported. 
1006 
 
1007 
Subconjunctival hemorrhage will commonly occur as a result of the intravitreal injection.  Mild 
1008 
discomfort, ocular hyperemia, increased lacrimation, discharge or itching lasting for a few days is 
1009 
also likely. 
1010 
 
1011 
Immediately following the injection, there may be elevation of intraocular pressure. It usually 
1012 
returns to normal spontaneously, but may need to be treated with topical drugs or a paracentesis to 
1013 
lower the pressure.  The likelihood of permanent loss of vision from elevated intraocular pressure is 
1014 
much less than 1%. 
1015 
 
1016 
A rare complication of injection is endophthalmitis.  It can be due to infection with pathogens such 
1017 
as bacteria of fungi or can be noninfectious. Clinical features include eyelid edema, conjunctival 
1018 
injection, corneal edema, anterior chamber and vitreous inflammation and hypopyon.   
1019 
Endophthalmitis is treated by intravitreal injection of antibiotics, and there is a risk of permanent 
1020 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
5-4 
loss of vision, including blindness.  A meta-analysis of 24 studies in adults reporting 
1021 
endophthalmitis after intravitreal injection of an anti-VEGF agent estimated the risk of 
1022 
endophthalmitis per injection to be 0.049% (95% CI, 0.038% to 0.065%). 28 
1023 
 
1024 
Retinal detachment is a rare complication of intravitreal injection.  If this occurs, surgery may be 
1025 
needed, which is usually successful at reattaching the retina.  However, a retinal detachment can 
1026 
produce permanent loss of vision and even blindness.  The risk of retinal detachment has been 
1027 
reported to be less than 0.1% in adults.29 
1028 
 
1029 
The risk of vitreous hemorrhage after intravitreal injection has been reported to be less than 1% in 
1030 
adults.29  When it occurs, it usually resolves spontaneously, but vitrectomy is sometimes needed, 
1031 
and vision loss may result in some cases.   Retinal detachment and vitreous hemorrhage can also 
1032 
occur from severe ROP. 
1033 
 
1034 
 
1035 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
6-1 
CHAPTER 6: STATISTICAL CONSIDERATIONS AND ANALYSES 
1036 
 
1037 
6.1 
Study Design 
1038 
The goal of the study is to find a dose of bevacizumab that is lower than what is currently 
1039 
considered the standard, and that can be tested in future studies.  The approach to the study design is 
1040 
detailed in section 3.1, and is summarized below.     
1041 
 
1042 
In brief, the study will begin by evaluating the effectiveness of 0.25 mg bevacizumab and if there is 
1043 
evidence of effectiveness, will reduce the dose by half until a dosage is found where the evidence 
1044 
suggests insufficient effectiveness.  If all doses meet the study effectiveness criteria, then up to 9 
1045 
total doses will be evaluated in this study.  Effectiveness for the purpose of this study is defined as 
1046 
at least 80% of eyes meeting the study’s definition of success (as defined in section 3.4).  
1047 
 
1048 
6.2 
Classification of Success/Failure and Decision to Increase, Repeat, or Decrease Dosage 
1049 
At each dosage level, the number of eyes injected and the number and proportion of eyes meeting 
1050 
success criteria as described in section 3.4 will be evaluated.   
1051 
 
1052 
The DSMC will review outcomes from the first 10 infants injected as well as preliminary outcomes 
1053 
from any additional (1-4) infants injected, and the committee will make a recommendation to 
1054 
reduce the dosage and test another 10-14 subjects, repeat the same dosage for another 10-14 
1055 
subjects, wait for outcomes of 1-4 additional infants injected, or stop the study. The DSMC will 
1056 
apply the following guidelines, but may make a different decision based on the specific study data: 
1057 
• If the success rate is 80% or greater, then the study will continue to the next lower dose.  
1058 
• If the success rate is greater than 70% but less than 80%, then an additional 10-14 infants 
1059 
will be evaluated at the same dose. 
1060 
• If the success rate is less than 70%, then another 10-14 infants will be evaluated at the next 
1061 
higher dose to confirm efficacy, unless the first dose (0.25 mg) is unsuccessful, or the 
1062 
previous successful dose was already tested on 2 sets of 10-14 infants. 
1063 
 
1064 
When reporting study results, both eyes of all infants will be included. 
1065 
 
1066 
6.3 
Additional Analyses 
1067 
 
1068 
6.3.1 
Description of Cohort 
1069 
At each dosage level, subject level and eye level characteristics will be tabulated including gender, 
1070 
race, gestational age, birth weight, examination findings in the study and non-study eye, and age at 
1071 
diagnosis of type 1 ROP.  
1072 
 
1073 
6.3.2 
Safety  
1074 
Adverse events reported at any time during the study will be tabulated for all enrolled infants and 
1075 
coded using the MedRA system.  For each dosage level, an estimate and 95% confidence interval of 
1076 
the following proportions will be obtained using the exact binomial method:  
1077 
• Proportion of infants for whom at least one event was reported 
1078 
• Proportion of infants with an adverse event thought by investigator to be related to study 
1079 
drug 
1080 
• Proportion of infants for whom at least one serious adverse event was reported  
1081 
• Proportion of infant deaths 
1082 
 
1083 


 
ROP1Protocolv3.1_11-28-16 clean 4-17-18 
 
6-2 
6.3.3 
Power for Analysis of Adverse Effects  
1084 
For rare side effects, Table 3 below specifies the chance of not observing at least 1 adverse event in 
1085 
a sample of 10 children for various event rates in the population. .   
1086 
 
1087 
Table 3:  Chance of Not Observing at Least One Event in a Sample of 10 Subjects 
1088 
Actual Probability 
of an Event 
Chance of Not Observing at Least One Event for a 
Given Dosage 
N=10 Subjects 
1% 
90% 
2% 
82% 
3% 
74% 
4% 
67% 
5% 
60% 
 
1089 
Hence, with the proposed sample size of 10 subjects at each dosage level, the study has a 60% 
1090 
probability for not observing at least one event for adverse events with 5% occurrence.   
1091 
 
1092 
6.3.4 
Plasma levels of VEGF and Avastin 
1093 
The parents of each infant enrolled in the study will be given the option to participate in a study to 
1094 
measure levels of VEGF and Avastin in the plasma. Participants in this optional study will have 
1095 
blood collected for analysis The distribution of VEGF and Avastin levels (median, range, and 
1096 
quartiles) will be described before injection, and at 2 weeks and 4 weeks post-injection.  For each 
1097 
dosage level, at 2, and 4-weeks post-injection, the change from pre-injection will be calculated, and 
1098 
a 95% confidence interval calculated for the change.  
1099 
 
1100 
6.3.5 
Twelve-month Corrected Age 
1101 
Descriptive statistics will be calculated to describe the cohort at each dosage level with respect to the 
1102 
following at 12-months corrected age:  
1103 
 
1104 
• Time since initial hospital discharge 
1105 
• Number of times re-hospitalized by 12 months 
1106 
• Number of infants with an increase in oxygen requirement prior to injection (yes, no, 
1107 
unknown) 
1108 
• Number of deaths  
1109 
• Number of infants with periventricular leukomalacia 
1110 
• Number of infants with hydrocephalus (with shunt placement) 
1111 
• Number of study eye and fellow eyes requiring additional treatment/s for ROP, and if 
1112 
retreated, type of treatment  
1113 
• Any adverse events or complications since the 4-week exam  
1114 
• Assessment of vision, amblyopia, strabismus, retinal structure, and refractive error   
1115 
• Most recent head circumference (in centimeters), reported by z scores 
1116 
• Most recent weight (in grams), reported by z scores 
1117 
 
1118 
In addition, the change from pre-injection with respect to z scores of head circumference and weight 
1119 
will be calculated.  
1120 
 
1121 
Exploratory analyses will evaluate whether these factors differ according to dosage level.
1122 


 
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7-1 
CHAPTER 7: REFERENCES 
1123 
 
1124 
1. 
Gilbert C. Retinopathy of prematurity: A global perspective of the epidemics, population of 
1125 
babies at risk and implications for control. Early Hum Dev 2008;84:77-82. 
1126 
2. 
Gilbert C, Rahi J, Eckstein M, O'Sullivan J, Foster A. Retinopathy of prematurity in middle-
1127 
income countries. Lancet 1997;350:12-14. 
1128 
3. 
McNamara JA, Tasman W, Brown GC, Federman JL. Laser photocoagulation for stage 3+ 
1129 
retinopathy of prematurity. Ophthalmology 1991;98:576-580. 
1130 
4. 
Kusaka S, Shima C, Wada K, et al. Efficacy of intravitreal injection of bevacizumab for 
1131 
severe retinopathy of prematurity: A pilot study. Br J Ophthalmol 2008;92:1450-1455. 
1132 
5. 
Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 
1133 
3+ retinopathy of prematurity. N Engl J Med 2011;364:603-615. 
1134 
6. 
Mintz-Hittner HA, Kuffel RR, Jr. Intravitreal injection of bevacizumab (Avastin) for 
1135 
treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina 2008;28:831-
1136 
838. 
1137 
7. 
International Committee for the Classification of Retinopathy of Prematurity. The 
1138 
International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 
1139 
2005;123:991-999. 
1140 
8. 
Early Treatment For Retinopathy Of Prematurity Cooperative Group. Revised indications 
1141 
for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of 
1142 
prematurity randomized trial. Arch Ophthalmol 2003;121:1684-1694. 
1143 
9. 
Hård AL, Hellström A. On safety, pharmacokinetics and dosage of bevacizumab in ROP 
1144 
treatment - a review. Acta Paediatr 2011;100:1523-1527. 
1145 
10. 
Geloneck MM, Chuang AZ, Clark WL, et al. Refractive Outcomes Following Bevacizumab 
1146 
Monotherapy Compared With Conventional Laser Treatment: A Randomized Clinical Trial. JAMA 
1147 
Ophthalmology 2014;doi: 10.1001/jamaophthalmol.2014.2772. 
1148 
11. 
Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the 
1149 
treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695-1715. 
1150 
12. 
Daily Med Current Medical Information. AVASTIN (bevacizumab) injection, solution 
1151 
[Genentech, Inc.]  
1152 
2013. 
1153 
13. 
Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and 
1154 
vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol 
1155 
2012;153:327-333. e321. 
1156 
14. 
Wang Y, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanized 
1157 
anti-VEGF antibody in vitro. Angiogenesis 2004;7:335-345. 
1158 
15. 
Harder BC, von Baltz S, Jonas JB, Schlichtenbrede FC. Intravitreal low-dosage 
1159 
bevacizumab for retinopathy of prematurity. Acta Ophthalmologica 2014;92:577-581. 
1160 
16. 
Zepeda-Romero LC, Liera-Garcia JA, Gutierrez-Padilla JA, Valtierra-Santiago CI, Avila-
1161 
Gomez CD. Paradoxical vascular-fibrotic reaction after intravitreal bevacizumab for retinopathy of 
1162 
prematurity. Eye (Lond) 2010;24:931-933. 
1163 
17. 
Mintz-Hittner HA. Avastin as monotherapy for retinopathy of prematurity. J AAPOS 
1164 
2010;14:2-3. 
1165 
18. 
Hu J, Blair MP, Shapiro MJ, Lichtenstein SJ, Galasso JM, Kapur R. Reactivation of 
1166 
retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol 2012;130:1000-1006. 
1167 
19. 
Dorta P, Kychenthal A. Treatment of type 1 retinopathy of prematurity with intravitreal 
1168 
bevacizumab (Avastin). Retina 2010;30:S24-31. 
1169 
20. 
Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of 
1170 
bevacizumab use in patients with retinopathy of prematurity: A multicenter study in Taiwan. 
1171 
Ophthalmology 2011;118:176-183. 
1172 


 
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7-2 
21. 
Chhablani J, Rani PK, Balakrishnan D, Jalali S. Unusual adverse choroidal reaction to 
1173 
intravitreal bevacizumab in aggressive posterior retinopathy of prematurity: the Indian Twin Cities 
1174 
ROP screening (ITCROPS) data base report number 7. Semin Ophthalmol 2014;29:222-225. 
1175 
22. 
Shah PK, Morris RJ, Narendran V, Kalpana N. Visual acuity and electroretinography 
1176 
findings 3 (1/2) years after the first intravitreal injection of bevacizumab (Avastin) in aggressive 
1177 
posterior retinopathy of prematurity. Indian J Ophthalmol 2011;59:73-74. 
1178 
23. 
Law JC, Recchia FM, Morrison DG, Donahue SP, Estes RL. Intravitreal bevacizumab as 
1179 
adjunctive treatment for retinopathy of prematurity. J AAPOS 2010;14:6-10. 
1180 
24. 
Darlow BA, Ells AL, Gilbert CE, Gole GA, Quinn GE. Are we there yet? Bevacizumab 
1181 
therapy for retinopathy of prematurity. Arch Dis Child Fetal Neonatal Ed 2013;98:F170-174. 
1182 
25. 
Fleck BW. Management of retinopathy of prematurity. Archives of Disease in Childhood 
1183 
Fetal and Neonatal Edition 2013;98:F454-456. 
1184 
26. 
Capone A, Jr., Ells AL, Fielder AR, et al. Standard image of plus disease in retinopathy of 
1185 
prematurity. Arch Ophthalmol 2006;124:1669-1670. 
1186 
27. 
Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of 
1187 
cryotherapy for retinopathy of prematurity. Preliminary results. Arch Ophthalmol 1988;106:471-
1188 
479. 
1189 
28. 
McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular 
1190 
endothelial growth factor agents: causative organisms and possible prevention strategies. Retina 
1191 
2011;31:654-661. 
1192 
29. 
Day S, Acquah K, Mruthyunjaya P, Grossman DS, Lee PP, Sloan FA. Ocular complications 
1193 
after anti-vascular endothelial growth factor therapy in Medicare patients with age-related macular 
1194 
degeneration. Am J Ophthalmol 2011;152:266-272. 
1195 
 
1196 
 
1197