Bevacizumab Treatment For Type 1 Retinopathy of Prematurity
Phase: PHASE2
Conditions: Retinopathy of Prematurity
Sponsor: Jaeb Center for Health Research

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BEVACIZUMAB TREATMENT FOR TYPE 
1 RETINOPATHY OF PREMATURITY 
 
Protocol Identifying Number: ROP4 
IND Sponsor: Jaeb Center for Health Research 
Funded by: National Eye Institute, National Institutes of Health 
 
 
Version Number: 2.0 
 
22 June 2023 
 
 

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PROTOCOL AMENDMENT #2 
22 June 2023 
This amendment provides for the following protocol changes:  
Protocol Change # 2:  
Current Protocol 
The study ends after the 12-months corrected age visit. 
Proposed Change 
Participants will be asked to complete a 24-months corrected age visit which includes a Bayley-4 
Test. The statistics section has been updates to include exploratory analyses summarizing these 
scores within and between groups. 
Rationale for Change 
Differences in neurodevelopmental outcomes would influence future choice of dose for 
bevacizumab. 
 
Current Protocol 
A reminder contact for the General Movements Assessment (GMA) is not included. 
Proposed Change 
Sites will call parents to remind them to film the General Movements Assessment (GMA). 
Rationale for Change: 
Compliance with receiving the GMA video has been poor. 
 
Additional Changes:  
In addition to the changes above, the following clarifications have been made to the protocol:  
1. Personnel and contact information updates. 
2. Stage 0 was added as an option in the classification of ROP. 
3. Clarifications to language in the statistics section:  
a. English and formatting clarifications throughout 
b. Clarified that retinal vascularization analyzes are at two and four months post-
injection 
c. Systemic morbidities tabulations were moved from secondary to safety analyses  
d. Between dose group analysis for refractive error and plasma VEGF have been 
removed to be consistent with SAP. 

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PROTOCOL AMENDMENT #1 
11 February 2022 
This amendment provides for the following protocol changes:  
Protocol Change # 1:  
Current Protocol 
Infants are eligible if one or both eyes have ROP and retinal vessels all in zone I. 
Proposed Change 
Infants would be eligible if one or both eyes have zone I ROP, defined as at least one clock hour 
of ROP in zone I. 
Rationale for Change 
Feedback from investigators is that many of them are not comfortable treating zone I ROP with 
laser; therefore, they are not offering ROP3 to many of these infants and instead treating them 
outside of the study with bevacizumab (or another anti-VEGF) We would like to give these 
infants and families the opportunity to participate in ROP4 and potentially receive low-dose 
bevacizumab. We expect this will increase recruitment in ROP4 (without significantly affecting 
ROP3), so we will have more data on the effects of low-dose vs. standard dose bevacizumab, 
including retinal outcomes, retinal vascular growth, and refractive error.  
 
Current Protocol 
General Movements Assessment (GMA) is not included. 
Proposed Change 
General Movements Assessment will be done at 54 (52-56) weeks PMA. 
Rationale for Change: 
Since many more infants with zone I ROP will now be eligible for this study, we would like to 
collect GMA test results to see if there is a safety signal in this developmental screening tool 
between low-dose and standard-dose bevacizumab. 
 
Current Protocol  
For unilateral cases of type 1 ROP, the current protocol restricts treatment options of the fellow 
eye: If the fellow eye has type 1 ROP in zone II or becomes eligible for treatment by developing 
type 1 ROP within 4 weeks of the study eye, the fellow eye will receive the randomized 

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treatment assigned to the first eye. If the study eye has failed, then then the investigator may 
choose to treat the fellow eye at investigator discretion. 
Proposed Change  
If both eyes are eligible, then both will receive the assigned treatment.  If one eye is eligible and 
the fellow eye is not, then the eligible eye will receive the randomized treatment.  If the fellow 
eye requires treatment at the same time or within 4 weeks of the first eye (based on investigator 
judgement), then the fellow eye will receive the same treatment and dose as the first eye unless 
the first eye has met failure criteria, then treatment of both eyes is at investigator discretion. The 
information regarding treatment previously in Section 2.2 Inclusion Criteria has been moved to 
Section 2.5 Randomization.  Sections 2.5 and 3.2 have been updated to specify treatment options 
for fellow eyes.   
 
Rationale for Change 
It is in the participant’s best interest to have a fellow eye treated at investigator discretion 
regardless of study eligibility. For example, if one eye is type 1 ROP and the other eye has 
impending type 1 ROP, the investigator may want to treat both eyes at the same time, to avoid a 
2nd procedure, including sedation for the procedure. 
 
Additional Changes:  
In addition to the changes above, the following clarifications have been made to the protocol:  
1. The schedule of study visits and procedures has been updated to reflect systemic outcome 
collection as specified in the protocol at the time of enrollment.  
2. Section 2.5 Randomization has been edited to clarify that randomization will be stratified 
by gestational age as <25 weeks and zero days vs ≥25 weeks and one day.  
3. Section 3.8 has been added to describe non-case report form data access. 
4. Section 8.2.2.3 Safety Analyses has been updated to reflect a comparison of mean blood 
pressure measurements between treatment groups. Furthermore, adverse events in 
untreated fellow eyes will be tabulated separately. 
5. The definition of plus disease has been updated to be consistent with the ICROP3 
classification. 
6. The timing of retinal imaging has been made consistent throughout the protocol. 
 
 

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KEY ROLES 
Protocol Chair 
Name, degree 
David K. Wallace, M.D., M.P.H. 
Title 
Professor and Chair 
Institution Name 
Vanderbilt Eye Institute 
2311 Pierce Ave 
Nashville, TN 37232Phone:  615-936-2020 
Email: david.wallace@vumc.org 
Signature/ Date 
 
Protocol Vice-Chair  
Name, degree 
G. Baker Hubbard, M.D. 
Title 
Thomas M. Aaberg Sr. Professor of Ophthalmology 
Institution Name 
The Emory Eye Center 
Emory University School of Medicine 
1365B Clifton Rd. NE 
Atlanta, GA 30322 
Email:  ghubba2@emory.edu  
Signature/ Date 
 
Protocol Vice-Chair 
Name, degree 
Daniel F. Martin, M.D. 
Title 
Chairman 
Institution Name 
Cole Eye Institute, Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH 44195 
Email:  martind5@ccf.org 
Signature/ Date 
 
Protocol Vice-Chair 
Name, degree 
William V. Good, M.D. 
Title 
Senior Scientist 
Institution Name 
Smith-Kettlewell Eye Research Institute 
2318  Fillmore Street 
San Francisco, CA 94115 
Email:  good@ski.org  
Signature/ Date 
 
 
 

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JCHR Protocol Director  
Name, degree 
Robert J. Henderson, M.S. 
Title 
Biostatistician, PEDIG Coordinating Center  
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Email: rhenderson@jaeb.org  
Signature/ Date 
 
JCHR Coordinating Center Director 
Name, degree 
Raymond T. Kraker, M.S.P.H. 
Title 
Director, PEDIG Coordinating Center  
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Email: rkraker@jaeb.org 
Signature/ Date 
 
Medical Monitor 
Name, degree 
 Michael X. Repka, MD, MBA 
Title 
Professor of Ophthalmology, Professor of Pediatrics 
Institution Name 
Johns Hopkins University School of Medicine 
233 Wilmer Institute 
Johns Hopkins Hospital 
Baltimore, MD 21287-9028 
Email: mrepka@jhmi.edu 
Signature/ Date 
 
Central Laboratory for Blood Testing 
Name, degree 
Mary E. Hartnett, M.D. 
Title 
Director of Pediatric Retina, Byers Eye Institute at Stanford University  
Institution Name 
Stanford University 
1651 Page Mill Rd 
Palo Alto, CA 94304 
Email: me.hartnett@stanford.edu 
Signature/ Date 
 
 

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TABLE OF CONTENTS 
 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 17 
1.1 Introduction ....................................................................................................................................... 17 
 Retinopathy of Prematurity ......................................................................................................... 17 
 Clinical Studies of ROP Treatment ............................................................................................. 18 
 Phase 1 Dosing De-escalation Study ........................................................................................... 19 
1.2 Study objectives ................................................................................................................................. 19 
1.3 Rational for the Current Study ........................................................................................................... 19 
1.4 Potential Risks and Benefits of Bevacizumab ................................................................................... 20 
 Known Potential Risks of Bevacizumab ..................................................................................... 20 
 Potential Adverse Effects of Intravitreous Injection ................................................................... 21 
 Known Potential Benefits of Bevacizumab ................................................................................. 22 
 Risks of Examination or Testing Procedures .............................................................................. 24 
1.5 Risk Assessment ................................................................................................................................ 24 
1.6 General Considerations...................................................................................................................... 24 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 25 
2.1 Participant Recruitment and Enrollment ........................................................................................... 25 
 Informed Consent and Authorization Procedures ....................................................................... 25 
2.2 Participant Inclusion Criteria ............................................................................................................. 25 
2.3 Participant Exclusion Criteria ............................................................................................................ 26 
2.4 Data Collection and Examination at Enrollment ............................................................................... 26 
 Historical Information ................................................................................................................. 26 
 ROP Classification ...................................................................................................................... 26 
 Retinal Images ............................................................................................................................. 27 
 Optional Imaging ......................................................................................................................... 28 
 Optional Blood Collection ........................................................................................................... 28 
2.5 Randomization ................................................................................................................................... 28 
CHAPTER 3: RANDOMIZED TRIAL PROCEDURES .................................................................................... 29 
3.1 Bevacizumab Dose and Injection ...................................................................................................... 29 
 Bevacizumab Injection ................................................................................................................ 29 
3.2 Treatment for ROP ............................................................................................................................ 29 
3.3 Exam Schedule .................................................................................................................................. 30 
3.4 Non-Case Report Form Data Access ................................................................................................. 31 
CHAPTER 4: STUDY DRUG ......................................................................................................................... 32 

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4.1 Study Agent(s) and Control Description ........................................................................................... 32 
 Acquisition .................................................................................................................................. 32 
 Formulation, Appearance, Packaging, and Labeling ................................................................... 32 
 Product Storage and Stability ...................................................................................................... 32 
 Preparation ................................................................................................................................... 32 
 Dosing and Administration .......................................................................................................... 32 
 Route of Administration .............................................................................................................. 32 
 Dose Adjustments/Modifications/Delays .................................................................................... 32 
 Duration of Therapy .................................................................................................................... 33 
 Tracking of Dose ......................................................................................................................... 33 
4.2 Study Agent Accountability Procedures ............................................................................................ 33 
CHAPTER 5: TESTING PROCEDURES ........................................................................................................ 34 
5.1 Procedures at Study Visits ................................................................................................................. 34 
5.2 Definition of Success / Failure .......................................................................................................... 36 
5.3 Side Effects of Bevacizumab ............................................................................................................. 36 
5.4 Additional Examinations ................................................................................................................... 36 
5.5 Additional Treatment ......................................................................................................................... 36 
CHAPTER 6: UNANTICIPATED PROBLEM AND ADVERSE EVENT REPORTING ....................................... 37 
6.1 Unanticipated Problems ..................................................................................................................... 37 
6.2 Adverse Events .................................................................................................................................. 37 
 Definitions ................................................................................................................................... 37 
 Reportable Adverse Events ......................................................................................................... 38 
 Relationship of Adverse Event to Study Treatment or Study Procedure .................................... 38 
 Severity (Intensity) of Adverse Event ......................................................................................... 38 
 Expectedness ............................................................................................................................... 39 
 Coding of Adverse Events ........................................................................................................... 39 
 Outcome of Adverse Event ......................................................................................................... 39 
6.3 Timing of Event Reporting ................................................................................................................ 40 
6.4 Safety Oversight ................................................................................................................................ 40 
6.5 Stopping Criteria ............................................................................................................................... 41 
 Participant Discontinuation of Study Drug ................................................................................. 41 
 Criteria for Suspending or Stopping Overall Study ..................................................................... 41 
6.6 Unmasking due to Adverse Event ..................................................................................................... 41 
CHAPTER 7: MISCELLANEOUS CONSIDERATIONS ................................................................................... 42 
7.1 Collection of Medical Conditions and Medications .......................................................................... 42 

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7.2 Prohibited Medications, Treatments, and Procedures ....................................................................... 42 
7.3 Precautionary Medications, Treatments, and Procedures .................................................................. 42 
7.4 Participant Compensation .................................................................................................................. 42 
7.5 Participant Withdrawal ...................................................................................................................... 42 
7.6 Confidentiality ................................................................................................................................... 42 
7.7 Contact Information Provided to the Coordinating Center ................................................................ 42 
CHAPTER 8: STATISTICAL CONSIDERATIONS .......................................................................................... 44 
8.1 Statistical and Analytical Plans ......................................................................................................... 44 
8.2 Study Objectives and Hypothesis ...................................................................................................... 44 
 Classification of Success/Failure by 4 Weeks Post-Injection...................................................... 44 
 Within Dose Groups ........................................................................................................... 44 
 Between Dose Groups ......................................................................................................... 44 
8.3 Additional Analyses Within Each Dose Cohort ................................................................................ 45 
 Baseline Characteristics ............................................................................................................... 45 
 At 2 and 4 Months Post-injection, and 6 and 12 Months Corrected Age .................................... 45 
 At 24 Months Corrected Age Only.............................................................................................. 47 
 Plasma Levels of VEGF .............................................................................................................. 47 
8.4 Additional Analyses Between Dose Cohorts ..................................................................................... 48 
8.5 Safety ................................................................................................................................................. 48 
 Power for Analysis of Adverse Effects ....................................................................................... 48 
8.6 Sample Size ....................................................................................................................................... 49 
8.7 Sensitivity Analyses for Primary Outcome ....................................................................................... 49 
 Tipping point analysis for Imaging / second ocular exam ........................................................... 49 
 Deaths as Failures ........................................................................................................................ 50 
8.8 Planned Interim Analyses .................................................................................................................. 50 
CHAPTER 9: DATA COLLECTION AND MONITORING .............................................................................. 51 
9.1 Case Report Forms and Data Collection ........................................................................................... 51 
9.2 Study Records Retention ................................................................................................................... 51 
9.3 Quality Assurance and Monitoring .................................................................................................... 51 
9.4 Protocol Deviations ........................................................................................................................... 52 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 53 
10.1 Ethical Standard ............................................................................................................................... 53 
10.2 Institutional Review Boards ............................................................................................................ 53 
10.3 Informed Consent Process ............................................................................................................... 53 
 Consent Procedures and Documentation ................................................................................... 53 

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 Participant and Data Confidentiality ......................................................................................... 53 
 Future Use of Stored Specimens and Data ................................................................................ 54 
CHAPTER 11: REFERENCES ....................................................................................................................... 55 
 
 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
ATS-HOTV 
Amblyopia Treatment Study – HOTV Visual Acuity Testing Protocol  
BEAT-ROP 
Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
D 
Diopter 
DD 
Disc Diopter 
DHHS 
Department of Health and Human Services 
DSMC 
Data safety and monitoring committee 
eCRF 
Electronic Case Report Form  
EDC 
Estimated Date of Confinement 
ETROP 
Early Treatment for ROP 
EVA 
Electronic Visual Acuity Tester 
FA 
Fluorescein Angiography 
FDA 
Food and Drug Administration 
FDR 
False Discovery Rate 
GCP  
Good clinical practice 
GEE 
Generalized Estimation Equations 
ICH 
International Council for Harmonization 
ICROP 
International Classification of ROP 
IND 
Investigational New Drug Application  
IRB 
Institutional Review Board 
IQ 
Intelligence Quotient 
ITT 
Intention to Treat 
IUGR 
Intrauterine growth restriction 
JCHR 
Jaeb Center for Health Research  
NIH 
National Institutes of Health 
OCT 
Optical Coherence Tomography 
OSHA 
Occupational Safety and Health Administration 
PACT 
Prism and Alternate Cover Test 
PEDIG 
Pediatric Eye Disease Investigator Group  
PMA 
Post-menstrual age 
QA 
Quality assurance 
QC 
Quality control 
RBM 
Risk based monitoring 
RCT 
Randomized clinical trial 
ROP 
Retinopathy of Prematurity 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation 
SE 
Spherical equivalent refractive error (Sphere + ½ Cylinder) 
US 
United States 
VEGF  
Vascular endothelial growth factor 
 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: Bevacizumab Treatment for Posterior Zone I Retinopathy of Prematurity 
(ROP4) 
I have read the protocol specified above. In my formal capacity as a Site Principal Investigator, 
my duties include ensuring the safety of the study participants enrolled under my supervision and 
providing the Jaeb Center for Health Research, which serves as the Coordinating Center for the 
protocol, with complete and timely information, as outlined in the protocol. It is understood that 
all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
required by the following United States (US) Code of Federal Regulations (CFR) applicable to 
clinical studies: 45 CFR Part 46 (protection of human subjects), 21 CFR Part 50 (informed 
consent and safeguards for children), 21 CFR Part 56 (institutional review boards), and 21 CFR 
Part 312 (FDA investigational new drug application). 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) 
to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and Good Clinical Practice Training. Further, 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
 
dd 
mmm 
yyyy 
Investigator’s Name: ____________________________________ 
Site Name / Number: ____________________________________ 
 
 
 

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PROTOCOL SUMMARY 
ITEM 
DESCRIPTION 
Title 
Bevacizumab Treatment for Type I Retinopathy of Prematurity (ROP4) 
Précis 
Type 1 retinopathy of prematurity in zone I represents the most severe type of ROP 
and has the worst prognosis.  It is unknown whether low-dose bevacizumab will be 
successful in these severe cases.  Also unknown is the timing and extent of 
peripheral retinal vascularization after low-dose bevacizumab compared with the 
standard dose. The current study will evaluate whether doses of 0.063 mg and 
0.25mg are effective as treatment for type 1 ROP in zone I.  
Investigational Drug 
Bevacizumab. 
Objectives 
The primary objective of the current protocol is to evaluate whether doses of 0.063 
mg and 0.25mg are effective as treatment for type 1 ROP in zone I. Secondary 
objectives are to compare 1) safety and efficacy, 2) refractive outcomes, and 3) the 
extent of retinal vascularization at 4 months post-injection between the two dose 
groups. 
Study Design 
Multicenter, randomized clinical trial.  
Number of Sites 
Up to forty (40) clinical sites in the North America  
Outcomes 
Primary Efficacy Outcome 
Treatment success, determined at 4 weeks, post injection, and meeting all the 
following criteria: 
• 
Improvement by the 4-day exam (3 to 5 days) 
• 
No recurrence of type 1 ROP within 4 weeks of injection 
• 
No severe neovascularization requiring additional treatment within 4 
weeks of injection. 
 
Secondary Efficacy Outcomes 
• 
Number of re-treatments 
• 
Number and types of ocular complications 
• 
Extent of retinal vascularization at 2 and 4-months post-injection 
• 
Neurodevelopment, by General Movements Assessment 
• 
Ocular alignment at 6, 12, and 24-months corrected age 
• 
Refractive error at 6, 12, and 24-months corrected age Vision at 6, 12, 
and 24-months corrected age Ocular exam findings at 6, 12, and 24-
months corrected age 
• 
Bayley-4 Scales of Infant and Toddler Development at 24-months 
corrected age 
 
Key Safety Outcomes 
• 
Proportion with at least 1 adverse event 
• 
Proportion with at least 1 adverse event related to study drug 
• 
Proportion with serious adverse events 
• 
Proportions of infant deaths 
• 
Complications after 4-week exam 
• 
Neurodevelopment, by General Movements Assessment 
 

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ITEM 
DESCRIPTION 
Population 
Key Inclusion Criteria: 
1. 
Birth weight < 1251 grams 
2. 
Newly diagnosed (within 2 days) type 1 ROP in zone I in one or both 
eyes 
Key Exclusion Criteria: 
1. 
Previous treatment for ROP 
2. 
Stage 4 or 5 ROP in either eye 
3. 
Treatment could not be done within 2 days of diagnosis of type 1 ROP 
4. 
Investigator unwilling to randomize or parent unwilling to accept random 
assignment to either treatment 
5. 
Transfer to another hospital not covered by study-certified examiners 
anticipated within the next 4 weeks 
6. 
Active ocular infection or purulent nasolacrimal duct obstruction 
 
Eye excluded (but the other eye may be eligible) if: 
7. 
Visually significant ocular anomaly (e.g., cataract, coloboma) 
8. 
Opacity that precludes an adequate view of the retina 
 
Sample Size 
A sample size of up to 80 participants (40 in each treatment group) is a convenience 
sample.  The study is not powered to evaluate a difference between dose levels.   
 
Phase 
Phase II Randomized Clinical Trial 
 
Treatment Groups 
Participants will be randomly assigned with equal probability to treatment of one or 
both eyes with type 1 ROP to either: 
1. 
Intravitreous bevacizumab 0.063 mg 
2. 
Intravitreous bevacizumab 0.25 mg 
 
Participant Duration 
Study exams will occur at 1 day, 1, 2, 3, and 4 weeks, and at 2 and 4-months post-
treatment. If type 1 ROP is still present at day 1, then an exam will occur at 4 days 
post-injection. Additional study exams will occur at ages (chronological age minus 
number of weeks born prematurely) of 6, 12, and 24 months. It is anticipated that 
non-study visits will occur more frequently, and the timing of these will be at 
investigator discretion. 
Protocol Overview/Synopsis 
Infants with type 1 ROP and no prior treatment for ROP will be randomly assigned 
(1:1) to treatment with either intravitreous bevacizumab 0.063 mg or either 
intravitreous bevacizumab 0.25 mg. Study exams will be at 1 day, 4 days (if no 
improvement on day 1), 1, 2, 3, and 4 weeks, and at 2 and 4-months post-treatment. 
Additional study exams will occur at corrected age 6 and 12 months. Non-study 
examinations will be at clinician discretion and are likely to occur more often. The 
primary outcome will be treatment success within each dose group, defined as 
improvement by the day 4 exam and no recurrence of type 1 ROP or severe 
neovascularization requiring additional treatment within 4 weeks of injection. 
Important secondary outcomes include safety and efficacy. refractive outcomes, 
and the extent of retinal vascularization at 2- and 4-months post-injection in each of 
the two dose groups. 

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STUDY SUMMARY FLOWCHART 
 
 
 
If NOT Eligible, Study Ends / 
Not Randomized 
Enrollment 
• 
Informed Consent  
• 
Eye Exam 
• 
One or both eyes with type 1 ROP in Zone 
1 
• 
Newly diagnosed within 2 days 
• 
No previous treatment for ROP 
If Eligible,  
RANDOMIZE 
No improvement 
4-Day Examination 
1-Day Examination 
Improvement 
1-Week Post-Injection Examination 
2-Week Post-Injection Examination 
3-Week Post-Injection Examination 
4-Week Post-Injection Examination (Primary Outcome) 
2-Month Post-Injection Examination 
4-Month Post-Injection Examination 
6-Month  Corrected Age Examination 
BEVACIZUMAB 0.063mg 
• 
As soon as possible, within 2 days of diagnosis. 
• 
Treatment with intravitreous bevacizumab 0.063mg 
• 
BEVACIZUMAB 0.25 mg 
• 
As soon as possible, within 2 days of diagnosis. 
• 
Treatment with intravitreous bevacizumab 0.25mg 
24-Month Corrected Age Examination 
12-Month Corrected Age Examination 

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SCHEDULE OF STUDY VISITS AND PROCEDURES 
 
 
Enroll 
1d 
4d 
1w* 
2w* 
3w* 
4w* 
2m* 
4m* 
6m† 
12m† 
24m† 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Ocular History 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ocular Exam/Classify ROP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Ocular Exam 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Retinal Imaging 
Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
Extent of Retinal Vascularization 
 
 
 
 
 
 
 
X 
X 
 
 
 
General Movements Assessment 
 
 
 
 
 
 
 
 
Xc 
 
 
 
Cycloplegic Refraction 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Vision Assessment 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Data on Additional treatments 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
Xd 
Xd 
Xc 
Xd 
Xd 
Xd 
Xe 
Xe 
Xe 
Xe 
Xe 
Systemic Outcomes 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Bayley-4 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional: 
 
 
 
 
 
 
 
 
 
 
 
 
Fluorescein Angiography  
Xb 
 
 
 
 
 
 
 
 
 
 
 
OCT 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Plasma VEGF 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
*Exams through 4 months are timed based on initial treatment (and re-treatment when indicated).  
†Exams 6 months and beyond are based on corrected age. There will be a check-up/retention call between the 12m and 24m visits. 
 
a Medical and ocular history to include concomitant medications and pre-existing medical conditions at time of enrollment   
b Retinal imaging done at enrollment, and prior to any additional treatment. Imaging is also done at 4-months if no additional treatment 
is planned. OCT and FA is optional. 
c General Movements Assessment will be recorded at home by parent(s) at 54 (52-56) weeks PMA. Sites will contact the parents to 
remind them to film the GMA. 
d All adverse events recorded at each visit until 4 weeks post-treatment  
e Only serious adverse events and ocular adverse events recorded beyond 4 weeks post-treatment  
 
 

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Chapter 1: Background Information 
1.1 Introduction 
 
 Retinopathy of Prematurity 
Retinopathy of prematurity (ROP) is a significant cause of childhood vision loss in the United 
States.1  It is characterized by retinal vascular abnormal alterations that may occur during the 
first several months after premature delivery. The vascular changes may be mild and regress with 
time, or they may continue to progress to preretinal neovascularization and fibrosis that may 
ultimately lead to retinal traction and detachment. Other sequelae include tortuosity of the retinal 
vessels, dragged retina, displacement of the macula, temporal folds of the retina, equatorial folds, 
chorioretinal scarring, retinal pigment abnormalities, retinoschisis, Coats'-like changes, increased 
incidence of lattice degeneration, vitreous hemorrhage, elevated retinal vessels, vitreous 
membranes, exudative and tractional retinal detachments, retinal breaks, amblyopia, myopia, 
strabismus, glaucoma, cataract, band keratopathy, microphthalmia, nystagmus, shallow anterior 
chamber, and steep corneal curvature.2-13  
 
Important risk factors for ROP include low birth weight, young gestational age, twin status, 
outborn status, and supplemental oxygen. Despite the judicious use of supplemental oxygen and 
effective screening and management of ROP in most developed countries, it continues to be a 
significant cause of visual impairment. Severe visual loss is particularly common in middle 
income countries such as China and India.1,14 In severe cases of ROP, vascular endothelial 
growth factor (VEGF) accumulates in the retina and vitreous, leading to retinal 
neovascularization and cicatrization. Peripheral retinal photocoagulation destroys the avascular 
retina that produces VEGF. More recently, treatments have targeted blockade of pro-angiogenic 
growth factors, such as vascular endothelial growth factor (VEGF). Anti-VEGF treatment of 
severe ROP may provide a more direct and effective approach to reducing intraocular VEGF 
levels and preventing retinal detachment. One such anti-VEGF antibody is bevacizumab, which 
binds several VEGF isoforms. Bevacizumab (trade name Avastin®; Genentech, Inc., South San 
Francisco, CA) is a humanized monoclonal antibody which binds to VEGF, prevents coupling of 
VEGF to its receptor, and inhibits angiogenesis. Initially approved by the FDA for anti-
angiogenic treatment of metastatic colorectal cancer, bevacizumab is used increasingly in the US 
and abroad as an off-label treatment for severe (type 1) ROP, given by intravitreous injection at a 
small fraction of the systemic dose for cancer. Intravitreous injection of bevacizumab is also 
used in the treatment of other ocular diseases involving neovascularization, including age-related 
macular degeneration and diabetic retinopathy. 
 
Examination findings in ROP are classified according to the international classification of ROP 
(ICROP)15 and the revised ICROP.16  Zone refers to location of disease, from zone I (most 
posterior) to zone III (most anterior). Stage refers to activity at the vascular/avascular border. 
Stage 1 is a demarcation line, stage 2 is a ridge, stage 3 is neovascular tissue, stage 4 is partial 
retinal detachment, and stage 5 is total retinal detachment. Plus disease is dilation and tortuosity 
of the posterior retinal vessels meeting or exceeding the amount seen in a standard photograph 
that has been used in many clinical trials. The Early Treatment for ROP (ETROP) study 
established “type 1 ROP” as the degree of disease severity for which treatment with laser is 

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indicated. Type 1 ROP is defined as any stage ROP in zone I with plus disease, stage 2 or 3 ROP 
in zone II with plus disease, or stage 3 ROP in zone I without plus disease.17 
 
 Clinical Studies of ROP Treatment 
The CRYO-ROP Study first demonstrated the effectiveness of peripheral retinal ablation in 
curtailing progression of ROP to cicatricial stages.18 However, the impact of peripheral retinal 
ablation on visual outcome was less dramatic than the structural benefit. The ETROP Study 
showed that treatment of eyes at high-risk prethreshold resulted in better visual and structural 
outcomes than treatment at threshold.17  Based on these results, laser was established as the 
standard of care in the US for treatment of type 1 ROP. Although laser usually prevents retinal 
detachment, it does not promote ongoing retinal vascular development, leaving areas of 
avascular peripheral retina which seem to be nonfunctional. Also, visual impairment and high 
myopia are common outcomes even among those infants successfully treated with laser.19,20 
Finally, although peripheral retinal ablation significantly reduces the incidence of retinal 
detachment and blindness, fewer than 20% of 5½ year old children whose eyes reached threshold 
for treatment in the CRYO-ROP study achieved 20/40 vision.21 In the ETROP Study, only about 
35% of children had visual acuity better than 20/40, even with earlier treatment.22 Many 
premature infants treated for ROP also develop other significant ocular defects. These data, 
coupled with improved survival rates of very low birth weight infants, support the need to 
develop better treatment strategies for severe ROP.  
 
In the past decade, intravitreous injections of anti-VEGF drugs have been used increasingly to 
treat severe ROP. The most commonly used agent is bevacizumab, and several case series and 
results from one randomized trial have shown that bevacizumab is effective in treating severe 
ROP.23-31 The BEAT-ROP study (Bevacizumab Eliminates the Angiogenic Threat of 
Retinopathy of Prematurity) was a randomized trial of bevacizumab monotherapy versus 
conventional laser therapy for zone I and posterior zone II, stage 3+ ROP.23 The primary 
outcome was recurrence of ROP in one or both eyes requiring retreatment before 54 weeks’ 
postmenstrual age. ROP recurred in 4 of 70 infants (6%) in the bevacizumab group and 19 of 73 
infants (26%) in the laser group (P = 0.002). When stratified by zone, results suggested a benefit 
of bevacizumab treatment over conventional laser therapy for zone I ROP but not for zone II 
ROP. In addition, high myopia was much less common after bevacizumab compared with laser. 
Among nonrandomized studies, Wu et al found that 37 of 41 eyes (90%) with stage 3 ROP 
regressed after a single bevacizumab injection. Four eyes required additional laser treatment, and 
4 eyes had a vitreous or pre-retinal hemorrhage.26  Quiroz-Mercado et al observed neovascular 
regression in 17 of 18 eyes with high-risk prethreshold, threshold, or stage 4 ROP after 
intravitreous bevacizumab.28 Travassos et al injected the worse eye of three patients with 
aggressive, posterior retinopathy of prematurity with 0.75 mg of bevacizumab as monotherapy or 
complementary to laser therapy. All injected eyes showed rapid regression of tunica vasculosa 
lentis and iris vessel engorgement, disappearance of iris rigidity, and regression of plus disease 
and retinal proliferation.30 
 
The RAINBOW study randomized 225 infants with ROP to treatment with the anti-VEGF agent 
ranibizumab 0.2 mg, ranibizumab 0.1 mg, or laser therapy.32 The primary outcome, treatment 
success, was defined as survival with no active retinopathy, no unfavorable structural outcomes, 
and no need for a different treatment modality at or before 24 weeks. Treatment success occurred 

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in 56 (80%) of 70 infants receiving ranibizumab 0.2 mg compared with 57 (75%) of 76 infants 
receiving ranibizumab 0.1 mg and 45 (66%) of 68 infants after laser therapy. The odds ratio 
(OR) of treatment success following ranibizumab 0.2 mg compared with laser was 2.19 (95% Cl 
0.99−4.82, p=0.051), for ranibizumab 0.1 mg compared with laser the OR was 1.57 (95% Cl 
0.76−3.26); for ranibizumab 0.2 mg compared with 0.1 mg the OR was 1.35 (95% Cl 
0.61−2.98). Death, serious and non-serious systemic adverse events, and ocular adverse events 
were evenly distributed between the three groups. 
 
 Phase 1 Dosing De-escalation Study 
BEAT-ROP used a dose of 0.625 mg, which was chosen empirically as half of the adult dose. 
Other investigators have used doses of bevacizumab between 0.25 mg and 0.625 mg.23  
However, these doses are likely much higher that necessary to effectively treat ROP. In addition, 
intravitreous bevacizumab reaches the systemic circulation, with large and persistent reductions 
in serum VEGF levels,33 raising concerns about potential systemic harm. VEGF is necessary for 
normal development of many tissues, including brain, lungs, bones, kidneys, and retina; thus, 
blocking VEGF’s action could be detrimental to premature infants. In particular, there is concern 
that anti-VEGF drugs increase the risk for neurodevelopmental disability.34,35  
 
To determine whether a much lower dose of bevacizumab than previously used may be effective 
in treating severe ROP, PEDIG conducted a masked, multicenter, dose de-escalation phase 1 
study.31 Success was defined as improvement in preinjection plus disease or zone I stage 3 ROP 
by 5 days after injection or sooner, and no recurrence of type 1 ROP or severe neovascularization 
requiring additional treatment within 4 weeks. One hundred twenty premature infants with type 1 
ROP were enrolled and treated, and success was achieved in 11 of 11 eyes at 0.25 mg, 14 of 14 
eyes at 0.125 mg, 21 of 24 eyes at 0.063 mg, 9 of 9 eyes at 0.031 mg, 13 of 13 eyes at 0.016 mg, 
9 of 9 eyes at 0.008 mg, and 9 of 10 eyes at 0.004 mg; but success was achieved in only 17 of 23 
eyes (74%) receiving 0.002 mg.36 These data were analyzed using a Bayesian statistical model, 
and it was calculated that there is a 94% probability that 0.063 mg is at least 95% effective in 
treating type 1 ROP. The probability that 0.125mg is at least 95% successful is 99%.  
 
1.2 Study objectives 
The primary objective of the current protocol is to evaluate whether doses of 0.063 mg and 
0.25mg are effective as treatment for type 1 ROP in zone I. Secondary objectives are to compare 
1) safety and efficacy, 2) refractive outcomes, and 3) the extent of retinal vascularization at 4 
months post-injection between the two dose groups.  
 
1.3 Rational for the Current Study 
Type 1 retinopathy of prematurity in zone I represents the most severe type of ROP and has the 
worst prognosis.  Most of these cases occur in very young infants, and many have a rapid onset 
of plus disease.  Some of these infants meet criteria for APROP (Aggressive Posterior ROP).  It 
is unknown whether low-dose bevacizumab will be successful in these severe cases.  Also 
unknown is the timing and extent of peripheral retinal vascularization after low-dose 
bevacizumab compared with the standard dose. The ROP1 study had an insufficient number of 
zone I cases to evaluate these questions. 
 

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1.4 Potential Risks and Benefits of Bevacizumab 
 
 Known Potential Risks of Bevacizumab 
Little is known about the safety of using bevacizumab for ROP,37  as the BEAT-ROP study 
provided little short-term and no long-term safety data. In the BEAT-ROP study, 5 infants 
undergoing bevacizumab injection and 2 infants undergoing laser treatment died before the age 
of 54 weeks, but the study was not powered to evaluate whether the death rate was any higher 
following bevacizumab injection.23  At 2 ½ years of age the death rate was similar between 
groups, with a total of 6 infants treated with bevacizumab and 7 infants in the laser treated group 
dying prior to age 2 ½ years.38  Angiogenesis is an important process in the normal development 
of other organ systems such as the lungs, kidneys, brain, and bones. Intravitreous bevacizumab 
reaches the systemic circulation, so there is potential for negative systemic side effects. The dose 
of bevacizumab used in the BEAT-ROP study (0.625 mg in 25 µl) was chosen empirically as 
one-half the adult dose used for macular degeneration.23 Reducing the dose of bevacizumab to 
0.063 mg is expected to reduce the likelihood of negative systemic side effects.39  
 
In a meta-analysis performed by Genentech, Inc. on all clinical trial results using intravenously 
administered bevacizumab (usually dosed as 5 mg/kg every 14 days) in adults, it was found that 
adult study participants were at an increased risk for certain adverse events, some of which were 
potentially fatal. These included wound healing complications, bowel perforation, hemorrhage, 
stroke, myocardial infarction, hypertension, congestive heart failure, and proteinuria. Warnings 
and precautions included in the package insert for intravenously administered bevacizumab 
include gastrointestinal perforations, surgery and wound healing complications, hemorrhage, 
non-gastrointestinal fistula formation, arterial thromboembolic events, hypertension, reversible 
posterior leukoencephalopathy syndrome, proteinuria, infusion reactions, ovarian failure, and 
infertility in females with reproductive potential.40  
 
The safety and pharmacokinetics of bevacizumab in pediatric patients have not been 
established,40  although there is potential for similar adverse events in infants as in adults. Doses 
administered to infants for treatment of ROP (typically 0.125 mg to 0.625 mg) are lower than 
those administered to adults for treatment of ocular conditions, and much less than intravenous 
doses used for cancer treatments. A study by Sato et al found serum concentrations of 
bevacizumab following a 0.5 mg intravitreous injection for ROP were well above concentrations 
required to completely block in vitro VEGF activities in human umbilical vein endothelial 
cells.41  There was an inverse relationship between the serum bevacizumab and serum VEGF 
concentrations. Sato et al concluded that bevacizumab has the ability to cross the blood retinal 
barrier and enter the systemic circulation in relatively high concentrations.41  Others have 
reported similar effects with a lower dose (0.375 mg) of bevacizumab.42  Because of the 
vasculoproliferative role that VEGF plays in the normal development of organs, systemic 
bevacizumab presents a potential risk to the developing organs of the premature neonate.   
 
Ocular side effects have been reported after intravitreous injections of bevacizumab. In some 
cases, retinal traction may be worsened by injection of bevacizumab, leading to retinal 
detachment,43 particularly if fibrovascular tissue has already begun to form.44 Regression of ROP 
following bevacizumab treatment may in some cases be transient, with recurrence of ROP 
occurring later than what is observed with laser treatment.45  Other complications observed 

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following bevacizumab treatment for ROP include cataract,46 retinal hemorrhage,25,26 transient 
vascular sheathing,26 choroidal ischemia,47 and abnormalities of the retinal periphery (large 
avascular areas, abnormal branching, shunts) and of the posterior pole (hyperfluorescent areas, 
absence of the foveal avascular zone). It is unknown if these changes will have an effect on 
vision.48    
 
It is unclear whether the mortality rate of premature infants receiving intravitreous bevacizumab 
is any higher than those treated with laser. In the BEAT-ROP study, 7 of 150 infants died prior to 
the 54-week post-menstrual age outcome examination (5 after intravitreous bevacizumab, 2 after 
laser).23 While the mortality was higher in infants receiving bevacizumab, this result was 
statistically non-significant, although it was acknowledged that the study was grossly 
underpowered to detect a difference (a sample of 2800 infants would be required to assess a 
death rate 1.5 times the 5.4% mortality rate observed in the ETROP study by 9 months at an 
alpha of 0.05 and 80% power).17  Another study reported death of 2 of 7 infants with ROP 
following a 0.75 mg bevacizumab injection, but attributed the mortality to complications of their 
previous systemic conditions.49 However, it is unclear whether systemic bevacizumab may have 
exacerbated the existing conditions, particularly in cases of multiple organ failure or lung failure. 
In the dose de-escalation phase 1 study conducted by PEDIG31 in which 120 infants were treated 
with low doses of bevacizumab ranging from 0.625 mg to 0.002 mg, 8 infants passed away 
during the study due to reasons judged by the Data Safety and Monitoring Committee to be 
unrelated to intravitreous bevacizumab. Additional dosing studies and long-term follow-up 
studies with a large number of infants are required to determine the safety of intravitreous 
bevacizumab injection for the treatment of ROP.23,37,50 
 
There are potential concerns about inhibiting VEGF in the developing infant, because drugs 
introduced into the vitreous enter the blood stream and are minimally diluted in the infant’s small 
blood volume. Testing of pharmacokinetics of bevacizumab in the blood stream is difficult even 
in animal models, because bevacizumab is a mouse monoclonal antibody and is not effective in 
mice and rats, the most commonly used models in ROP. VEGF is neuroprotective and its 
inhibition may adversely affect the developing organs, such as lung, kidney and brain.34,35 
Therefore, long-term safety data on neural structure and cognitive development are very 
important. 
 
Bevacizumab package inserts warn of the potential risk of ovarian failure and infertility in 
females with reproductive potential,40 and it is unclear if this same risk applies to female 
neonates.  
 
 Potential Adverse Effects of Intravitreous Injection 
Rarely, the topical drugs used to anesthetize the eye before the injections (proparacaine, 
tetracaine, or xylocaine) can cause an allergic reaction, seizures, and an irregular heartbeat. 
Generally, infants will have already been exposed to topical anesthetic during diagnostic 
examinations. 
 
Temporary stinging, burning and conjunctival redness may occur with the use of proparacaine. A 
rare, severe, immediate-type, apparently hyperallergic corneal reaction characterized by acute, 

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intense, and diffuse epithelial keratitis, a gray, ground glass appearance, sloughing of large areas 
of necrotic epithelium, corneal filaments and iritis with descemetitis has also been reported. 
Subconjunctival hemorrhage will commonly occur as a result of the intravitreous injection. Mild 
discomfort, ocular hyperemia, increased lacrimation, discharge, or itching lasting for a few days 
is also likely. 
 
Immediately following the injection, there may be elevation of intraocular pressure. It usually 
returns to normal spontaneously but may need to be treated with topical drugs or a paracentesis 
to lower the pressure. Indirect ophthalmoscopy is performed immediately post-injection to 
ensure adequate posterior circulation.  
 
A rare complication of injection is endophthalmitis. It can be due to infection with pathogens 
such as bacteria of fungi or can be noninfectious. Clinical features include eyelid edema, 
conjunctival injection, corneal edema, anterior chamber and vitreous inflammation and 
hypopyon. Endophthalmitis is treated by intravitreous injection of antibiotics, and there is a risk 
of permanent severe loss of vision. A meta-analysis of 24 studies in adults reporting 
endophthalmitis after intravitreous injection of an anti-VEGF agent estimated the risk of 
endophthalmitis per injection to be 0.049% (95% CI, 0.038% to 0.065%). 51 
 
Retinal detachment is a rare complication of intravitreous injection. If this occurs, surgery may 
be needed, which is usually successful at reattaching the retina. However, a retinal detachment 
can produce permanent and sometimes severe loss of vision. The risk of retinal detachment has 
been reported to be less than 0.1% in adults.52 
 
The risk of vitreous hemorrhage after intravitreous injection has been reported to be less than 1% 
in adults.52  When it occurs, it usually resolves spontaneously, but vitrectomy is sometimes 
needed, and vision loss may result in some cases. Retinal detachment and vitreous hemorrhage 
can also occur from severe ROP. 
 
Some infants have oxygen desaturations or bradycardic episodes before, during, or after the 
injection.  
 
 Known Potential Benefits of Bevacizumab 
The BEAT-ROP trial (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of 
Prematurity), was a randomized trial of bevacizumab monotherapy versus conventional laser 
therapy for zone I and posterior zone II, stage 3+ ROP.23  Results of the BEAT-ROP trial 
suggested a benefit of bevacizumab treatment over conventional laser therapy for zone I ROP. In 
addition, the incidence of high myopia was much less common after bevacizumab compared 
with laser. The authors reported that the recurrence of ROP was higher in the laser group than the 
bevacizumab group, but the outcomes from the laser treated group were much poorer than those 
reported in the Early Treatment For Retinopathy Of Prematurity Cooperative Group (ETROP) 
study.17   
 
Prior to the BEAT-ROP study, Mintz-Hittner and Kuffel reported on a retrospective, 
consecutive, noncomparative case series of moderate and severe stage 3 ROP in zone I or 
posterior zone II treated by bilateral intravitreous injections of bevacizumab.29 Eleven infants 

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received intravitreous injections of bevacizumab (0.625 mg in 0.025 mL) and never had laser 
therapy. All 22 eyes were treated successfully (no retinal detachment, macular ectopia, high 
myopia, anisometropia, or other ocular abnormalities) with only 1 injection. No complications 
(local or systemic) were encountered. They concluded that intravitreous injection of 
bevacizumab was safe and effective in treating stage 3 ROP in zone I and posterior zone II in a 
small series of patients.  
 
In a retrospective chart review of 23 consecutive eyes of 14 patients, Kusaka et al53 evaluated the 
short-term efficacy of intravitreous injections of bevacizumab for severe retinopathy of 
prematurity (ROP). Patients received an intravitreous injection of bevacizumab (0.5 mg), either 
as the initial treatment (15 eyes) or at the end of vitrectomy (eight eyes). After injection of 
bevacizumab as the initial treatment, reduced neovascular activity was seen on fluorescein 
angiography in 14 of 15 eyes. In three eyes, a tractional retinal detachment developed or 
progressed after bevacizumab injection. No other ocular or systemic adverse effects were 
identified. These results suggest that intravitreous injection of bevacizumab seems to be 
associated with reduced neovascularization without apparent ocular or systemic adverse effects, 
and is beneficial for treating severe ROP. 
 
Dorta and Kychenthal reported on a noncomparative consecutive case series 12 consecutive eyes 
of 7 premature infants with type 1 retinopathy of prematurity treated with only one intravitreous 
injection of bevacizumab (0.625mg).25 All eyes showed regression of the disease with no 
additional treatment needed. No complications attributable to the bevacizumab were seen in any 
of their patients. An epiretinal hemorrhage was seen in one eye as a consequence of the injection 
procedure. The hemorrhage spontaneously reabsorbed without consequence. The authors 
concluded that intravitreous bevacizumab is a useful therapy for type 1 ROP.  
 
Wu et al26 investigated the effects and complications of bevacizumab as treatment of ROP in 
Taiwanese patients. They reported results of a multicenter, retrospective case series study of 27 
patients (49 eyes) receiving intravitreous injections of bevacizumab (0.625 mg). Patients were 
followed for at least 6 months after bevacizumab injection. All of the eyes received only a single 
injection. A total of 37 of 41 eyes (90%) with stage 3 ROP regressed after bevacizumab injection 
only. Four eyes (10%) required additional laser treatment. Of 6 eyes (3 patients) with stage 4A 
ROP, 2 eyes (1 patient; 33%) regressed after bevacizumab injection and 4 eyes (67%) regressed 
after bevacizumab injection and subsequent vitrectomy. The 2 eyes with stage 5 ROP exhibited 
decreased vascular tortuosity after bevacizumab injection, but the retina failed to reattach after 
vitrectomy. Major complications included vitreous or pre-retinal hemorrhage in 4 eyes (8%) and 
transient vascular sheathing in 2 eyes (4%). The authors concluded that bevacizumab injection 
seems effective and well tolerated in some cases of ROP, especially in stage 3 ROP.  
 
Law et al49 reported the results of bevacizumab used in eyes with ROP at high risk for 
progression. Records of all infants with ROP treated with bevacizumab were reviewed. 
Bevacizumab was given when conventional laser therapy was not possible in patients with poor 
pupillary dilation from iris rubeosis, dense vitreous hemorrhage, or increasing vascular activity 
and vitreoretinal traction despite completed laser therapy. Thirteen eyes of 7 infants were treated 
with an intravitreous injection of 0.75 mg bevacizumab. Injection was not used as monotherapy 
in any case. Definitive treatment (laser or vitrectomy) was completed successfully within 72 

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hours of injection. No systemic complications attributable to bevacizumab treatment were 
recorded within 2 to 17 months of follow-up. The authors concluded that treatment with 
bevacizumab may be used to improve visualization for more definitive laser or surgical treatment 
and may facilitate disease regression without obvious systemic toxicity.  
 
 Risks of Examination or Testing Procedures 
There is a rare risk of an allergic response to the topical medications used to anesthetize the eye 
or dilate the pupil. There may be some redness or bleeding on the surface of the eye after the 
examination. Some infants have oxygen desaturations or bradycardic episodes during or after the 
eye exams. 
 
There are no known risks associated with OCT or fundus photographs. The bright flashes used to 
take the photographs may be annoying, but are not painful and cause no damage. 
 
For fluorescein angiography, both the skin and urine are expected to turn yellow/orange for up to 
24 hours after the injection of fluorescein dye. There is a small risk of discomfort or phlebitis at 
the site of the injection. An allergic reaction to the dye used to do the fluorescein angiography 
imaging is rare. A rash or pruritus (itching) can develop, but the incidence of true anaphylactic 
reactions is less than 0.1%.54   
 
1.5 Risk Assessment 
The Sponsor has determined that the protocol’s level of risk is consistent with 45 CFR 46.405 
and 21 CFR 50.52, which indicates research involving greater than minimal risk but presenting 
the prospect of direct benefit to the individual child involved in the research. 
 
1.6 General Considerations 
The study is being conducted in compliance with the policies described in the study policies 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
 

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Chapter 2: Study Enrollment and Screening 
1 
2.1 Participant Recruitment and Enrollment 
2 
Up to 80 participants are expected to be enrolled and have treatment randomly assigned.  As the 
3 
enrollment goal approaches, sites will be notified of the end date for recruitment. Study 
4 
participants whose parents have signed an informed consent form can be randomized (or 
5 
enrolled) up until the end date, which means the recruitment goal might be exceeded.  
6 
 
7 
Study participants will be recruited from approximately 40 clinical centers in North America. All 
8 
eligible participants will be included without regard to gender, race, or ethnicity. There is no 
9 
restriction on the number of participants to be enrolled or randomized by each site toward the 
10 
overall recruitment goal. 
11 
 
12 
 Informed Consent and Authorization Procedures 
13 
A participant will be considered for the study after undergoing a routine examination (as part of 
14 
standard care) that identifies type 1 ROP in one or both eyes that meets the eligibility criteria. 
15 
The study will be discussed with the infant’s parent(s) or guardian(s) (referred to subsequently as 
16 
parent(s)).  
17 
Potential eligibility may be assessed as part of a routine-care examination.  Before completing any 
18 
procedures or collecting any data that are not part of usual care, written or electronic informed 
19 
consent will be obtained. 
20 
A parent/legal guardian will be provided with the Informed Consent Form to read and will be given 
21 
the opportunity to ask questions. If the parent is interested in the study, the investigator will meet 
22 
with the parent to discuss the study, and if the parent agrees to participate, the Informed Consent 
23 
Form will be signed.  A copy of the signed consent form will be provided to the parent and the 
24 
original signed informed consent will be added to the participant’s study record. 
25 
As part of the informed consent process, the parent will be asked to sign an authorization for release 
26 
of personal information. The authorization form may be combined with the consent or may be on 
27 
a separate form if the site requires their own process. The investigator, or his or her designee, will 
28 
review the study-specific information that will be collected and to whom that information will be 
29 
disclosed.  After speaking with the parent, questions will be answered about the details regarding 
30 
authorization. 
31 
A participant is considered enrolled when the informed consent form has been signed and HIPAA 
32 
authorization has been provided. 
33 
2.2 Participant Inclusion Criteria 
34 
The study participant must have at least one eye meeting all of the inclusion criteria in order to 
35 
be eligible to participate.   
36 
 
37 
1. Birth weight < 1251 grams 
38 
2. Newly diagnosed (within 2 days) type 1 ROP (as defined in section 2.4.2) in zone I, in 
39 
one or both eyes 
40 
3. Parent understands the protocol and is willing to provide consent. 
41 

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42 
2.3 Participant Exclusion Criteria 
43 
Participants meeting any of the following exclusion criteria will be excluded from study 
44 
participation. 
45 
 
46 
1. Previous treatment for ROP 
47 
2. Stage 4 or 5 ROP in either eye 
48 
3. Treatment could not be done within 2 days of diagnosis of type 1 ROP 
49 
4. Investigator unwilling to randomize or parent unwilling to accept randomized 
50 
assignment to either treatment 
51 
5. Transfer to another hospital anticipated within the next 4 weeks where exams by 
52 
study-certified examiners are not available.  If hospital discharge is anticipated within 
53 
the next 4 weeks, parents unable or unwilling to return to the PEDIG site for 
54 
outpatient follow-up visits. 
55 
6. Active ocular infection or purulent nasolacrimal duct obstruction in either eye 
56 
 
57 
One eye will be excluded, and other eye may be eligible, if either of the following are present: 
58 
• Visually significant ocular anomaly (e.g., cataract, coloboma)  
59 
• Opacity that precludes an adequate view of the retina 
60 
 
61 
2.4 Data Collection and Examination at Enrollment 
62 
 
63 
 Historical Information 
64 
Historical information recorded at enrollment will include gestational age at birth, birth weight, 
65 
current weight, head circumference, gender, race, ethnicity, concurrent medical conditions (e.g. 
66 
intraventricular hemorrhage, periventricular leukomalacia, hydrocephalus), and current 
67 
medications.   
68 
 
69 
 ROP Classification 
70 
Classification of ROP on day of examination when type 1 ROP is diagnosed: 
71 
ROP will be classified by the investigator using the revised International Classification of 
72 
Retinopathy of Prematurity (ICROP) criteria.55,56   
73 
 
74 
Location, extent, and stage of disease, as well as presence of pre-plus, plus disease, or aggressive 
75 
posterior ROP, will be recorded as follows: 
76 
 
77 
Location: Location will be recorded as follows:  
78 
• Zone I: circle centered on the optic nerve with a radius of twice the distance from 
79 
the center of the optic nerve to the center of the macula  
80 
• Zone II: extends centrifugally from the edge of zone I to the nasal ora serrata and 
81 
is concentric to zone I 
82 
• Zone III:  residual crescent of retina anterior to zone II 
83 
 
84 
Stage: Disease stage will be recorded as stages 0-5 as defined:  
85 
• Stage 0: Incomplete retinal vascularization without demarcation line or ridge 
86 
• Stage 1: Demarcation line 
87 

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• Stage 2: Ridge  
88 
• Stage 3: Extraretinal fibrovascular proliferation  
89 
• Stage 4: Partial retinal detachment. Stage 4 will be further classified based on 
90 
location of the partial retinal detachment (not eligible): 
91 
o Stage 4A: Extrafoveal  
92 
o Stage 4B: Foveal  
93 
• Stage 5: Total retinal detachment (not eligible) 
94 
 
95 
Extent of Disease (clock hours): Extent of the highest stage will be recorded in 30-degree 
96 
increments, or clock hours. 
97 
 
98 
Extent of Retinal Vascularization: The extent of retinal vascularization in each quadrant will be 
99 
classified as:  
100 
• Posterior Zone I - when optic nerve is centered using a 28D lens, no retinal vessels 
101 
extend even to the edge of the lens view 
102 
• Anterior Zone I - when optic nerve is centered using a 28D lens, retinal vessels extend to 
103 
the edge of the lens view or beyond (when placing the optic nerve at the edge of the view 
104 
with a 28D lens, and the other lens edge approximates the zone I – zone II border)  
105 
• Posterior Zone II - posterior one-third of zone II 
106 
• Mid Zone II - mid one-third of zone II 
107 
• Anterior Zone II - anterior one-third of zone II 
108 
• Zone III - vascularized to within one-disc diameter of the ora serrata nasally, but not 
109 
temporally   
110 
• Full Vascularization - within one-disc diameter of the ora serrata 
111 
 
112 
Plus Disease: A diagnosis of plus disease is made when there is abnormal dilation and tortuosity 
113 
of retinal blood vessels in zone I, and the degree of abnormality meets or exceeds that shown in 
114 
representative photographs of plus disease from ICROP3.57  
115 
 
116 
Pre-plus Disease: A diagnosis of pre-plus disease will be made when there is abnormal dilation 
117 
and tortuosity, but it is insufficient for plus disease. 
118 
 
119 
Type 1 ROP is the degree of disease severity for which treatment is indicated. It is defined as: 
120 
• Zone I, any stage ROP with plus disease, or 
121 
• Zone I, stage 3 ROP without plus disease, or 
122 
• Zone II, stage 2 or 3 ROP with plus disease (zone II is not eligible for this study) 
123 
 
124 
 Retinal Images 
125 
Wide-angle retinal images will be obtained after enrollment and at the time of any additional 
126 
treatment.  Imaging will be done at 4 months post-injection if no additional treatment is planned, 
127 
such as prophylactic laser.  Six images will be obtained for each eye: anterior segment, posterior 
128 
pole, superior, temporal, inferior, and nasal as described in the ROP Procedures Manual.  These 
129 
images will later be reviewed by masked expert readers for purposes of quality control. 
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Investigators will be informed throughout the study if their clinical diagnoses disagree with those 
131 
of expert readers. 
132 
 
133 
If a participating site or location does not have a retinal camera, a second examination will be 
134 
done by a study-certified examiner after enrollment and if there is treatment failure to assess the 
135 
location, extent, and stage of disease, as well as presence of pre-plus or plus disease.  Results of 
136 
this exam will only be used for quality control, similar to review of retinal images.  
137 
 
138 
 Optional Imaging 
139 
Optical Coherence Tomography (OCT) and Fluorescein Angiography (FA) will be offered as an 
140 
optional part of the study at sites with those imaging capabilities. OCT and/or FA imaging will 
141 
occur at enrollment and at the time of any additional treatment as described in the ROP 
142 
Procedures Manual.  OCT and/or FA will also be done at 4 months post-injection if no additional 
143 
treatment is planned, such as prophylactic laser.   
144 
 
145 
 Optional Blood Collection 
146 
The parents of each infant enrolled in the study will be given the option to participate in a study 
147 
to measure plasma levels of VEGF for both groups. Participants in this optional study will have 
148 
blood collected at enrollment, 2 weeks, 4 weeks, and 4 months post-injection.  Scavenged blood 
149 
may be used when feasible. Parents will be asked for permission to use these blood samples for 
150 
future biomarker studies. A single, centralized laboratory will be used for VEGF measurements, 
151 
and details of sample management will be included in the manual of procedures. 
152 
 
153 
2.5 Randomization 
154 
Eligible participants will be randomly assigned with equal probability to receive either: 
155 
  
156 
• Intravitreous bevacizumab 0.063 mg, or  
157 
• Intravitreous bevacizumab 0.25 mg 
158 
 
159 
If both eyes are eligible, then both will receive the assigned treatment.  If one eye is eligible and 
160 
the fellow eye is not, then the eligible eye will receive the randomized treatment.  If the fellow 
161 
eye requires treatment at the same time or within 4 weeks of the first eye (based on investigator 
162 
judgement), then the fellow eye will receive the same treatment and dose as the first eye unless 
163 
the first eye has met failure criteria, then treatment of both eyes is at investigator discretion.  
164 
 
165 
Randomization will be stratified by gestational age (< 25 weeks and zero days vs > 25 weeks and 
166 
one day). 
167 
 
168 
Once a study participant is randomized, that participant will be included regardless of whether 
169 
the assigned treatment is received. Thus, the investigator must not proceed to randomize an 
170 
individual until they confirm that the individual is eligible and the parent(s) will accept 
171 
whichever treatment group is assigned through randomization.
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Chapter 3: Randomized Trial Procedures 
173 
 
174 
3.1 Bevacizumab Dose and Injection 
175 
The study is being conducted under Investigational New Drug Application (IND-122552) as 
176 
intravitreal injection of bevacizumab for ROP in children is not FDA approved. 
177 
 
178 
All participants will receive a single intravitreal injection of bevacizumab in one or both eyes 
179 
following enrollment into the study.  The injection/s should be given as soon as possible but no 
180 
later than 2 calendar days after the diagnosis of type 1 ROP meeting all of the inclusion criteria 
181 
and none of the exclusion criteria.    
182 
 
183 
Eyes meeting eligibility criteria will receive a single dose of 0.063 mg or 0.25mg bevacizumab 
184 
provided by the pharmacy at the investigator’s institution.  A coordinator at each site will be 
185 
unmasked to dosage as they will be required to process the prescription/s to the pharmacy per 
186 
their usual institutional ordering mechanism.  The pharmacy will prepare the bevacizumab in a 
187 
sterile manner, adhering to USP 789, 797, and 800 standards.  Syringes containing bevacizumab 
188 
at the appropriate study concentration will be prepared.  If one eye is injected, then two syringes 
189 
will be prepared.  If two eyes are injected, then four syringes will be prepared.  One syringe will 
190 
serve as a backup and will only be used if the other syringe is compromised for any reason; 
191 
otherwise, the backup syringe will be discarded if unused.  The investigator at the site will be 
192 
masked to the dosage level.   
193 
 
194 
 Bevacizumab Injection 
195 
The bevacizumab injection(s) will be given preferably within 24 hours, but no later than 2 days, 
196 
after the diagnosis of type 1 ROP.  The ophthalmologist may choose to give the intravitreal 
197 
injection(s) in the operating room or at the bedside, with or without anesthesia given after 
198 
consultation with the institutional neonatologist.  A binocular indirect ophthalmoscope with an 
199 
appropriate condensing lens will be available, and the pupils will be dilated. 
200 
 
201 
If only one eye is to be treated, the treating investigator and a second person will review the 
202 
Bevacizumab Study Syringe Label to confirm which eye will receive the intravitreal injection. 
203 
 
204 
Prior to injection, it should be confirmed that the label information on the study syringe to be 
205 
used for injection matches the information on the Bevacizumab Study Syringe Preparation Form.  
206 
 
207 
The investigator who gives the injection must have previous experience giving intravitreal 
208 
injections.   
209 
 
210 
The injection will be done as outlined in the ROP Procedures Manual. 
211 
 
212 
3.2 Treatment for ROP 
213 
If both eyes are eligible, then both will receive the assigned treatment.  If one eye is eligible and 
214 
the fellow eye is not, then the eligible eye will receive the randomized treatment.  If the fellow 
215 
eye requires treatment within 4 weeks of the first eye (i.e., has type 1 ROP, or, in the 
216 
investigator’s judgment, requires treatment for ROP), then the fellow eye will receive the same 
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treatment and dose as the first eye unless the first eye has met failure criteria, then treatment of 
218 
both eyes is at investigator discretion.  
219 
 
220 
After 4 weeks, treatment will be at investigator discretion.  Examinations in addition to those 
221 
listed in 3.3 will be at investigator discretion. 
222 
 
223 
3.3 Exam Schedule 
224 
The exam schedule is as follows: 
225 
 
226 
Table 1: Visit Schedule 
227 
Visit 
Target Day 
Target 
Window 
(Around 
Target Day) 
Allowable Window 
(Around 
Target  
Day) 
ROP diagnosis 
Enrollment / Randomization 
N/A 
N/A 
N/A 
Randomized Treatment 
Day of Randomization 
+ 1 day 
+ 2 days 
1-day post-injection 
Treatment Date + 1 day 
0 days 
0 to 3 days 
4-day post-injection if no 
improvement at 1-day 
Treatment Date + 4 days 
3 to 5 days 
3 to 5 days 
1 week post-injection 
Treatment Date + 1 week 
6 to 8 days 
6 to 10 days 
2 weeks post-injection 
Treatment Date + 2 weeks 
11 to 17 days 
11 to 17 days 
3 weeks post-injection 
Treatment Date + 3 weeks 
18 to 24 days 
18 to 24 days 
4 weeks post-injection 
(primary outcome) 
Treatment Date + 4 weeks 
25 to 31 days 
25 to 53 days 
2 months post-injection 
Treatment Date + 2 months 
54 to 68 days 
39 to 83 days 
4 months post-injection 
Treatment Date + 4 months 
115 to 129 
days 
84 to 168 days 
6 months corrected age 
EDC + 6 months 
169 to 197 
days 
124 to 242 days 
12 months corrected age 
EDC + 12 months 
335 to 395 
days 
243 to 547 days 
24 months corrected age 
EDC + 24 months 
700 to 760 
days 
548 to 912 days 
6,12, and 24 months visits are calculated post corrected age (defined as number of days since the 
228 
date of birth minus number of days the baby was preterm). 
229 
 
230 
If any study-mandated examination is deferred because of an infant’s unstable medical status, 
231 
then that examination will be done as soon as possible. 
232 
 
233 
The goal will be for all participants to complete all scheduled visits.  However, participants who 
234 
(because of unforeseen circumstances) are unable or unwilling to return for all follow-up visits 
235 
will be permitted to return for key visits only as an alternative to withdrawal from the study.  When 
236 
a participant is placed into this status, missed visits will not be recorded as protocol deviations 
237 
(since they would not be recorded as protocol deviations if the participant was dropped from the 
238 
study). 
239 
 
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Additional office visits may occur as needed. 
241 
 
242 
3.4 Non-Case Report Form Data Access 
243 
Participants will be able to access GMA results via reports from the patient menu. Sites can 
244 
request optional blood test results from the coordinating center. 
 
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Chapter 4: Study Drug 
246 
 
247 
4.1 Study Agent(s) and Control Description 
248 
 
249 
 Acquisition 
250 
Intravitreous bevacizumab will be provided by the pharmacy at the investigator’s institution. 
251 
 
252 
 Formulation, Appearance, Packaging, and Labeling 
253 
Syringes containing bevacizumab at the appropriate study concentration will be prepared by the 
254 
pharmacy at the investigator’s institution. If one eye is injected, then two syringes will be 
255 
prepared. If two eyes are injected, then four syringes will be prepared. Two syringes (one for 
256 
each planned injection) will serve as backups and will only be used if the other syringes are 
257 
compromised for any reason; otherwise, the backup syringes will be discarded if unused. All 
258 
syringes will be packaged and labeled as outlined in the ROP Procedures Manual. 
259 
 
260 
 Product Storage and Stability 
261 
Bevacizumab used in the study will be provided by the study pharmacy at the investigator’s 
262 
institution and diluted to the appropriate concentration by the institution per the procedures 
263 
outlined in the ROP Procedures Manual. The institution pharmacy will prepare the bevacizumab 
264 
syringes in a sterile manner, adhering to USP standards 789, 797, and 800.  Syringes must be 
265 
refrigerated at 2 to 8⸰ Celsius and protected from light and must be used within 8 hours once 
266 
prepared. 
267 
 
268 
 Preparation 
269 
Bevacizumab used in the study will be diluted to the appropriate concentration by the study 
270 
pharmacy at the investigator’s institution per the procedures outlined in the ROP Procedures 
271 
Manual. The pharmacy will prepare the bevacizumab in a sterile manner, adhering to USP 
272 
standards 789, 797, and 800.  
273 
 
274 
 Dosing and Administration 
275 
Bevacizumab at the proper study concentration and dose will be administered by intravitreous 
276 
injection as outlined in the ROP Procedures Manual. 
277 
 
278 
 Route of Administration 
279 
Bevacizumab will be administered by intravitreous injection as outlined in the ROP Procedures 
280 
Manual. 
281 
 
282 
 Dose Adjustments/Modifications/Delays 
283 
The dose should not be adjusted for any reason without first consulting with the protocol chair. 
284 
For infants randomized to bevacizumab, the injection will be given preferably within 24 hours, 
285 
but no later than 2 days, after the diagnosis of type 1 ROP. If injection is delayed beyond 2 days 
286 
after diagnosis for any reason, the injection may still be done after consultation with the protocol 
287 
chair. For analysis purposes, even if the dose is delayed, participants will be counted towards the 
288 
randomly assigned treatment arm. 
289 
    
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 Duration of Therapy 
291 
After initial injection, additional treatment is described in Chapter 5.  
292 
 
293 
 Tracking of Dose 
294 
All syringes will be packaged and labeled by the study pharmacy at the investigator’s institution 
295 
and diluted to the appropriate concentration by the institution per the procedures outlined in the 
296 
ROP Procedures Manual. The pharmacy will prepare the bevacizumab in a sterile manner, 
297 
adhering to USP standards 789, 797, and 800. A second trained and delegated pharmacist will 
298 
check that the preparation was compounded correctly and release syringes for use.  
299 
 
300 
4.2 Study Agent Accountability Procedures 
301 
Drug accountability procedures will be detailed in the ROP Procedures Manual. If only one eye 
302 
is to be treated, the treating investigator and a second person will review the Bevacizumab Study 
303 
Syringe Label to confirm which eye will receive the intravitreous injection. 
304 
 
305 
The investigator who gives the injection must have previous experience giving intravitreous 
306 
injections. If the injection is the first given by the investigator for ROP, then it must be given 
307 
with the assistance of an ophthalmologist who has previously given intravitreous injections for 
308 
ROP.
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Chapter 5: Testing Procedures  
310 
The following procedures will be performed in both groups at each visit as defined in the ROP 
311 
Procedures Manual:  
312 
 
313 
5.1 Procedures at Study Visits 
314 
Classification of ROP will be determined at each follow-up exam prior to 6 months corrected age 
315 
as described in section 2.4.2.  Data will be collected for both eyes.  
316 
 
317 
At 2 and 4 months post-injection, and 6 and 12 months corrected age, data will be collected on 
318 
additional treatment(s) for ROP and complications since the last study exam. 
319 
 
320 
At 2- and 4-months post-injection, investigators will use scleral depression to determine extent of 
321 
retinal vascularization in each quadrant, classified as: 
322 
 
323 
• Posterior Zone I  
324 
• Anterior Zone I    
325 
• Posterior Zone II   
326 
• Mid Zone II    
327 
• Anterior Zone II  
328 
• Zone III    
329 
• Full Vascularization 
330 
 
331 
Additional participant level data collected 6, 12, and 24-months corrected age will include the 
332 
following:  
333 
 
334 
• Date of initial hospital discharge 
335 
• Number of times re-hospitalized  
336 
• Most recent head circumference (in centimeters) and date obtained 
337 
• Most recent weight (in grams) and date obtained 
338 
• Current supplemental oxygen requirement, or date supplemental oxygen discontinued 
339 
• Date and cause of death (if applicable) 
340 
• Presence or history of systemic co-morbidities including:  
341 
o Periventricular leukomalacia 
342 
o Hydrocephalus (with shunt placement) 
343 
• Other systemic outcomes 
344 
 
345 
Additional ocular data collected at 6, 12, and 24-months corrected age age will include the 
346 
following (in both eyes where applicable):   
347 
 
348 
• Ocular Alignment: 
349 
o Alignment will be assessed by the cover test. If a tropia or intermittent tropia is 
350 
detected, then it will be quantified by the prism and alternate cover test (PACT), if 
351 
able, or by the Krimsky test if unable to do PACT. 
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• Assessment of Vision and Amblyopia: 
353 
o Vision will be assessed in each eye by fixing and following.   
354 
o For infants and young children with a manifest tropia, amblyopia will be assessed 
355 
using binocular fixation patterns in best spectacle correction (if worn). For those 
356 
without strabismus or with a microtropia, fixation preference will be assessed 
357 
using the induced tropia test. 
358 
• Cycloplegic Refraction  
359 
• Ocular Exam:  
360 
o Assessment of cornea, anterior segment, lens, optic nerve and retina.   
361 
Additional data will be collected at the time points specified: 
362 
 
363 
• General Movements Assessment:  The GMA test will be administered at 54 weeks (52-
364 
56) PMA.  See ROP Procedures Manual for details. 
365 
• Bayley-4 Test: The Bayley-4 test of infant and toddler development will be administered 
366 
at 2 years corrected age. See ROP Procedures Manual for details.  
367 
 
368 
• Retinal imaging/ Second exam:  
369 
Wide-angle retinal images will be obtained at the time of any additional treatment (laser or 
370 
bevacizumab).  Imaging will be done at 4-months post-injection if no additional treatment is 
371 
planned such as prophylactic laser.  Six images should be obtained for each eye: anterior 
372 
segment, posterior pole, superior, temporal, inferior, and nasal. These images will later be 
373 
reviewed by masked expert readers for purposes of quality control. Investigators will be 
374 
informed throughout the study if their clinical diagnoses disagree with those of expert readers.  
375 
If a participating site or location does not have a retinal camera, a second examination will be 
376 
done by a study-certified examiner after enrollment and if there is treatment failure to assess the 
377 
location, extent, and stage of disease, as well as presence of pre-plus or plus disease. Results of 
378 
this exam will only be used for quality control, similar to review of retinal images.  
379 
 
380 
• OCT and FA:  
381 
o At sites with imaging capabilities, OCT and/or FA imaging will be obtained at the 
382 
time of any additional treatment.  OCT and/or FA will also be done at 4 months 
383 
post-injection if no additional treatment is planned, such as prophylactic laser.     
384 
• Plasma levels of VEGF:  
385 
o For infants participating in the optional study of plasma VEGF level, their blood 
386 
will be collected at 2 weeks, 4 weeks, and 4 months post-injection. Scavenged 
387 
blood may be used when feasible. 
388 
• Adverse Events:  
389 
o After the 4-week ocular exam or hospital discharge (whichever is later), only 
390 
serious adverse events (see section 6.2.1), ocular adverse events, and any events 
391 
judged by the investigator to be related to injection and/or treatment will be 
392 
recorded.  
393 
 
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5.2 Definition of Success / Failure 
395 
Assessment of success/failure will be standardized by certifying investigators as knowledgeable 
396 
with respect to the revised International Classification of Retinopathy of Prematurity (ICROP) 
397 
criteria,55 upon which exam findings and failure criteria will be based. 
398 
 
399 
Success is defined as (1) improvement* by the 4-day exam (3 to 5 days), and (2) no recurrence 
400 
of type 1 ROP within 4 weeks of injection, and (3) no severe neovascularization requiring 
401 
additional treatment within 4 weeks of injection.  If any of these criteria are not met, then a 
402 
retinal image or second examination will be done by a study-certified examiner.  Failure can be 
403 
declared as early as the 4-day post-injection examination (3 to 5 days), and treatment can then be 
404 
started at investigator discretion.   
405 
 
406 
*Improvement by the 4-day exam is defined as follows: 
407 
• For eyes with pre-treatment plus disease, improvement by the 4-day post-injection exam 
408 
is defined as plus disease no longer being present.  
409 
• For eyes with pre-treatment zone I, stage 3, with pre-plus disease, improvement by the 4-
410 
day post-injection exam is defined as: (1) pre-plus no longer present (neither plus nor pre-
411 
plus disease), or (2) a reduction in severity and/or extent of extraretinal 
412 
neovascularization.   
413 
• For eyes with pre-treatment zone I, stage 3, with neither plus nor pre-plus disease, 
414 
improvement by the 4-day post-injection exam is defined as a reduction in severity and/or 
415 
extent of extraretinal neovascularization.    
416 
 
417 
The investigator will be masked to dosage.   
418 
 
419 
5.3 Side Effects of Bevacizumab 
420 
Data will be collected at each follow-up visit to evaluate potential adverse effects of injection as 
421 
described in section 6.2.   
422 
 
423 
5.4 Additional Examinations 
424 
Investigators may perform additional examinations at their discretion.  Failure may occur at any 
425 
exam prior to 4 weeks starting with the 4-day post-injection exam.  Success cannot be declared 
426 
until the 4-week exam. 
427 
 
428 
5.5 Additional Treatment 
429 
Treatment is at investigator discretion after the 4-week outcome examination, or sooner if an eye 
430 
meets criteria for failure. Investigators should not treat the eye with laser or additional injections 
431 
prior to the 4-week outcome examination, unless failure criteria are met and confirmed. If there 
432 
is a strong rationale for earlier treatment in an eye in the absence of meeting failure criteria, the 
433 
Protocol Chair or his/her designee should be called to discuss it before treatment is given.   
434 
 
 
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Chapter 6: Unanticipated Problem and Adverse Event Reporting  
436 
6.1 Unanticipated Problems 
437 
Site investigators will promptly report to the Coordinating Center on an eCRF all unanticipated 
438 
problems meeting the criteria below. Sites must report Unanticipated Problems to the IRB within 
439 
seven (7) calendar days of recognition. For this protocol, an unanticipated problem is an incident, 
440 
experience, or outcome that meets all of the following criteria: 
441 
 
442 
• Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
443 
that are described in the protocol related documents, such as the IRB-approved research 
444 
protocol and informed consent document; and (b) the characteristics of the participant 
445 
population being studied 
446 
• Related or possibly related to participation in the research (possibly related means there is 
447 
a reasonable possibility that the incident, experience, or outcome may have been caused 
448 
by the procedures involved in the research) 
449 
• Suggests that the research places participants or others at a greater risk of harm than was 
450 
previously known or recognized (including physical, psychological, economic, or social 
451 
harm)   
452 
 
453 
The Coordinating Center also will report to the IRB all unanticipated problems not directly 
454 
involving a specific site such as unanticipated problems that occur at the Coordinating Center or 
455 
at another participating entity such as a pharmacy or laboratory. These instances must be 
456 
reported to the JCHR IRB within seven calendar days of recognition. The Director of the Human 
457 
Research Protection Program will report to the appropriate regulatory authorities if the IRB 
458 
determines that the event indeed meets the criteria of an Unanticipated Problem that requires 
459 
further reporting.  
460 
 
461 
6.2 Adverse Events 
462 
 
463 
 Definitions 
464 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
465 
relationship between the adverse event and the drug(s) under investigation.  
466 
 
467 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
468 
• Results in death. 
469 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
470 
become life-threatening, is not necessarily considered a serious adverse event). 
471 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
472 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
473 
to conduct normal life functions (sight threatening). 
474 
• Is a congenital anomaly or birth defect. 
475 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
476 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
477 
the outcomes listed above). 
478 
 
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 Reportable Adverse Events 
480 
For this protocol, all adverse events between the time of study eye treatment until 4 weeks will be 
481 
recorded.58  Any events between randomization and initial treatment will be entered as prior 
482 
medical conditions.   
483 
 
484 
After 4 weeks, only serious adverse events (see section 6.2.1), ocular adverse events, and any 
485 
events judged by the investigator to be related to study injection and/or study treatment will be 
486 
recorded. There will be no imputation of data for participants who die or are lost to follow-up 
487 
prior to the six-month corrected age outcome visit.  
488 
 
489 
All reportable Adverse Events whether volunteered by the participant’s parents, discovered by 
490 
study personnel during questioning, or detected through physical examination, laboratory test, or 
491 
other means will be reported on an adverse event form online. Each adverse event form is 
492 
reviewed by the Medical Monitor to verify the coding and the reporting that is required. 
493 
 
494 
 Relationship of Adverse Event to Study Treatment or Study Procedure 
495 
The study investigator will assess the relationship of each adverse event to be related or 
496 
unrelated by deciding if there is a reasonable possibility that the adverse event may have been 
497 
caused by the treatment or study procedure. The investigator brochure will list potential adverse 
498 
events that may be expected.  
499 
 
500 
To ensure consistency of adverse event causality assessments, investigators should apply the 
501 
following general guideline when determining whether an adverse event is related: 
502 
 
503 
Yes 
504 
There is a plausible temporal relationship between the onset of the adverse event and 
505 
administration of the study treatment and the adverse event cannot be readily explained 
506 
by the participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
507 
adverse event follows a known pattern of response to the study treatment. 
508 
 
509 
No 
510 
Evidence exists that the adverse event has an etiology other than the study treatment (e.g., 
511 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
512 
medication); and/or the adverse event has no plausible temporal relationship to study 
513 
treatment administration.   
514 
 
515 
 Severity (Intensity) of Adverse Event 
516 
The severity (intensity) of an adverse event will be rated on a three point scale: (1) mild, (2) 
517 
moderate, or (3) severe. A severity assessment is a clinical determination of the intensity of an 
518 
event. Thus, a severe adverse event is not necessarily serious. For example, itching for several 
519 
days may be rated as severe, but may not be clinically serious. 
520 
 
521 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
522 
participant’s daily activities. 
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• MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
524 
participant and may interfere with daily activities, but is usually ameliorated by simple 
525 
therapeutic measures and participant is able to continue in study. 
526 
• SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may 
527 
cause discontinuation of study drug, and generally requires systemic drug therapy or 
528 
other treatment. 
529 
 
530 
 Expectedness 
531 
For a serious adverse event that is considered possibly related to study drug, the Medical Monitor 
532 
will classify the event as unexpected if the nature, severity, or frequency of the event is not 
533 
consistent with the risk information previously described below. 
534 
 
535 
 Coding of Adverse Events 
536 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will 
537 
enter a preliminary MedDRA code which the Medical Monitor may accept or change (the 
538 
Medical Monitor’s MedDRA coding will be used for all reporting). The Medical Monitor will 
539 
review the investigator’s assessment of causality and may agree or disagree. Both the 
540 
investigator’s and Medical Monitor’s assessments will be recorded. The Medical Monitor will 
541 
have the final say in determining the causality as well as whether an event is classified as a 
542 
serious adverse event and as a serious unanticipated event. 
543 
 
544 
 Outcome of Adverse Event 
545 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
546 
 
547 
• RECOVERED/RESOLVED: The participant recovered from the AE/SAE without sequelae. 
548 
Record the AE/SAE stop date. 
549 
 
550 
• RECOVERED/RESOLVED WITH SEQUELAE: The event persisted and had stabilized 
551 
without change in the event anticipated. Record the AE/SAE stop date. 
552 
 
553 
• FATAL: A fatal outcome is defined as the SAE that resulted in death. Only the event that 
554 
was the cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time 
555 
of death; however, were not the cause of death, will be recorded as “resolved” at the time of 
556 
death. Primary and secondary (if applicable) causes of death will be recorded. 
557 
 
558 
• NOT RECOVERED/NOT RESOLVED (ONGOING): An ongoing AE/SAE is defined as the 
559 
event was ongoing with an undetermined outcome. 
560 
 
An ongoing outcome will require follow-up by the site in order to determine the final 
561 
outcome of the AE/SAE. 
562 
 
The outcome of an ongoing event at the time of death that was not the cause of death, 
563 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
564 
date.  
565 
 
566 

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• UNKNOWN: An unknown outcome is defined as an inability to access the participant or 
567 
the participant’s records to determine the outcome (for example, a participant that was 
568 
lost to follow-up). 
569 
 
570 
If any reported adverse events are ongoing when a participant completes the study (or 
571 
withdraws), adverse events classified as suspected, unexpected serious adverse reactions 
572 
(SUSARs) will be followed until they are either resolved, or have no prospect of improvement or 
573 
change, even after the participant has completed all applicable study visits/contacts. For all other 
574 
adverse events, data collection will end at the time the participant completes the study. Note: 
575 
participants should continue to receive appropriate medical care for an adverse event after their 
576 
participation in the study ends. 
577 
 
578 
6.3 Timing of Event Reporting 
579 
Serious or unexpected adverse events must be reported to the Coordinating Center within 24 
580 
hours via completion of the online serious adverse event form. 
581 
 
582 
Other reportable adverse events will be reported within 3 days of the investigator becoming 
583 
aware of the event by completion of an electronic case report form.  
584 
 
585 
The Coordinating Center will notify all participating investigators of any adverse event that is 
586 
serious, related, and unexpected. Notification will be made no later than 15 calendar days after 
587 
the Coordinating Center becomes aware of the event, and no later than seven calendar days 
588 
where the event is fatal or life-threatening. 
589 
 
590 
Each principal investigator is responsible for reporting serious study-related adverse events and 
591 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
592 
Ethics Committee. Where the JCHR IRB is the overseeing IRB, sites must report all serious, 
593 
related adverse events regardless of whether they are expected/anticipated and regardless of 
594 
whether they are fatal or life-threatening to the JCHR IRB within seven (7) calendar days.  
595 
 
596 
The Coordinating Center will be responsible for notifying the FDA of any unexpected fatal or 
597 
life-threatening suspected adverse reaction as soon as possible, but in no case later than seven (7) 
598 
calendar days after initial receipt of the information. In addition, the Coordinating Center will 
599 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety 
600 
report of potential serious risks, from clinical trials or any other source, as soon as possible, but 
601 
in no case later than 15 calendar days after the sponsor determines that the information qualifies 
602 
for reporting.  
603 
 
604 
6.4 Safety Oversight 
605 
The study Medical Monitor will review all adverse events that are reported during the study. 
606 
SAEs related to study treatment typically will be reviewed within 24 hours of reporting. Other 
607 
AEs typically will be reviewed on a weekly basis. Additionally, the Medical Monitor will review 
608 
compiled safety data at periodic intervals (generally timed to the review of compiled safety data 
609 
by the DSMC). 
610 
 
611 

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A Data and Safety Monitoring Committee (DSMC) will review compiled safety data at periodic 
612 
intervals, with a frequency of no less than twice a year. The DSMC can request modifications to 
613 
the study protocol or suspension or outright stoppage of the study if deemed necessary based on 
614 
the totality of safety data available. Details regarding DSMC review will be documented in a 
615 
separate DSMC charter. 
616 
 
617 
6.5 Stopping Criteria 
618 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
619 
Monitoring Committee) prior to the preplanned completion of follow-up for all study 
620 
participants. 
621 
 
622 
 Participant Discontinuation of Study Drug 
623 
Rules for discontinuing study drug use are described below.  
624 
 
625 
• The investigator believes it is unsafe for the participant to continue to receive the drug. 
626 
This could be due to the development of a potential side effect of the drug, a new medical 
627 
condition or worsening of an existing condition; or participant behavior contrary to the 
628 
indications for use of the drug that imposes on the participant’s safety. 
629 
• The participant requests that the treatment be stopped. 
630 
 
631 
Even if the study drug is discontinued, the participant will be encouraged to remain in the study 
632 
through the final study visit.  
633 
 
634 
 Criteria for Suspending or Stopping Overall Study 
635 
The objective of the safety review is to decide whether the study (or study agent for an individual 
636 
or study cohort) should continue per protocol, proceed with caution, be further investigated, be 
637 
discontinued, or be modified and then proceed. Suspension of enrollment (for a particular group, 
638 
a particular study site or for the entire study) is a potential outcome of a safety review. 
639 
Subsequent review of serious, unexpected, and related AEs by the Medical Monitor, DSMB, 
640 
IRB, the sponsor(s), or the FDA or relevant local regulatory authorities may also result in 
641 
suspension of further study agent administration at a site. The FDA and study sponsor(s) retain 
642 
the authority to suspend additional enrollment and study agent for the entire study, as applicable. 
643 
 
644 
6.6 Unmasking due to Adverse Event 
645 
Parents, investigators, and examiners will be masked to randomized treatment group.  If a parent 
646 
or investigator believes they need to be unmasked to randomized dosage, the investigator should 
647 
contact the protocol chair first to discuss the case if possible.      
648 

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Chapter 7: Miscellaneous Considerations 
649 
 
650 
7.1 Collection of Medical Conditions and Medications 
651 
A pre-existing condition is defined as any medical condition that is either present at screening, a 
652 
chronic disease, or a prior condition that could impact the participant’s health during the course 
653 
of the study (e.g., prior myocardial infarction or stroke). Pre-existing conditions will be recorded. 
654 
 
655 
All medications that the participant is currently taking at enrollment or during the course of the 
656 
study will be recorded. Preventative treatment also will be recorded (nutraceuticals will not be 
657 
recorded). 
658 
 
659 
7.2 Prohibited Medications, Treatments, and Procedures 
660 
There are no prohibited medications, treatments, or procedures.  
661 
 
662 
7.3 Precautionary Medications, Treatments, and Procedures 
663 
There are no study defined rescue medications, treatments, or procedures.  
664 
 
665 
7.4 Participant Compensation 
666 
Participant compensation will be specified in the informed consent form. 
667 
 
668 
7.5 Participant Withdrawal 
669 
Participation in the study is voluntary, and a parent may withdraw at any time.  
670 
If a parent is considering withdrawal from the study, the principal investigator should personally 
671 
speak to the individual about the reasons, and every effort should be made to accommodate the 
672 
parent to allow continued participation if possible.  
673 
 
674 
The goal for the study is to have as few losses to follow-up as possible. The Coordinating Center 
675 
will assist in the tracking of study participants who cannot be contacted by the site. The 
676 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 
677 
Study participants who have an adverse event attributable to a study treatment or procedure at 
678 
the time of withdrawal will be asked to continue in follow-up until the adverse event has 
679 
resolved or stabilized. 
680 
 
681 
For participants who withdraw, their data will be used up until the time of withdrawal. Those that 
682 
receive off-protocol treatment will be encouraged to remain in the study. 
683 
 
684 
7.6 Confidentiality 
685 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
686 
used instead of their name. Protected health information gathered for this study will be shared 
687 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
688 
participant information may also be provided to research sites involved in the study. 
689 
 
690 
7.7 Contact Information Provided to the Coordinating Center 
691 
The Coordinating Center will be provided with contact information for each study participant. 
692 
Permission to obtain such information will be included in the Informed Consent Form. The contact 
693 
information will be maintained in a secure database and will be maintained separately from the 
694 

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study data. 
695 
 
696 
Phone contact or mailings from the Coordinating Center may be made with each study 
697 
participant to facilitate the scheduling of the study participant for follow-up visits. A study 
698 
participant-oriented newsletter may be sent once a year. A study logo item may be sent once a 
699 
year. 
700 
 
701 

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Chapter 8: Statistical Considerations 
702 
8.1 Statistical and Analytical Plans 
703 
The approach to sample size and statistical analyses are summarized below.    
704 
 
705 
8.2 Study Objectives and Hypothesis 
706 
 
707 
 Classification of Success/Failure by 4 Weeks Post-Injection  
708 
 
709 
 Within Dose Groups 
710 
The number of eyes with type 1 ROP injected with each dose (0.063 mg or 0.25 mg) of 
711 
bevacizumab within four weeks of enrollment and proportion of eyes meeting success criteria as 
712 
described in section 5.2 will be evaluated along with a 95% confidence interval (CI) for the 
713 
proportion.  The point estimate and CI will be adjusted to control for any correlation arising from 
714 
participants contributing two eyes to the analysis.    
715 
 
716 
As an estimate of precision, the potential half-widths for an uncorrected 95% CI for various 
717 
success proportions and various sample sizes are summarized in Table 2 below:  
718 
 
719 
Table 2:   Expected Half-width 95% Confidence Interval for Various Within Dose Group 
720 
Success Proportions and Sample Sizes 
721 
Sample Size  
Observed Success Rate Within Dose Group 
70% 
80% 
90% 
20 
20% 
18% 
13% 
25 
18% 
16% 
12% 
30 
16% 
14% 
11% 
35 
15% 
13% 
10% 
40 
14% 
12% 
9% 
 
722 
 Between Dose Groups 
723 
The difference between dose groups (0.25 mg vs 0.063 mg within study eyes only) with respect 
724 
to the proportion of eyes meeting success criteria as described in section 5.2 will be evaluated 
725 
along with a 95% CI for the difference between groups. 
726 
   
727 
For study eyes, the point estimate and CI will be adjusted to control for any correlation arising 
728 
from participants contributing two eligible eyes to the analysis. To use the information of these 
729 
participants as much as possible, a time to event analysis will be performed. 
730 
 
731 
The estimated power to reject a two-sided null hypothesis of no difference between dose groups 
732 
in favor of the alternative that they are different is given in Table 3 below for various effect sizes 
733 
and sample sizes:   
734 
 
735 
Table 3: Estimated Power for Various Effect Sizes and Sample Sizes 
736 
Sample Size Each Dose Group 

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True 
Difference 
Between 
Dose Groups 
20 
25 
30 
35 
40 
90% vs 70% 
(20%) 
23% 
30% 
38% 
45% 
52% 
90% vs 75% 
(15%) 
13% 
18% 
23% 
27% 
32% 
90% vs 80% 
(10%) 
7% 
9% 
11% 
13% 
16% 
 
737 
8.3 Additional Analyses Within Each Dose Cohort 
738 
The following tabulations or summarizations will be done within each dose cohort: 
739 
 
740 
 Baseline Characteristics 
741 
Participant level and eye level characteristics will be tabulated including gender, race, gestational 
742 
age, birth weight, examination findings in each eye at time of injection, and age at diagnosis of 
743 
type 1 ROP.  
744 
 
745 
 At 2 and 4 Months Post-injection, and 6 and 12 Months Corrected Age 
746 
The following will be tabulated:   
747 
• The number of and types of additional treatment/s for ROP  
748 
• The number of and types of ocular complications  
749 
• The proportion of eyes with extent of retinal vascularization (2, 4-months post-injection 
750 
only) in the eye classified by investigator as: 
751 
o Posterior Zone I  
752 
o Anterior Zone I    
753 
o Posterior Zone II   
754 
o Mid Zone II    
755 
o Anterior Zone II  
756 
o Zone III    
757 
Full Vascularization 
758 
• In addition, we will calculate the proportion and 95% confidence interval for 
759 
treated eyes that achieve either Zone III or full vascularization. 
760 
 
761 
General movements assessment (GMA):  A certified GMA expert will review the video taken at 
762 
52 to 56 weeks PMA and grade the infant’s movements as normal, absent, and abnormal as 
763 
follows:    
764 
• Normal: fidgety general movements are intermittently or continuously present 
765 
• Absent: fidgety general movements are not observed or are sporadically present 
766 
• Abnormal: fidgety general movements are exaggerated in speed and amplitude 
767 
 
768 
The proportion of infants with normal, absent, and abnormal gradings will be tabulated by 
769 
treatment group.   
770 

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771 
Additional participant level data collected at 6, 12, and 24 months will be tabulated or 
772 
summarized:   
773 
• Summary statistics of time from enrollment to initial hospital discharge 
774 
• The number of times re-hospitalized  
775 
• The most recent head circumference (in centimeters)  
776 
o The median, quartiles, and range will be calculated 
777 
• The most recent weight (in grams)  
778 
o The median, quartiles, and range will be calculated 
779 
• Whether or not current supplemental oxygen required (yes/no) 
780 
• Proportion of participants died; cause of death  
781 
• Proportion of participants with the presence or history of systemic co-morbidities 
782 
including:  
783 
o Periventricular leukomalacia 
784 
o Hydrocephalus (with shunt placement) 
785 
 
786 
Additional ocular data collected at 6, 12, and 24-months corrected age will be tabulated or 
787 
summarized as follows:     
788 
• Ocular Alignment:  
789 
o If able to test ocular alignment at distance, the following will be tabulated: 
790 
▪ Number (%) with intermittent tropia or constant tropia 
791 
o If able to test ocular alignment at near, the following will be tabulated: 
792 
▪ Number (%) with intermittent tropia or constant tropia 
793 
o Number (%) with tropia defined as intermittent or constant at distance OR near. 
794 
The number (%) of children with nystagmus absent or present.  
795 
• Assessment of Vision 
796 
o The % of eyes able to fix and follow 
797 
• Assessment of Amblyopia at participant level:  
798 
o Responses by fixation preference testing will be tabulated:   
799 
• Strongly prefers fixation with one eye (will not fix with the other eye for 
800 
more than 1 sec) - Amblyopia strongly suspected 
801 
• Mild or no fixation preference – amblyopia not strongly suspected 
802 
• Unable to cooperate for testing 
803 
• Cycloplegic Refraction in each eye:  
804 
o Spherical equivalent cycloplegic refractive error (Summary statistics)  
805 
o Proportion of eyes and 95% CI with Myopia? <-5 vs >=-5 spherical equivalent  
806 
o Proportion of eyes and 95% CI with Hyperopia? >+5 vs <=+5 spherical 
807 
equivalent 
808 
• Ocular Exam:  
809 
The proportion of children with each of the following will be tabulated if known for eyes 
810 
injected: 
811 
o 
Most severe abnormality in the eye based upon clinical exam: 
812 
• Essentially normal 
813 
• Straightening of temporal vessels (suggestive of traction) 
814 
• Macular ectopia 
815 

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• Stage 4A retinal detachment (sparing fovea) 
816 
• Stage 4B retinal detachment (involving fovea) 
817 
• View of macula blocked 
818 
• Total retinal detachment 
819 
• All view of posterior pole and near periphery is blocked due to 
820 
anterior segment opacity  
821 
• Enucleation due to ROP  
822 
• Enucleation due to other causes 
823 
• Unable to determine (e.g. view impossible due to corneal 
824 
opacity unrelated to ROP, or to miotic pupil)    
825 
o 
Normal or abnormal cornea 
826 
o 
Normal or abnormal anterior segment 
827 
o 
Normal or abnormal lens  
828 
o 
Optic nerve atrophy absent, questionable, present, or view obscured  
829 
• A binary indicator will be evaluated for each as present vs 
830 
(absent or questionable), not including view obscured 
831 
 
832 
 At 24 Months Corrected Age Only 
833 
At 24 months corrected age, the Bayley Scales of Infant and Toddler Development Fourth 
834 
Edition Test (Bayley-IV) will be administered. The Bayley has five major component scales that 
835 
are tested for each child: Cognitive, Language, Motor, Social-Emotional, and Adaptive Behavior. 
836 
Scores for each scale range from 45 to 155, with a SD of 15.  
837 
 
838 
The scores for each domain will be summarized with descriptive statistics and 95% confidence 
839 
intervals for means. Data will be included only from participants who complete the outcome at 
840 
the time point in question. There will be no imputation of data for participants who do not 
841 
complete the outcome. 
842 
 
843 
Each of the five Bayley composite subscale scores also will be categorized as normal, slightly 
844 
impaired, or significantly impaired. Participants with scores 85 or higher are considered 
845 
normal.34,59 Participants with scores 70 to 84 are considered slightly impaired; and participants 
846 
with scores <70 are considered significantly impaired. The proportion of participants within each 
847 
score category will be calculated for each treatment group. 
848 
 
849 
 
850 
 Plasma Levels of VEGF 
851 
The parents of each infant enrolled in the study will be given the option to participate in a study 
852 
to measure levels of VEGF in the plasma. Participants in this optional study will have blood 
853 
collected for analysis. The distribution of VEGF levels (median, range, and quartiles) will be 
854 
described before injection, and at 2 weeks, 4 weeks post-injection, and 4 months post-injection.  
855 
The change from pre-injection will be calculated, and a 95% confidence interval calculated for 
856 
the change.  
857 
 
858 
 
859 

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860 
 
861 
8.4 Additional Analyses Between Dose Cohorts 
862 
The analyses below will be done between dose cohorts. Point estimates and CI’s will be adjusted 
863 
to control for any correlation arising from participants contributing two eyes to the analyses.  
864 
There will be no adjustment of the type 1 error rate as these analyses are exploratory. 
865 
 
866 
At 2- and 4-months post-injection:  
867 
• The proportion and 95% CI of treated eyes that achieve either Zone III or full 
868 
vascularization. 
869 
 
870 
At 24-months corrected age 
871 
• The mean and 95% CI for differences between treatment group for each domain of 
872 
the Bayley-IV 
873 
 
874 
8.5 Safety 
875 
Adverse events reported at any time during the study will be tabulated for all enrolled infants and 
876 
coded using the MedRA system.  An estimate and 95% confidence interval of the following 
877 
proportions will be obtained using the exact binomial method:  
878 
• Proportion of infants for whom at least one event was reported 
879 
• Proportion of infants with an adverse event thought by investigator to be related to study 
880 
drug 
881 
• Proportion of infants for whom at least one serious adverse event was reported  
882 
• Proportion of infant deaths 
883 
• Complications after the four-week exam will be listed. 
884 
• The change in systolic and diastolic blood pressure measures at 1, 2, 3, and 4-weeks post-
885 
treatment between treatment groups will be evaluated.  
886 
• The proportion and 95% CI of participants with the presence or history of systemic co-
887 
morbidities including:  
888 
o Periventricular leukomalacia 
889 
o Hydrocephalus (with shunt placement) 
890 
Adverse events in fellow eyes will be tabulated separately. 
891 
 
892 
 Power for Analysis of Adverse Effects 
893 
For rare side effects, Table 4 below specifies the chance of not observing at least 1 adverse event 
894 
in a sample of 30 children for various event rates in the population.    
895 
 
896 

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Table 4:  Chance of Not Observing at Least One Event in a Sample of 30 Participants 
897 
Actual Probability 
of an Event 
Chance of Not Observing at Least One Event for a Given Dosage 
N=30 Participants 
1% 
74% 
2% 
55% 
3% 
40% 
4% 
29% 
5% 
21% 
 
898 
Hence, with the proposed sample size of 30 participants the study has a 21% probability for not 
899 
observing at least one event for adverse events with 5% occurrence.   
900 
 
901 
 
902 
8.6 Sample Size 
903 
The objective of the current protocol is to obtain estimates of treatment effect in eyes treated 
904 
with 0.063mg and 0.25mg bevacizumab; and to explore whether the treatment effect differs 
905 
between the two dose groups.  Effectiveness for the purpose of this study is defined using the 
906 
study’s definition of success (as defined in section 5.2). 
907 
 
908 
The sample size has not been statistically calculated.  A sample size of up to 80 participants (40 
909 
participants per dose group) is a convenience sample.  Tables 2, 3, and 4 above indicate the level 
910 
of statistical power/precision the study would have for various sample sizes.   
911 
 
912 
It is estimated that 80% of participants will have type 1 ROP in zone I in both eyes at the time of 
913 
enrollment.  An estimated 10% may have bilateral ROP at time of enrollment (or within 4 weeks 
914 
of enrollment) where the fellow eye has zone II ROP; and 10% may be unilateral with only one 
915 
eye with ROP in zone I during the study.   
916 
 
917 
8.7 Sensitivity Analyses for Primary Outcome 
918 
 
919 
 Tipping point analysis for Imaging / second ocular exam 
920 
Wide-angle retinal images will be obtained after enrollment and at the time of any additional 
921 
treatment.  Imaging will be done at 4 months post-injection if no additional treatment is planned, 
922 
such as prophylactic laser.  Six images will be obtained for each eye: anterior segment, posterior 
923 
pole, superior, temporal, inferior, and nasal as described in the ROP Procedures Manual.  These 
924 
images will later be reviewed by masked expert readers for purposes of quality control. 
925 
Investigators will be informed throughout the study if their clinical diagnoses disagree with those 
926 
of expert readers. 
927 
 
928 
If a participating site or location does not have a retinal camera, a second examination will be 
929 
done by a study-certified examiner after enrollment and if there is treatment failure to assess the 
930 
location, extent, and stage of disease, as well as presence of pre-plus or plus disease.  Results of 
931 
this exam will only be used for quality control, similar to review of retinal images.  
932 
 
933 

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The number of discrepancies between the site diagnosis and the retinal image reviewer diagnosis 
934 
OR diagnosis by second study certified ROP examiner will be calculated at each visit.  If there 
935 
are cases where the investigator declared failure and masked review of the images OR second 
936 
study certified examiner does not confirm failure, then a sensitivity tipping point analysis will be 
937 
done to evaluate the number of discrepancies required to tip results from significant to not or 
938 
vice versa. If there are discrepancies at enrollment, a sensitivity analysis excluding those 
939 
participants will be performed. 
940 
 
941 
 Deaths as Failures  
942 
A sensitivity analysis for the primary outcome will be performed where are counted as failures.   
943 
 
944 
8.8 Planned Interim Analyses 
945 
There will be no interim analyses for futility, efficacy, or re-estimation of sample size.  
946 
 
947 
 
948 

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Chapter 9: Data Collection and Monitoring 
949 
 
950 
9.1 Case Report Forms and Data Collection  
951 
The main study data will be collected through electronic case report forms (CRFs). These 
952 
electronic CRFs from the study website are considered the primary source documentation. 
953 
When data are directly collected in electronic case report forms, this will be considered the 
954 
source data. Each participating site will maintain appropriate medical and research records for 
955 
this trial, in compliance with ICH E6 and regulatory and institutional requirements for the 
956 
protection of confidentiality of participants. 
957 
 
958 
9.2 Study Records Retention 
959 
Study documents will be retained for a minimum of 3 years following the submission of the final 
960 
financial report for the last grant cycle for which the study is conducted or 2 years following the 
961 
date a marketing application is approved for the drug for the indication for which it is being 
962 
investigated; or if not approved, 2 years after the IND is withdrawn, whichever is later. No 
963 
records will be destroyed without the written consent of the sponsor. It is the responsibility of the 
964 
sponsor to inform the investigators when study documents no longer need to be retained. 
965 
 
966 
9.3 Quality Assurance and Monitoring 
967 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
968 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
969 
conducted and data are generated, documented and reported in compliance with the protocol, 
970 
Good Clinical Practice (GCP) and the applicable regulatory requirements. Adverse events will be 
971 
prioritized for monitoring. 
972 
 
973 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
974 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
975 
Investigations — A Risk-Based Approach to Monitoring” (August 2013). Study conduct and 
976 
monitoring will conform with 21 Code of Federal Regulations (CFR) 312. 
977 
 
978 
The data of most importance for monitoring at the site are participant eligibility and adverse 
979 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
980 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
981 
verity and completeness of the key site data. Elements of the RBM may include: 
982 
• Qualification assessment, training, and certification for sites and site personnel 
983 
• Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
984 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
985 
review of entered data and edits, statistical monitoring, study closeout 
986 
• On-site monitoring (site visits): source data verification, site visit report 
987 
• Communications with site staff 
988 
• Patient retention and visit completion 
989 
• Quality control reports 
990 
• Management of noncompliance 
991 
• Documenting monitoring activities 
992 
• Adverse event reporting and monitoring 
993 

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Coordinating Center representatives or their designees may visit the study facilities at any time in 
994 
order to maintain current and personal knowledge of the study through review of the records, 
995 
comparison with source documents, observation and discussion of the conduct and progress of 
996 
the study. 
997 
 
998 
9.4 Protocol Deviations 
999 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1000 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
1001 
the study site staff. As a result of deviations, corrective actions are to be developed by the site 
1002 
and implemented promptly. 
1003 
 
1004 
The site PI/study staff is responsible for knowing and adhering to the JCHR IRB requirements 
1005 
(i.e., reporting qualifying deviations to the JCHR IRB within seven (7) calendar days of 
1006 
identification). Further details about the handling of protocol deviations will be included in the 
1007 
monitoring plan.
1008 
 
 
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Chapter 10: Ethics/Protection of Human Participants 
1010 
 
1011 
10.1 Ethical Standard 
1012 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1013 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1014 
21 CFR Part 56, and/or the ICH E6. 
1015 
 
1016 
10.2 Institutional Review Boards 
1017 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1018 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
1019 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
1020 
require review and approval by the IRB before the changes are implemented to the study. All 
1021 
changes to the consent form will be IRB approved; a determination will be made regarding 
1022 
whether previously consented participants need to be re-consented. 
1023 
 
1024 
10.3 Informed Consent Process 
1025 
 Consent Procedures and Documentation 
1026 
Informed consent is a process that is initiated prior to the parent agreeing to have their child 
1027 
participate in the study and continues throughout the individual’s study participation. Extensive 
1028 
discussion of risks and possible benefits of participation will be provided to the participants and 
1029 
their families. Consent forms will be IRB-approved and the parent will be asked to read and 
1030 
review the document. The investigator will explain the research study to the parent and answer 
1031 
any questions that may arise. All parent(s) will receive a verbal explanation in-person or via 
1032 
phone/video conference in terms suited to their comprehension of the purposes, procedures, and 
1033 
potential risks of the study and of their child’s rights as research participants. Parent(s) will have 
1034 
the opportunity to carefully review the consent form and ask questions prior to signing. 
1035 
 
1036 
The parent(s) should have the opportunity to discuss the study with their surrogates or think 
1037 
about it prior to agreeing to participate. The parent will sign the informed consent document 
1038 
prior to any procedures being done specifically for the study. The participants may withdraw 
1039 
consent at any time throughout the course of the trial. The parent will be provided with a copy of 
1040 
the informed consent document for their records. The rights and welfare of the participants will 
1041 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1042 
affected if they decline to participate in this study. 
1043 
 
1044 
 Participant and Data Confidentiality 
1045 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1046 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
1047 
samples and imaging in addition to the clinical information relating to participants. Therefore, 
1048 
the study protocol, documentation, data, and all other information generated will be held in strict 
1049 
confidence. No information concerning the study or the data will be released to any unauthorized 
1050 
third party without prior written approval of the sponsor. 
1051 
 
1052 
The study monitor, other authorized representatives of the Jaeb Center for Health Research, or 
1053 
representatives of the IRB may inspect all documents and records required to be maintained by 
1054 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
1055 

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pharmacy records for the participants in this study. The clinical study site will permit access to 
1056 
such records. 
1057 
 
1058 
The study participant’s contact information will be securely stored at each clinical site for 
1059 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1060 
secure location for as long a period as dictated by local IRB and Institutional regulations. 
1061 
Study participant research data, which is for purposes of statistical analysis and scientific 
1062 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research. Individual 
1063 
participants and their research data will be identified by a unique study identification number.  
1064 
 
1065 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1066 
obtained from the NIH. This certificate protects identifiable research information from forced 
1067 
disclosure. It allows the investigator and others who have access to research records to refuse to 
1068 
disclose identifying information on research participation in any civil, criminal, administrative, 
1069 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
1070 
researchers and institutions from being compelled to disclose information that would identify 
1071 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1072 
promote participation in studies by helping assure confidentiality and privacy to participants 
1073 
 
1074 
The study data entry and study management systems used by clinical sites and by the Jaeb Center 
1075 
for Health Research Coordinating Center research staff will be secured and password protected. 
1076 
At the end of the study, all study databases will be de-identified and archived at the Jaeb Center 
1077 
for Health Research and made available to the public. 
1078 
 
1079 
 Future Use of Stored Specimens and Data 
1080 
After testing for VEGF levels, any remaining blood or serum samples will be saved in a de-
1081 
identified manner and possibly used for other studies in the future, but will not be used for whole 
1082 
genome sequencing or other such genetic testing that could reidentify the participants.  All 
1083 
samples will be destroyed once all analyses are completed, results and published, and it is 
1084 
determined samples no longer need to be saved for future studies.  
1085 

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Chapter 11: References 
1086 
1. 
Gilbert C. Retinopathy of prematurity: a global perspective of the epidemics, population 
1087 
of babies at risk and implications for control. Early Hum Dev. 2008;84:77-82.  
1088 
2. 
Reese A. Symposium: Retrolental Fibroplasia (Retinopathy of Prematurity). American 
1089 
Journal of Ophthalmology. 1955;40(2):159. doi:10.1016/0002-9394(55)91614-7 
1090 
3. 
A Classification of Retrolental Fibroplasia. American Journal of Ophthalmology. 
1091 
1953;36(10):1335. doi:10.1016/0002-9394(53)90791-0 
1092 
4. 
Harris GS. Retinopathy of prematurity and retinal detachment. Can J Ophthalmol. Jan 
1093 
1976;11(1):21-25.  
1094 
5. 
Hittner HM, Rhodes LM, McPherson AR. Anterior segment abnormalities in cicatricial 
1095 
retinopathy of prematurity. Ophthalmology. May 1979;86(5):803-16. doi:10.1016/s0161-
1096 
6420(79)35437-9 
1097 
6. 
Kalina RE. Treatment of retrolental fibroplasia. Surv Ophthalmol. Jan-Feb 
1098 
1980;24(4):229-36. doi:10.1016/0039-6257(80)90044-2 
1099 
7. 
Kushner BJ. Strabismus and amblyopia associated with regressed retinopathy of 
1100 
prematurity. Arch Ophthalmol. Feb 1982;100(2):256-61. 
1101 
doi:10.1001/archopht.1982.01030030258004 
1102 
8. 
Kushner BJ, Sondheimer S. Medical treatment of glaucoma associated with cicatricial 
1103 
retinopathy of prematurity. Am J Ophthalmol. Sep 1982;94(3):313-7. doi:10.1016/0002-
1104 
9394(82)90356-7 
1105 
9. 
Nissenkorn I, Yassur Y, Mashkowski D, Sherf I, Ben-Sira I. Myopia in premature babies 
1106 
with and without retinopathy of prematurity. Br J Ophthalmol. Mar 1983;67(3):170-3. 
1107 
doi:10.1136/bjo.67.3.170 
1108 
10. 
Tasman W. Vitreoretinal changes in cicatricial retrolental fibroplasia. Trans Am 
1109 
Ophthalmol Soc. 1970;68:548-94.  
1110 
11. 
Tasman W. Retinal detachment in retrolental fibroplasia. Albrecht von Graefes Archiv fur 
1111 
klinische und experimentelle Ophthalmologie Albrecht von Graefe's archive for clinical and 
1112 
experimental ophthalmology. 1975;195(2):129-39. doi:10.1007/bf00417115 
1113 
12. 
Tasman W. Late complications of retrolental fibroplasia. Ophthalmology. Oct 
1114 
1979;86(10):1724-40. doi:10.1016/s0161-6420(79)35346-5 
1115 
13. 
Tysinger JW, Jr., Weidenthal DT. Nasal heterotopia of the macula in retinopathy of 
1116 
prematurity. Am J Ophthalmol. Apr 1977;83(4):499-500. doi:10.1016/0002-9394(77)90555-4 
1117 
14. 
Gilbert C, Rahi J, Eckstein M, O'Sullivan J, Foster A. Retinopathy of prematurity in 
1118 
middle-income countries. Lancet. 1997;350(9070):12-4.  
1119 
15. 
An international classification of retinopathy of prematurity. The Committee for the 
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Classification of Retinopathy of Prematurity. Arch Ophthalmol. Aug 1984;102(8):1130-4. 
1121 
doi:10.1001/archopht.1984.01040030908011 
1122 
16. 
International Committee for the Classification of Retinopathy of P. The International 
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Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. Jul 2005;123(7):991-9. 
1124 
doi:10.1001/archopht.123.7.991 
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17. 
Early Treatment for Retinopathy of Prematurity Cooperative G. Revised indications for 
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the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of 
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1988;106(4):471-9. doi:10.1001/archopht.1988.01060130517027 
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19. 
Quinn GE, Dobson V, Davitt BV, et al. Progression of myopia and high myopia in the 
1133 
Early Treatment for Retinopathy of Prematurity study: findings at 4 to 6 years of age. J aapos. 
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Apr 2013;17(2):124-8. doi:10.1016/j.jaapos.2012.10.025 
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20. 
Connor KM, SanGiovanni JP, Lofqvist C, et al. Increased dietary intake of omega-3-
1136 
polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nature medicine. Jul 
1137 
2007;13(7):868-873. doi:10.1038/nm1591 
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Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: Snellen Visual Acuity 
1139 
and Structural Outcome at 5½ Years After Randomization. Arch Ophthalmol. 1996;114(4):417-
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424. doi:10.1001/archopht.1996.01100130413008 
1141 
22. 
Good WV, Hardy RJ, Dobson V, et al. Final visual acuity results in the early treatment 
1142 
for retinopathy of prematurity study. Arch Ophthalmol. 2010;128(6):663-71. 
1143 
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1144 
23. 
Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for 
1145 
stage 3+ retinopathy of prematurity. N Engl J Med. Feb 17 2011;364(7):603-15. 
1146 
doi:10.1056/NEJMoa1007374 
1147 
24. 
Roohipoor R, Ghasemi H, Ghassemi F, Karkhaneh R, Riazi-Esfahani M, Nili-
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Ahmadabadi M. Intravitreal bevacizumab in retinopathy of prematurity: an interventional case 
1149 
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1678-9 
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25. 
Dorta P, Kychenthal A. Treatment of type 1 retinopathy of prematurity with intravitreal 
1152 
bevacizumab (Avastin). Retina. Apr 2010;30(4 Suppl):S24-31. 
1153 
doi:10.1097/IAE.0b013e3181ca1457 
1154 
26. 
Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of 
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bevacizumab use in patients with retinopathy of prematurity: a multicenter study in taiwan. 
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27. 
Micieli JA, Surkont M, Smith AF. A systematic analysis of the off-label use of 
1158 
bevacizumab for severe retinopathy of prematurity. Am J Ophthalmol. Oct 2009;148(4):536-
1159 
543.e2. doi:10.1016/j.ajo.2009.05.031 
1160 
28. 
Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas ML, Salazar-Teran N, 
1161 
Chan RV. Antiangiogenic therapy with intravitreal bevacizumab for retinopathy of prematurity. 
1162 
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Mintz-Hittner HA, Kuffel RR, Jr. Intravitreal injection of bevacizumab (avastin) for 
1164 
treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina. 
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Wallace DK, Kraker RT, Freedman SF, et al. Assessment of lower doses of intravitreous 
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bevacizumab for retinopathy of prematurity: A phase 1 dosing study. JAMA Ophthalmol. Jun 01 
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Stahl A, Lepore D, Fielder A, et al. Ranibizumab versus laser therapy for the treatment of 
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randomised controlled trial. Lancet. Oct 26 2019;394(10208):1551-1559. doi:10.1016/s0140-
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Wu WC, Lien R, Liao PJ, et al. Serum levels of vascular endothelial growth factor and 
1178 
related factors after intravitreous bevacizumab injection for retinopathy of prematurity. JAMA 
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bevacizumab injections for retinopathy of prematurity. Pediatrics. Apr 2016;137(4):e20153218. 
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36. 
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intravitreous bevacizumab for retinopathy of prematurity. JAMA Ophthalmol. Apr 23 
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1192 
KA, Mintz-Hittner HA; BEAT-ROP Cooperative Group. Refractive outcomes following 
1193 
bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical 
1194 
trial. JAMA Ophthalmol. 2014 Nov;132(11):1327-33. doi: 10.1001/jamaophthalmol.2014.2772. 
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Shah PK, Morris RJ, Narendran V, Kalpana N. Visual acuity and electroretinography 
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posterior retinopathy of prematurity. Indian J Ophthalmol. Jan-Feb 2011;59(1):73-4.  
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1245 
International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. Jul 
1246 
2005;123(7):991-999.  
1247 
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Capone A, Jr., Ells AL, Fielder AR, et al. Standard image of plus disease in retinopathy 
1248 
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Chiang MF, Quinn GE, Fielder AR, et al. International Classification of Retinopathy of 
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58. 
Kong L, Bhatt AR, Demny AB, et al. Pharmacokinetics of bevacizumab and its effects on 
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Rodriguez SH, Peyton C, Lewis K, et al. Neurodevelopmental Outcomes Comparing 
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1260