A Prospective, Single-Blind, Randomized Study to Evaluate Intravitreal Aflibercept Injection (IAI) Versus Sham as PROphylaxis Against CONversion to Neovascular Age-Related Macular Degeneration (AMD) in High-Risk Eyes
Phase: PHASE2
Conditions: Age-Related Macular Degeneration
Sponsor: Jeffrey S Heier

NCT02462889 
 
 
 
 
Sponsor-Investigator: Jeffrey S. Heier, MD 
 
 
 
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Clinical Study Protocol 
 
A Prospective, Single-Blind, Randomized Study to Evaluate Intravitreal Aflibercept 
Injection (IAI) versus Sham as PROphylaxis against CONversion to Neovascular Age-
Related Macular Degeneration (AMD) in High-Risk Eyes 
 
 
 
Compound: 
Intravitreal Aflibercept Injection 2 mg  
 
 
Study Name: 
IAI versus Sham as Prophylaxis against 
Conversion to Neovascular AMD  (PRO-
CON) 
 
 
Clinical Phase: 
II 
 
 
Study Number: 
 
Version & Date of Issue: 
VGFTe-AMD-1507 
 
 
3.0 dated 23-NOV-2015 
 
 
Primary Investigator: 
Jeffrey S. Heier, MD 
 
 
 
 
 
 
 
 
 
 
 

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CLINICAL STUDY PROTOCOL SYNOPSIS 
TITLE:  
A Prospective, Single-Blind, Randomized Study to Evaluate Intravitreal 
Aflibercept Injection (IAI) versus Sham as Prophylaxis against 
Conversion to Neovascular Age-Related Macular Degeneration (AMD) 
in High-Risk Eyes     
 
TITLE IN LAY TERMS:  IAI as Prophylaxis against Conversion to Neovascular AMD  (PRO-
CON)  
 
SITE LOCATION(S) 
 
 
Ophthalmic Consultants of Boston, Boston, MA 
New Jersey Retina, NJ 
Retina-Vitreous Associates Medical Group, Los Angeles, CA 
Retina Consultants of Houston, Houston, TX 
 
OBJECTIVE(S):  
To evaluate IAI 2mg as prophylaxis against the conversion to 
neovascular age-related macular degeneration (AMD) in high-risk eyes. 
 
STUDY DESIGN:  
Multicenter, prospective, active-controlled, single-blind study involving 
128 subjects randomized 1:1 to receive IAI every three months for 24 
months versus sham injections. 
 
STUDY DURATION:  
18-month enrollment period, then 24-month treatment period 
 
ESTIMATED STUDY 
COMPLETION DATE:  
September 2018 
POPULATION 
128 enrolled subjects with high-risk non-neovascular AMD in one eye 
(study eye) defined as having: 
• Intermediate AMD in the study eye, defined as the presence of 
greater than ten intermediate sized drusen (≥ 63 and <125 μm), 1 or 
more large druse (≥125 μm), and/or retinal pigmentary changes. and  
• Neovascular AMD in the fellow eye 
 
 
TREATMENT(S) 
 
Study Drug:  
Dose/Route/Schedule:  
Intravitreal aflibercept injection 
2 mg / intravitreal injection / Q3-month for 24 months 
Placebo:  
Dose/Route/Schedule:  
Sham injection 
Q3-month for 24 months 
 
 

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ENDPOINT(S) 
 
Primary:  
Proportion of subjects converting to neovascular AMD at 24 months, 
characterized by the development of choroidal neovascularization 
(CNV).  The development of CNV will be assessed by: 
• CNV leakage on FA, and 
• Evidence of any fluid on SD-OCT. 
Conversion will be confirmed by the reading center (“confirmed 
conversion”).  The Kaplan-Meier method will be used to estimate time 
to conversion using the conversion criterion, and the log-rank test will 
be used to compare the time course among treatment groups. 
 
Secondary:  
 
 
 
 
 
 
 
 
 
Interim: 
 
 
Exploratory Analyses: 
• Mean change in visual acuity at 24 months compared to baseline  
• Percentage of subjects losing < 15 ETDRS letters at 24 months as 
compared to baseline 
• Incidence and severity of potential ocular side effects including 
endophthalmitis, retinal detachment, cataract, and intraocular 
inflammation 
• Incidence and severity of systemic side effects 
• Development/progression of geographic atrophy. 
 
An interim analysis will be performed at Month 12. 
 
In subjects who choose to participate in the genomics sub-study, blood 
samples will be taken for exploratory DNA analysis. 
 
In subjects who convert to neovascular AMD, additional analyses 
include: 
• Mean change in visual acuity at conversion 
• Mean change in visual acuity at 24 months 
• Mean number of IAI injections through 24 months. 
• Mean size of choroidal neovascular membrane at 24 months per 
FA 
• Detection of conversion to neovascular AMD by OCT 
angiography 
• Correlation of CNV detection by OCT angiography relative to FA 
• Timing of CNV detection by OCT angiography relative to FA 
 
In subjects who choose to participate in the home monitoring sub-
study, exploratory analyses include the correlation between an alert 
generated by Paxos CheckupTM application (“app”) and a confirmed 
conversion at subject’s next office visit. 
 

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PROCEDURES AND 
ASSESSMENTS:  
Enrolled subjects will be evaluated at Baseline and every three months 
thereafter for a 24-month study period.  Assessments at each visit 
include: 
• Manifest refraction and ETDRS visual acuity testing 
• Slit lamp exam and dilated fundus exam 
• Spectral-domain optical coherence tomography (SD-OCT) using 
Avanti device 
• OCT angiography using Avanti AngioVueTM 
• Fluorescein angiography (FA) 
Fundus photography will also be performed at Baseline, Month 12 and 
Month 24 visits. 
 
Required assessments at a Suspected Conversion Visit (SCV, see 
Section 6.2.5) include: 
• Manifest refraction and ETDRS visual acuity testing 
• Slit lamp exam and dilated fundus exam 
• Spectral-domain optical coherence tomography (SD-OCT) using 
Avanti device;  
• OCT angiography using Avanti AngioVueTM  
And, per investigator’s discretion: 
• FA (required if investigator believes conversion has occurred) 
• Fundus photography. 
 
At any time during the 24-month study period, in the event of 
conversion of the study eye to neovascular AMD, the investigator will 
treat subject with IAI at a frequency per his/her discretion. 
 
Subjects participating in the genomics sub-study will have a blood 
sample taken upon enrollment into the main study.   
 
Subjects participating in the home monitoring sub-study will be 
trained to use the Paxos CheckupTM app on a personal wireless device 
to perform at-home testing at least twice per week including the 
Visual Acuity and Amsler Grid tests within the app. 
 
STATISTICAL PLAN 
The Kaplan-Meier method will be used to estimate time to conversion 
using the conversion criterion, and the log-rank test will be used to 
compare the time course among treatment groups 
 
 

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TABLE OF CONTENTS 
Clinical Study Protocol Synopsis ....................................................................................... 2 
List of Tables ...................................................................................................................... 8 
List of Figures ..................................................................................................................... 8 
List of Appendices .............................................................................................................. 8 
1. 
Introduction and Rationale ...................................................................................... 9 
1.1 
Introduction ............................................................................................................. 9 
1.2 
Rationale ................................................................................................................. 9 
1.2.1 Rationale for Study Design ........................................................................... 10 
1.2.2 Rationale for Dose Selection ........................................................................ 10 
2. 
Study Objectives ................................................................................................... 10 
2.1 
Primary Objective ................................................................................................. 10 
2.2 
Secondary Objectives............................................................................................ 10 
2.3 
Exploratory Objectives ......................................................................................... 11 
3. 
Study Design ......................................................................................................... 11 
3.1 
Study Description and Duration............................................................................ 11 
3.2 
Planned Interim Analysis ...................................................................................... 12 
4. 
Selection, Withdrawal, and Replacement of Subjects .......................................... 12 
4.1 
Number of Subjects Planned ................................................................................. 12 
4.2 
Study Population ................................................................................................... 13 
4.2.1 Inclusion Criteria .......................................................................................... 13 
4.2.2 Exclusion Criteria ......................................................................................... 14 
4.3 
Premature Withdrawal from the Study ................................................................. 16 
4.4 
Replacement of Subjects ....................................................................................... 16 
5. 
Study Treatments .................................................................................................. 16 
5.1 
Investigational Treatment ..................................................................................... 16 
5.2 
Reference Treatment ............................................................................................. 16 
5.3 
Background Treatment(s) ..................................................................................... 16 
5.4 
Treatment on Conversion ...................................................................................... 17 
5.5 
Dose Modification and Stopping Rules ................................................................ 17 
5.5.1 Dose Modification ........................................................................................ 17 
5.5.2 Study Drug Stopping Rules .......................................................................... 17 

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5.5.2.1 
Reasons for Permanent Discontinuation of Study Drug ....................... 17 
5.5.2.2 
Reasons for Temporary Discontinuation of Study Drug ...................... 18 
5.6 
Method of Treatment Assignment ........................................................................ 18 
5.6.1 Masking......................................................................................................... 18 
5.6.2 Emergency Unmasking ................................................................................. 18 
5.7 
Treatment Logistics and Accountability ............................................................... 19 
5.7.1 Packaging, Labeling, and Storage ................................................................. 19 
5.7.2 Supply and Disposition of Treatments .......................................................... 19 
5.7.3 Treatment Accountability ............................................................................. 20 
5.7.4 Treatment Compliance .................................................................................. 20 
5.8 
Concomitant Medications and Procedures............................................................ 21 
5.8.1 
Permitted Medications and Procedures ..................................................... 21 
5.8.2 
Prohibited Medications and Procedures .................................................... 21 
6. 
Study Schedule of Events and Visit Descriptions................................................. 22 
6.1 
Schedule of Events .............................................................................................. 222 
6.2 
Study Visit Descriptions ....................................................................................... 23 
6.2.1 Screening/Day –14 to Day -1 (window) ....................................................... 24 
6.2.2 Treatment Period ........................................................................................... 24 
6.2.2.1 
Baseline/Day 0 (window) ..................................................................... 24 
6.2.2.2 
Month 3, 6, 9, 12, 15, 18, 21 (window: ± 7 days for each visit)  .......... 25 
6.2.3 End of Study Visit/Month 24 (window: ± 7 days)/Early Termination ......... 26 
6.2.4 Early Termination Visit ................................................................................ 26 
6.2.5 Suspected Conversion Visits (SCV) ............................................................. 26 
6.2.6 Other Interim Visits ...................................................................................... 27 
6.2.7 Required Visits Post-Conversion…………………………………………...28 
7. 
Safety Definitions, Reporting, and Monitoring .................................................... 28 
7.1 
Definitions............................................................................................................. 28 
7.1.1 Adverse Event ............................................................................................... 28 
7.1.2 Serious Adverse Event .................................................................................. 29 
7.2 
Recording and Reporting Adverse Events ............................................................ 30 
7.2.1 Deaths ........................................................................................................... 30 
7.2.2 Pregnancy and Other Events that Require Accelerated Reporting ............. 300 

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7.2.3 Reporting Adverse Events Leading to Withdrawal from the Study ............. 31 
7.2.4 Abnormal Vital Signs Results ....................................................................... 31 
7.2.5 Follow-up ...................................................................................................... 32 
7.3 
Evaluation of Severity and Causality .................................................................... 32 
7.3.1 Evaluation of Severity................................................................................. 322 
7.3.2 Evaluation of Causality ............................................................................... 322 
8. 
Study Variables ..................................................................................................... 33 
8.1 
Demographic and Baseline Characteristics .......................................................... 33 
8.2 
Primary and Secondary Endpoints ........................................................................ 33 
9. 
Statistical Plan ....................................................................................................... 34 
9.1 
Statistical Hypothesis ............................................................................................ 34 
9.2 
Determination of Sample Size .............................................................................. 35 
9.3 
Analysis Sets ......................................................................................................... 35 
9.3.1 Efficacy Analysis Sets .................................................................................. 35 
9.3.2 Safety Analysis Set ....................................................................................... 35 
9.4 
Subject Disposition ............................................................................................... 35 
9.5 
Statistical Methods ................................................................................................ 36 
9.5.1 Demography and Baseline Characteristics ................................................... 36 
9.5.2 Efficacy Analyses ......................................................................................... 36 
9.5.3 Safety Analysis ............................................................................................. 36 
9.5.4 Interim Analysis ............................................................................................ 36 
10. 
Data Management and Electronic Systems ........................................................... 37 
10.1 
Electronic Systems ................................................................................................ 37 
11. 
Study Monitoring .................................................................................................. 37 
11.1 
Monitoring of Study Sites ..................................................................................... 37 
11.2 
Source Document Requirements ........................................................................... 37 
11.3 
Case Report Form Requirements .......................................................................... 38 
12. 
Audits and Inspections .......................................................................................... 38 
13. 
Ethical and Regulatory Considerations ................................................................. 39 
13.1 
Good Clinical Practice Statement ......................................................................... 39 
13.2 
Informed Consent.................................................................................................. 39 
13.3 
Subject Confidentiality and Data Protection......................................................... 40 

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13.4 
Institutional Review Board ................................................................................... 40 
14. 
Protocol Amendments ........................................................................................... 40 
15. 
Premature Termination of the Study or Close-out of a Site .................................. 41 
15.1 
Premature Termination of the Study ..................................................................... 41 
16. 
Study Documentation............................................................................................ 41 
16.1 
Certification of Accuracy of Data ......................................................................... 41 
16.2 
Retention of Records............................................................................................. 41 
17. 
Confidentiality ...................................................................................................... 41 
18. 
Financing and Insurance ....................................................................................... 41 
19. 
Publication Policy ................................................................................................. 41 
20. 
References ............................................................................................................. 42 
 
 
 
 
LIST OF TABLES 
Table 1 
Schedule of Events ........................................................................................ 23 
 
LIST OF FIGURES 
 
LIST OF APPENDICES 
Appendix A - Paxos CheckupTM Application Procedures ................................................ 42 
 
21.1 For the Practice Sites .................................................................................... 42 
 
21.2 For the Subject .............................................................................................. 42 
 
 

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1.0                 INTRODUCTION AND RATIONALE 
1.1 
Introduction 
Age-related macular degeneration (AMD) has surpassed cataract as the leading cause of visual 
impairment in the developed world, accounting for more than 50% of all blindness in the United 
States1.  According to a 2004 study by the Eye Diseases Prevalence Research Group, 8 million 
Americans had bilateral intermediate dry AMD and 2 million had advanced AMD, defined as 
neovascularization or geographic atrophy2.  Although dry AMD is significantly more prevalent, 
neovascular AMD continues to account for more than 90% of significant visual loss3. 
1.2 
Rationale 
There has been extensive research evaluating risk factors and conversion rates related to the 
transformation from advanced dry AMD to neovascular AMD, an event that can lead to precipitous 
vision loss without prompt treatment.  Risk factors that have been found to be statistically 
significant include age, gender, race, and smoking4.   Over a mean follow-up time of 6.3 years, 
The Age-Related Eye Disease Study (AREDS) reported a 10% conversion rate in at least one eye 
of patients with bilateral drusen without advanced AMD.  When they looked at fellow eyes of 
patients with unilateral neovascular AMD, the rate went up to 35% over a mean follow-up time of 
6.3 years5.  With the advent of the anti-VEGF treatment era, patients with unilateral neovascular 
AMD have been studied closer and varying conversion rates have been reported from 5 to 20% 
per year of follow-up6.  One study included evidence of neovascularization by SD-OCT (e.g. 
subretinal fluid) in addition to fluorescein angiographic findings and reported conversion rates as 
high as 60% per year6. 
       Although there has been a tremendous effort to establish treatment prevention for this subset 
of patients, high-dose vitamins and antioxidants based on the AREDS has been the only proven 
treatment with a modest reduction in risk of 25% over 5 years7.  With the overwhelming success 
of anti-VEGF agents in neovascular AMD, researchers have asked whether anti-VEGF agents can 
affect the natural course of high-risk dry AMD.  Barbazetto and associates reviewed the fellow 
eyes of patients enrolled in MARINA and ANCHOR studies and found that conversion rates in 
fellow eyes among treatment cohorts (receiving monthly ranibizumab in the study eye) was not 
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(sham injection in MARINA and photodynamic therapy in ANCHOR).  Their conversion rates to 
neovascular AMD in fellow eyes, which were based on fluorescein angiography readings, were 
21-26% over 12 months and 35-39% over 24 months5.  They concluded that the fractional serum 
anti-VEGF concentrations achieved after intravitreal injection in the treatment eye did not have an 
effect on the conversion rate of the fellow eye. 
       With such significant conversion rates among patients who have unilateral neovascular AMD, 
the next logical question would be whether direct intravitreal anti-VEGF in eyes with high-risk 
dry AMD would provide a prophylactic effect against the conversion to neovascular AMD.  Such 
a prophylactic effect could be extremely valuable because of its impact on vision preservation and 
quality of life, especially to patients who already suffer visual impairment in one eye.   
1.2.1 
Rationale for Study Design 
Neovascularization in AMD is highly dependent on the presence of elevated levels of free VEGF.  
Inhibition of free VEGF with aflibercept may influence the rate of developing choroidal 
neovascularization. 
1.2.2 
Rationale for Dose Selection 
The 2 mg aflibercept dose was chosen as its safety profile has been established in previous clinical 
studies with IVT aflibercept. 
 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to evaluate IAI 2 mg as prophylaxis against the conversion 
to neovascular age-related macular degeneration (AMD) in high-risk eyes at 24 months. 
2.2 
Secondary Objectives 
The secondary objectives of the study are to evaluate: 
• Mean change in visual acuity at 24 months compared to baseline 

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• Percentage of subjects losing < 15 ETDRS letters at 24 months and change in visual 
acuity from baseline; 
• Incidence and severity of potential ocular side effects of endophthalmitis, retinal 
detachment, cataract, and intraocular inflammation 
• Incidence and severity of systemic side effects; and 
• Development/progression of geographic atrophy. 
2.3 
Exploratory Objectives 
Additional exploratory analysis will include:  
• In subjects who choose to participate in the genomics sub-study, blood samples will be 
taken for exploratory DNA analysis. 
• In subjects who convert to neovascular AMD, additional analyses include: 
o Mean change in visual acuity at conversion 
o Mean change in visual acuity at 24 months 
o Mean number of IAI injections through 24 months 
o Mean size of choroidal neovascular membrane at 24 months per FA 
o Detection of conversion to neovascular AMD by OCT angiography 
o Correlation of CNV detection by OCT angiography relative to FA 
o Timing of CNV detection by OCT angiography relative to FA 
• In subjects who choose to participate in the home monitoring sub-study, exploratory 
analyses include the correlation between an alert generated by the Paxos CheckupTM 
application (“app”) and a confirmed conversion at subject’s next office visit. 
 
3. 
STUDY DESIGN 
3.1 
Study Description and Duration 
This is a prospective, single-blind, randomized study to evaluate intravitreal aflibercept injection 
(IAI) versus sham as prophylaxis against conversion to neovascular age-related macular 
degeneration (AMD) in “high-risk” subjects.  High risk is defined as having intermediate AMD in 
one eye (study eye), defined as the presence of greater than ten intermediate sized drusen (≥ 63 

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and <125 μm), 1 or more large druse (≥125 μm), and/or retinal pigmentary changes and 
neovascular AMD in the fellow eye. 
128 subjects will be enrolled in the trial and randomized in a 1:1 ratio to receive either IAI every 
three months for 24 months or sham injections.  Enrollment will be stratified in order to ensure a 
balance between the two treatment groups for subjects who were diagnosed with exudative AMD 
within the past two years versus those diagnosed more than two years prior to Baseline.   
Study assessments will be conducted at required visits every three months and include manifest 
refraction and ETDRS visual acuity testing, slit lamp exam and dilated fundus exam, spectral-
domain optical coherence tomography (SD-OCT) using Avanti device, and OCT angiography 
using Avanti AngioVueTM, and fluorescein angiography.  Fundus photography will also be 
performed at Baseline, Month 12 and Month 24 visits. 
In the event of conversion to neovascular AMD in the study eye at any point during the study, the 
investigator will treat the subject with IAI at a frequency per his/her discretion. 
In subjects who participate in the genomics sub-study, blood samples will be taken for exploratory 
DNA analysis. 
Subjects participating in the home monitoring sub-study will be trained to use the Paxos 
CheckupTM app on a personal wireless device to perform at-home testing twice per week 
including the Visual Acuity and Amsler Grid tests within the app. 
3.2 
Planned Interim Analysis 
Interim analyses will be performed when all subjects have completed Month 12 visits.  See Section 
9.5.4 for specific analyses. 
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS 
4.1 
Number of Subjects Planned 
128 subjects will be enrolled in a 1:1 ratio: 64 subjects will be randomized to IAI treatment every 
three months for 24 months and 64 control subjects will receive sham injections every three months 
for 24 months.  Enrollment will be stratified in order to ensure a balance between the two treatment 

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groups for subjects who were diagnosed with exudative AMD within the past two years versus 
those diagnosed more than two years prior to Baseline. 
4.2 
Study Population 
Eligible subjects will have high-risk non-neovascular AMD in one eye (study eye) defined as 
having: 
• Intermediate AMD in the study eye, and 
• Neovascular AMD in the fellow eye 
4.2.1 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for inclusion in the study: 
• Study eye must have a diagnosis of non-exudative age-related degeneration 
characterized by the presence of greater than ten intermediate sized drusen (≥ 63 and 
<125 μm), 1 or more large druse (≥125 μm), and/or retinal pigmentary changes. 
• Fellow (non-study) eye must have CNV lesion (i.e., leakage on fluorescein 
angiography and/or subretinal, intraretinal, or sub-RPE fluid on OCT) secondary to 
age-related macular degeneration OR history of CNV lesion secondary to age-related 
macular degeneration, as confirmed by current or past treatment or current or past 
diagnostic imaging.   
• Subject must be willing and able to comply with clinic visits and study-related 
procedures. 
• Subject must provide signed informed consent. 
• Subject must be able to understand and complete study-related questionnaires. 
• In order to participate in the home monitoring sub-study, subjects must have an 
approved wireless device (i.e. iPhone, iPad, or iPod running iOS 6.0 or later) or be 
willing to use a loaned device and have access to a wireless Internet connection for the 
duration of the study. 
 

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4.2.2 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
• Evidence of neovascular AMD in the study eye at time of enrollment or anytime in the 
past.  The reading center must confirm that there is no evidence of neovascular AMD 
in the study eye prior to enrollment. 
• Previous treatment with verteporfin PDT, anti-VEGF therapy, laser, external beam 
radiation or other AMD therapy in the study eye.  
• History of macular hole in study eye. 
• History of vitrectomy in study eye. 
• Lens extraction or implantation within the last 3 months. 
• Capsulotomy within the last 1 month. 
• Lens or other media opacity that would preclude good fundus photography or 
angiography within the next 2 years. 
• Macular edema or signs of diabetic retinopathy more severe than 10 microaneurysms 
or blot hemorrhages. 
• Retinal changes related to high myopia and/or myopic correction greater than 8.00 
diopters spherical equivalent [sphere + ½ cylinder]. 
• Any progressive ocular disease that would affect visual acuity within the next 2 years. 
• Previous participation in any studies of investigational drugs likely to have ocular 
effects within 30 days preceding the initial study treatment. 
• Concurrent use of systemic anti-VEGF agents. 
• Active or recent (within 4 weeks) intraocular inflammation (grade trace or above) in 
the study eye. 
• Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye. 
• For subjects who have undergone prior refractive or cataract surgery in the study eye, 
the preoperative refractive error in the study eye cannot exceed 8 diopters of myopia. 
• Uncontrolled glaucoma in the study eye (defined as intraocular pressure > 25 mmHg) 
despite treatment with anti-glaucoma medication). 
• Subjects who are unable to be photographed to document CNV due to known allergy 
to fluorescein dye, lack of venous access or cataract obscuring the CNV. 

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• Subjects with other ocular diseases that can compromise the visual acuity of the study 
eye such as amblyopia and anterior ischemic optic neuropathy. 
• Current treatment for active systemic infection. 
• Evidence of significant uncontrolled concomitant diseases such as cardiovascular 
disease, nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal 
disorders. 
• History of recurrent significant infections or bacterial infections. 
• Inability to comply with study or follow-up procedures. 
• Pregnancy (positive pregnancy test) or lactation   
Premenopausal women not using adequate contraception.  The following are 
considered effective means of contraception:  surgical sterilization or use of oral 
contraceptives, barrier contraception with either a condom or diaphragm in conjunction 
with spermicidal gel, an IUD, or contraceptive hormone implant or patch. 
• Any other condition that the investigator believes would pose a significant hazard to 
the subject if the investigational therapy were initiated 
• Participation in another simultaneous medical investigation or trial 
• Pregnant or breast-feeding women 
• Sexually active men* or women of childbearing potential** who are unwilling to 
practice adequate contraception during treatment and for at least 3 months after the last 
intravitreal injection of aflibercept (adequate contraceptive measures include stable use 
of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more 
menstrual cycles prior to screening; intrauterine device [IUD]; bilateral tubal ligation; 
vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus 
contraceptive sponge, foam, or jelly) 
*Contraception is not required for men with documented vasectomy. 
**Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of child bearing potential.  Pregnancy testing and contraception are not required for 
women with documented hysterectomy or tubal ligation. 

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4.3 
Premature Withdrawal from the Study 
A subject has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator has the right to withdraw a subject from the study in the event of illness, adverse 
event (“AE”), treatment failure, protocol violation, cure, and for administrative or other reasons.  
An excessive rate of withdrawals would render the study uninterpretable; therefore, unnecessary 
withdrawal of subjects will be avoided. 
Should a subject (or a subject’s legally authorized guardian or representative) decide to withdraw, 
all efforts will be made to complete and report observations as thoroughly as possible.  Early 
termination procedures will be followed. 
4.4 
Replacement of Subjects 
Subjects prematurely withdrawn from the study can be replaced, if needed, to ensure an adequate 
number of evaluable subjects.  The investigator, in cooperation with the study statistician, will 
decide whether or not to replace withdrawn subjects. 
 
5. 
STUDY TREATMENTS 
5.1 
Investigational Treatment:  
IAI 2 mg at baseline and at an interval of every 3 months thereafter for 24 months (total of 8 
injections), until/unless conversion occurs. 
5.2 
Reference Treatment 
Observation with sham injections at baseline and at an interval of every 3 months thereafter for 24 
months (total of 8 sham injections), until/unless conversion occurs. 
5.3 
Background Treatment(s) 
Many subjects will be currently taking AREDS vitamin supplements and may continue to do so 
throughout the study. 

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If a subject is currently receiving therapy in his fellow eye other than IAI, treatment will be 
switched to IAI.  IAI is the only treatment allowed by the study for the treatment of neovascular 
AMD.  Subject may not have received any treatment for exudative AMD in his fellow eye other 
than IAI within 28 days prior to Day 0. 
5.4 
 Treatment on Conversion 
In the event of conversion to neovascular AMD in subject’s study eye, the investigator will treat 
subject with IAI at a frequency per his/her discretion. 
5.5 
Dose Modification and Stopping Rules 
5.5.1 
Dose Modification 
Dose modification for an individual subject is not allowed. 
5.5.2 
Study Drug Stopping Rules 
Subjects who discontinue from study drug will be exited from the study and must perform an Early 
Termination Visit approximately one month following last dose of study drug.   
5.5.2.1 
Reasons for Permanent Discontinuation of Study Drug:  
The subject may be withdrawn from the study for any reasons: if it is in the best interest of the 
subject, illness, adverse events, or worsening condition.  The PI may request the withdrawal of a 
subject because of protocol violations, administrative reasons, or any other valid and ethical 
reasons.   
If a subject discontinues from the study, he or she will not be allowed to re-enter the study. 
Reasons for subject discontinuation may include, but are not limited to, the following: 
• Sensory rhegmatogenous retinal detachment or Stage 3 or 4 macular hole 
• Investigator determination that it is not in the best interest of the subject to continue 
participation 
• Pregnancy 

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• Need for anti-VEGF therapy other than IAI in either eye for a condition requiring treatment 
other than AMD. 
• SAE 
• Any other safety concerns 
In the event of an adverse event in the study eye that is considered by the investigator to be severe 
in intensity, serious consideration should be given to discontinuing the subject from the study.   
5.5.2.2 
Reasons for Temporary Discontinuation of Study Drug 
Temporary discontinuation is not allowed in the study. 
5.6 
Method of Treatment Assignment 
Subjects will be randomized in a 1:1 ratio to treatment and observations groups by simple random 
assignment. 
5.6.1 
Masking 
Subjects will be masked to the identity of treatment (IAI or observation).  Sham injections will be 
performed to preserve the mask.  When performing a sham injection, the ophthalmologist will 
ensure that injection preparation is identical to an IAI injection besides the actual injection.   
5.6.2   
Emergency Unmasking 
Emergency unmasking of treatment assignment for a subject may be necessary due to a medical 
emergency, a serious adverse event SAE that is unexpected and for which a causal relationship to 
study drug cannot be ruled out, or any other significant medical event (e.g. pregnancy). 
If emergency unmasking is required for a medical emergency: 
• Only an investigator will make the decision to unmask the treatment assignment. 
• Only the subject with the medical emergency will be unmasked. 
• The investigator or coordinator will notify Regeneron and/or designee that the subject has 
been unmasked. 

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5.7 
Treatment Logistics and Accountability 
5.7.1 
Packaging, Labeling, and Storage 
2.0 mg intravitreal aflibercept injection is formulated as a sterile liquid to a final concentration of 
40 mg/mL intravitreal aflibercept injection in 5% sucrose, 10 mM sodium phosphate pH 6.3, 
0.03% polysorbate 20, and 40 mM NaCl. Intravitreal aflibercept injection 2.0 mg study drug will 
be supplied by Regeneron Pharmaceuticals Inc. in sealed, sterile 3 mL vials with a “withdrawable” 
volume of approximately 0.5 mL. Vials must be used only once (defined as entered with a needle). 
The volume of injection will be 0.05 mL for the 2 mg dose. For study drug in vials, the study drug 
will be withdrawn using aseptic technique.  
 
Study drug will be shipped to the site via overnight shipping using cold packs to maintain a 
temperature of 2° to 8° C. The investigator, or an approved representative (e.g. pharmacist), will 
ensure that all study drugs are stored in a secured area, under recommended storage conditions and 
in accordance with applicable regulatory requirements. The shipping box is to be opened and 
stored immediately at the site in a refrigerator intended for investigational products at a 
temperature of 2° to 8°C.  
 
When vials are removed from the refrigerator, the solution should be visually inspected and it 
should have no evidence of turbidity. If particulates, cloudiness, or discoloration are visible, the 
vial must not be used. Exposure of the material to temperatures outside these limits, except for 
warming prior to administration, is not recommended and may result in loss of activity. Records 
of actual storage conditions (i.e. temperature log) at the study site must be maintained; and must 
include a record of the dates, when the refrigerator was checked, the initials of person checking, 
and the temperature. 
5.7.2 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2 to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. During site close-out, and following drug reconciliation 
and documentation, all  unopened vials of study drug will be destroyed. 

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5.7.3 
Treatment Accountability 
All drug accountability records will be kept current. 
The investigator will account for all opened and unopened vials of study drug.  These records will 
contain the dates, quantity, and study medication 
• dispensed to each subject, 
• returned from each subject (if applicable), and 
• disposed of at the site. 
All accountability records will be made available for inspection by regulatory agency inspectors. 
5.7.4 
Treatment Compliance 
All drug compliance records will be kept current and will be made available for inspection by 
regulatory agency inspectors.

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5.8 
Concomitant Medications and Procedures 
Subjects may take oral AREDS formula vitamins during the study. 
IAI will be provided, as needed, for the subject’s fellow eye and may be administered per 
investigator’s discretion.  If a subject is currently receiving therapy in his fellow eye other than 
IAI, treatment will be switched to IAI.  IAI is the only treatment allowed by the study for the 
treatment of neovascular AMD.  Subject may not have received any treatment for exudative AMD 
other than IAI in his fellow eye within 28 days prior to Day 0. 
5.8.1 
Permitted Medications and Procedures 
Upon confirmation of conversion of study eye to neovascular AMD, the investigator will treat 
subject with IAI at a frequency per his/her discretion. 
5.8.2 
Prohibited Medications and Procedures 
No other treatment for choroidal neovascularization should be given to the study eye, including, 
but not limited to, laser photocoagulation, photodynamic therapy, pegaptanib therapy, 
transpupillary thermotherapy, external beam radiation therapy, submacular surgery, or other 
surgical intervention for AMD. 
No other experimental or investigational treatments are permitted during this study; this includes 
ocular experimental and investigational treatments in the study eye.  
Elective vitrectomy surgery is not allowed in the study eye during study participation. Onset of 
glaucoma during study participation should be treated as clinically indicated. Cataract surgery in 
the study eye may be performed if clinically indicated and should occur > 30 days after the 
previous study injection. 
Treatment of CNV in the non-study eye during the follow-up period should follow the best 
medical judgment of the treating ophthalmologist for the subject. 
Subjects may continue to receive all medications and standard treatments administered for their 
conditions at the discretion of their treating physician. 

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6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
6.1 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 

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Table 1 
Schedule of Events 
Day 
Screening 
Baseline/ 
Day 0 
Month 
3F 
Month 
6 
Month 
9 F 
Month 
12 
Month 
15 F 
Month 
18 
Month 
21 F 
Month 
24/ Early 
Term 
Suspected 
Conversion 
Visit (SCV)A 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Ophthalmic 
History 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ETDRS Refraction & 
Visual Acuity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Exam: 
SLE & DFE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCTB 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT AngiographyB 
X 
X 
X 
X F 
X 
X F 
X 
X F 
X 
X F 
X 
Fundus PhotographyB 
X 
X 
 
 
 
X F 
 
 
 
X F 
XA 
Fluorescein 
AngiographyB 
X 
X 
X 
X F 
X 
X F 
X 
X F 
X 
X  
XA 
Administer Study 
Drug or Sham 
Injection 
 
X 
X 
X F 
X 
X F 
X 
X F 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy TestC 
X 
 
 
 
 
 
 
 
 
 
 
Blood SampleD 
 
X 
 
 
 
 
 
 
 
 
 
At-home MonitoringE 
 
 
 
 
 
 
 
 
 
 
 
 
A – See Section 6.2.5 for discussion of SCV.  FA and FP performed per investigator discretion.  If investigator believes conversion has occurred, FA must be 
performed and submitted to reading center along with SD-OCT for confirmation of conversion prior to treatment. 
B – Study eye only. 
C – Women of child-bearing potential (WOCBP) only. 
D – For subjects participating in genomics sub-study only. 
E – For subjects participating in home monitoring sub-study only.  See Appendix A for at-home monitoring procedures. 
F – Visit or assessment is not required if confirmation of conversion to exudative AMD in study eye precedes the visit.

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6.2 
Study Visit Descriptions 
6.2.1 
Screening/Day –14 to Day -1 (window) 
After the subject has provided informed consent, the following information will be collected: 
• Inclusion/exclusion 
• Demographics 
• Medical and ophthalmic history 
• Concomitant medications  
• Date of initial fellow eye diagnosis of exudative AMD  
The following procedures and assessments will be conducted: 
• Vital signs including sitting blood pressure, and pulse 
• Urine pregnancy test for WOCBP only 
• ETDRS refraction and visual acuity (VA) testing 
• Ophthalmic exam including slit lamp exam (SLE) and dilated fundus exam (DFE) 
• Spectral-domain optical coherence tomography (SDOCT) using Avanti device 
• OCT angiography using Avanti AngioVueTM 
• Fundus photography (FP) 
• Fluorescein angiography (FA) 
6.2.2 
Treatment Period 
6.2.2.1 
Baseline/Day 0 
The Baseline/Day0 visit may occur on the same day as the Screening visit.  If this is the case, the 
assessments performed at Screening do not need to be repeated.   
The following information will be collected: 
• Concomitant medications 

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The following procedures and assessments will be conducted: 
• Vital signs including sitting blood pressure, and pulse  
• For subjects participating in home monitoring sub-study, train subject on proper usage of 
the Paxos CheckupTM app (see Appendix A for specific procedures) 
• ETDRS refraction and VA testing 
• Ophthalmic exam including SLE and DFE 
• SDOCT using Avanti device 
• OCT angiography using Avanti AngioVueTM 
• FP 
• FA 
• Blood draw for genomic testing 
• Administer IAI or sham injection 
• Assess adverse events 
6.2.2.2 
Month 3, 6, 9, 12, 15, 18, 21 (window: ± 7 days for each visit) 
The following information will be collected: 
• Concomitant medications 
• Assess adverse events 
The following procedures and assessments will be conducted: 
• Vital signs including sitting blood pressure, and pulse 
• ETDRS refraction and VA testing 
• Ophthalmic exam including SLE and DFE 
• SDOCT using Avanti device 
• OCT angiography using Avanti AngioVueTM 
• FA  

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• FP (Month 12 only) 
• Administer IAI or sham injection, unless conversion to neovascular AMD is confirmed at 
current visit.  If this is the case, initiate IAI therapy per investigator’s discretion. 
6.2.3 
End of Study Visit/ Month 24 (window: ± 7 days)/ Early Termination  
The following information will be collected: 
• Concomitant medications 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs including sitting blood pressure, and pulse 
• ETDRS refraction and VA testing 
• Ophthalmic exam including SLE and DFE 
• SDOCT using Avanti device 
• OCT angiography using Avanti AngioVueTM 
• FA 
• FP 
• For subjects participating in home monitoring sub-study, ensure subject returns any loaned 
device, if applicable. 
6.2.4 
Early Termination Visit 
Subjects who are withdrawn from the study should be instructed to return to the clinic for end of 
study assessments, as described in section 6.2.3. 
6.2.5 
Suspected Conversion Visits (SCV) 
Given the nature of the subject population, unscheduled visits due to suspected conversion to 
neovascular AMD are likely.  These visits may be prompted by vision changes or other complaints 
in subject’s study eye or an alert from the home monitoring app (for participating subjects).  In the 

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event of an alert from the home monitoring app, the study investigator or designee should promptly 
review the home testing data in the app, speak to the subject, if appropriate, and decide whether to 
bring the subject in for an SCV. 
The following information will be collected: 
• Concomitant medications 
• Assess adverse events 
The following procedures and assessments will be conducted: 
• Vital signs including sitting blood pressure, and pulse 
• ETDRS refraction and VA testing 
• Ophthalmic exam including SLE and DFE 
• SDOCT using Avanti device 
• OCT angiography using Avanti AngioVueTM 
The following procedures may be performed per investigator’s discretion: 
• FA  
• FP  
If investigator believes that conversion to neovascular AMD has occurred, then FA must be 
performed and sent to the reading center along with the SDOCT for confirmation prior to 
treatment.  
If confirmed by reading center, initiate IAI therapy per investigator’s discretion. 
6.2.6 
Other Interim Visits 
If subject is seen at an interim visit for a reason that is unrelated to his/her study eye, subject’s 
study eye should not be examined or evaluated. 

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6.2.7 
Required Visits Post-Conversion 
If there is a confirmed conversion to neovascular AMD in the subject’s study eye during the study, 
the subject will stay in the study and will be treated with IAI.  The frequency of office visits, testing 
procedures, and treatment with IAI is at the investigator’s discretion, according to standard care.   
The following study visits will not be required if conversion precedes the visit:  Month 3, Month 
9, Month 15, and Month 21.   
Following conversion, required study visits will include:  Month 6, Month 12, Month 18, and 
Month 24, only.  Assessments at these required visits are the same as listed for the respective visits 
above, except that OCT-A, FP, and administration of IAI or sham will not be required.  OCT-A, 
FP, and administration of IAI may be performed per investigator’s discretion.  If OCT-A, and FP 
are performed at these visits following conversion, they should not be submitted to the reading 
center.   
FA will also not be required at the Month 6, Month 12, or Month 18 visits, if the visits follows a 
confirmed conversion.  However, FA is required at the Month 24 visit and should be submitted to 
the reading center. 
Furthermore, in the event of conversion to neovascular AMD, required study visits occurring after 
conversion (e.g. Months 6, 12, 18, 24) may be performed +/- 30 days from the target date rather 
than +/- 7 days from the target date. 
 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
7.1 
Definitions 
7.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a subject administered a study drug, which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease that is temporally 
associated with the use of a study drug, whether or not considered related to the study drug.   

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An AE also includes any worsening (i.e. any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
7.1.2 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated to 
study drug (e.g. a car accident in which a subject is a passenger). 
• Is life threatening – in the view of the investigator, the subject is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a more 
severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  In-patient 
hospitalization is defined as admission to a hospital or an emergency room for longer than 
24 hours.  Prolongation of existing hospitalization is defined as a hospital stay that is longer 
than was originally anticipated for the event, or is prolonged due to the development of a 
new AE as determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of one’s 
ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent 1 of the other serious outcomes listed above (e.g., intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias 
or convulsions that do not result in hospitalization; or development of drug dependency or 
drug abuse).  Any malignancy (other than basal cell skin cancers) would be considered a 
medically important event. 

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7.2 
Recording and Reporting Adverse Events 
All AEs and SAEs will be recorded on the CRF and in the subject’s source documents.  Ophthalmic 
exam or vital signs abnormalities will be recorded as AEs only if they are deemed clinically 
significant by the investigator. 
All SAEs, regardless of assessment of causal relationship to study drug will be reported to 
Regeneron Pharmaceuticals, Inc. 
The investigator will promptly report to the IRB all unanticipated problems involving risks to 
subjects.  This includes death from any cause and all SAEs related to the use of the study drug.  
All SAEs will be reported to the IRB, regardless of assessed causality. 
7.2.1 
Deaths 
Any AE that results in death is considered an SAE.  Deaths that occur from the time the subject 
signs the informed consent form (“ICF”) until 90 days after dosing will be reported to the 
appropriate IRB and to Regeneron Pharmacovigilance and Risk Management (or designee) within 
24 hours of learning of the death.   
Any available autopsy reports and relevant medical reports will be sent to Regeneron 
Pharmaceuticals, Inc. as soon as possible. 
To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax 914-345-7476 
SAE hotline: 914-593-1504 
7.2.2 
Pregnancy and Other Events that Require Accelerated Reporting 
The following events will be reported to Regeneron Pharmaceuticals, Inc. within 24 hours of 
learning of the event: 
Overdose:  Accidental or intentional overdose of the study drug or concomitant medication, 
whether or not it is considered an AE. 
Pregnancy:  Although it is not considered an AE, the investigator will report to Regeneron 
Pharmaceuticals, Inc., any pregnancy occurring in a female subject or female partner of a male 

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subject, during the study or within 90 days following the last dose of study drug.  The investigator 
will follow the pregnancy until delivery, or longer.  If the pregnancy continues to term (delivery), 
the health of the infant will also be reported to Regeneron Pharmaceuticals, Inc. 
To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax 914-345-7476 
SAE hotline: 914-593-1504 
7.2.3 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a subject’s withdrawal from the study will be reported to Regeneron 
Pharmaceuticals Inc. within 30 days. All SAEs leading to a subject’s withdrawal from the study 
will be reported. To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax 914-345-7476 
SAE hotline: 914-593-1504 
7.2.4 
Abnormal Vital Signs Results 
The criteria for determining whether an abnormal objective test finding will be reported as an AE 
are as follows: 
• the test result is associated with accompanying symptoms, and/or 
• the test result requires additional diagnostic testing or medical/surgical intervention, and/or 
• the test result leads to a change in dosing (outside of protocol-stipulated dose adjustments), 
discontinuation from the study, significant additional concomitant drug treatment, or other 
therapy. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 

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7.2.5 
Follow-up 
Adverse event information will be collected until the end of study visit, or the early termination 
visit, if the subject withdraws consent. 
The investigator must make every effort to obtain follow-up information on the outcome of any 
SAE until the event is considered chronic and/or stable. 
7.3 
Evaluation of Severity and Causality 
7.3.1 
Evaluation of Severity 
The severity of an AE will be graded by the investigator using a 3–point scale (mild, moderate, or 
severe) and reported in detail as indicated on the CRF and/or SAE form, as appropriate. 
• Mild:  Does not interfere in a significant manner with the subject’s normal functioning 
level.  It may be an annoyance.  Prescription drugs are not ordinarily needed for relief of 
symptoms, but may be given because of personality of the subject. 
• Moderate:  Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
• Severe:  Produces significant impairment of functioning or incapacitation and is a definite 
hazard to the subject’s health.  Treatment for symptom may be given and/or subject 
hospitalized. 
7.3.2 
Evaluation of Causality 
The relationship to treatment will be determined by the investigator and reported on the CRF 
and/or SAE form, as appropriate.  The following terms will be used: 
Not Related:  likely or clearly due to causes other than the study drug. 
Related:  possibly, probably, or definitely related to the study drug. 

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8. 
STUDY VARIABLES 
8.1 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (e.g. age, race, etc.), disease 
characteristics including medical history, and medication history for each subject. 
8.2 
Primary and Secondary Endpoints 
The primary endpoint in the study is the proportion of subjects converting to neovascular AMD at 
24 months, characterized by the development of choroidal neovascularization (CNV).  The 
development of CNV will be assessed by: 
• CNV leakage on FA, and 
• Evidence of any fluid on SD-OCT. 
Conversion will be confirmed by the reading center.  The Kaplan-Meier method will be used to 
estimate time to conversion using the conversion criteria, and the log-rank test will be used to 
compare the time course among treatment groups. 
The secondary endpoints are: 
• Mean change in visual acuity at 12 months and 24 months compared to baseline; 
• Percentage of subjects losing < 15 ETDRS letters at 12 months and 24 months as compared 
to baseline; 
• Incidence and severity of potential ocular side effects including endophthalmitis, retinal 
detachment, cataract, and intraocular inflammation 
• Incidence and severity of systemic side effects; and 
• Development/progression of geographic atrophy. 
 
In subjects who choose to participate in the genomics sub-study, blood samples will be taken for 
exploratory DNA analysis. 
 
In subjects who convert to neovascular AMD, additional exploratory analyses include: 

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• Mean change in visual acuity at conversion; 
• Mean change in visual acuity at 24 months; 
• Mean number of IAI injections through Month 24 
• Mean size of choroidal neovascular membrane at 24 months per FA 
• Detection of conversion to neovascular AMD by OCT angiography 
• Correlation of CNV detection by OCT angiography relative to FA 
• Timing of CNV detection by OCT angiography relative to FA. 
 
In subjects who choose to participate in the home monitoring sub-study, exploratory analyses 
include the correlation between an alert generated by Paxos CheckupTM application (“app”) and 
a confirmed conversion at subject’s next office visit. 
 
9. 
STATISTICAL PLAN 
9.1 
Statistical Hypothesis 
The percentage of subjects who convert to neovascular AMD in the study eye through months 12 
and 24 will be examined by treatment group.   
Chi-square tests for contingency tables will be used to compare conversion rates between subjects 
whose study eyes were randomized to control (sham) versus IAI.   
The Kaplan-Meier method will be used to estimate time to conversion using the conversion 
criterion, and the log-rank test will be used to compare the time course among treatment groups.   
For converters, time to conversion will be calculated as number of days between first treatment 
date and first conversion date defined as SD-OCT and/or FA examination date, onset date for 
adverse event, procedure date for concurrent ocular procedure, and start date for concomitant 
medication.  
For non-converters, follow-up time will be calculated as days from first treatment date to last study 
date.  Statistical significance will be defined as P < .05.   
The primary statistical analyses will be performed on an intent-to-treat basis. 

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9.2 
Determination of Sample Size 
Sample sizes were calculated by setting the power at .80 and the alpha level at .05 for detecting a 
70% reduction in conversion to neovascular AMD yielding N = 102 subjects (51 treatment and 51 
control). 
Prior studies have shown that, of those who had neovascular AMD in one eye, conversion rates 
from non-neovascular to neovascular AMD in high-risk fellow eyes was 10-60% over 1-2 years.  
We assume a 35% conversion rate over 2 years. 
An assumed 8% loss due to death and dropouts per year was used for all calculations. 
9.3 
Analysis Sets 
9.3.1 
Efficacy Analysis Sets 
The full analysis set (“FAS”) includes all randomized subjects who received any study drug; it is 
based on the treatment allocated (as randomized).  Efficacy endpoints will be analyzed using the 
FAS. 
9.3.2 
Safety Analysis Set 
The safety analysis set (“SAF”) includes all randomized subjects who received any study drug; it 
is based on the treatment received (as treated).  Treatment compliance/ administration and all 
clinical safety variables will be analyzed using the SAF. 
9.4 
Subject Disposition 
The following will be provided: 
• The total number of screened subjects who met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized subjects who received a randomization number 
• The total number of subjects in each analysis set (e.g.FAS, SAF, etc.) 
• The total number of subjects who discontinued the study, and the reasons for 
discontinuation 

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9.5 
Statistical Methods 
9.5.1 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group.  
Continuous variables will be summarized with mean, median, standard deviation, minimum, and 
maximum.  Categorical variables will be summarized with frequency and percentage. 
9.5.2 
Efficacy Analyses 
Efficacy endpoints from all enrolled subjects will be analyzed by treatment group.  
9.5.3 
Safety Analysis 
Adverse events from all enrolled subjects will be utilized to summarize safety data by treatment 
group. 
9.5.4 
Interim Analysis 
After all subjects have completed the Month 12 visit, the following will be analyzed: 
 
• Proportion of subjects converting to neovascular AMD at 12 months, characterized 
by the development of choroidal neovascularization (CNV).  The development of 
CNV will be assessed by: 
o CNV leakage on FA, and 
o Evidence of any fluid on SD-OCT. 
Conversion will be confirmed by the reading center (“confirmed conversion”).   
• Mean change in visual acuity at 12 months compared to baseline 
• Percentage of subjects losing < 15 ETDRS letters at 12 months as compared to 
baseline 
• Incidence and severity of potential ocular side effects including endophthalmitis, 
retinal detachment, cataract, and intraocular inflammation 
• Incidence and severity of systemic side effects 
 

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10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at the study site. 
The CRF data for this study will be collected on paper-based forms and transmitted to the contract 
research organization (CRO) for data entry into the study database, a Microsoft Access database.   
10.1  
Electronic Systems 
Electronic systems used to process and/or collect data in this study will include the following: 
• Study sites’ electronic medical records systems. 
• Microsoft Access-based database designed and maintained by the study CRO. 
11. 
STUDY MONITORING 
11.1 
Monitoring of Study Sites 
The study monitor and/or designee (e.g. CRO monitor) will visit each site prior to enrollment of 
the first subject, and periodically during the study.  In accordance with International Conference 
on Harmonisation (“ICH”) guidelines, the monitor will compare the CRF entries with the 
appropriate source documents.  Additional review may include, but is not limited to, subject ICFs, 
documentation of subject recruitment and follow-up, AEs, SAEs, and concomitant therapy; as well 
as records of study drug dispensing, compliance, and accountability.  A copy of the drug dispensing 
log will be provided to the study monitor upon request. 
11.2 
Source Document Requirements 
Investigator will prepare and maintain adequate and accurate subject records (source documents). 
The investigator will keep all source documents on file with the CRF.  Case report forms and 
source documents will be available at all times for inspection by authorized representatives of the 
regulatory authorities. 

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11.3 
Case Report Form Requirements 
A CRF for each subject enrolled in the study will be completed and signed by the study investigator 
or authorized designee. The CRF will be typed or filled out using indelible ink.  The writing will 
be legible. Errors will be crossed out but not obliterated, the correction inserted, and the change 
initialed and dated by the investigator or authorized designee. The investigator will ensure the 
accuracy, completeness, legibility, and timeliness of the data reported in the CRFs.  Case report 
forms will be available at all times for inspection by authorized representatives of the regulatory 
authorities. 
12. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the regulatory authorities.  
Should this occur, the investigator will be responsible for: 
• Informing Regeneron of a planned inspection by the authorities as soon as notification is 
received 
• Providing access to all necessary facilities, study data, and documents for the inspection or 
audit 
• Communicating any information arising from inspection by the regulatory authorities to 
the Regeneron immediately 
• Taking all appropriate measures requested by the regulatory authorities to resolve the 
problems found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.   
In all instances, the confidentiality of the data will be respected. 

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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Good Clinical Practice Statement 
It is the responsibility of the investigator(s) to ensure that this clinical study will be conducted in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that 
are consistent with the ICH guidelines for Good Clinical Practice (GCP) and applicable regulatory 
requirements. 
13.2 
Informed Consent 
The principles of informed consent are described in ICH Guidelines for GCP. 
Regeneron will have the right to review and comment on the informed consent form. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each subject prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the subject in 
language that he/she can understand.  The ICF will be signed and dated by the subject and by the 
investigator or authorized designee who reviewed the ICF with the subject.   
Subjects who can write but cannot read will have the ICF read to them before signing and dating 
the ICF. 
Subjects who can understand but who can neither write nor read will have the ICF read to them in 
presence of an impartial witness, who will sign and date the ICF to confirm that informed consent 
was given. 
The original ICF will be retained by the investigator as part of the subject's study record, and a 
copy of the signed ICF will be given to the subject. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF will 
be reviewed and updated appropriately.  All study subjects will be informed of the new information 
and provide their written consent if they wish to continue in the study.  The original signed revised 
ICF will be maintained in the subject’s study record and a copy will be given to the subject. 

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13.3 
Subject Confidentiality and Data Protection 
The investigator will take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained.   
The subject's and investigator's personal data will be treated in compliance with all applicable laws 
and regulations.   
13.4 
Institutional Review Board  
An appropriately constituted IRB/IEC, as described in ICH Guidelines for GCP, will review and 
approve:  
• The protocol, ICF, and any other materials to be provided to the subjects (e.g. advertising) 
before any subject may be enrolled in the study  
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the subjects, in which 
case the IRB will be informed as soon as possible  
Ongoing studies will be reviewed by the IRB/EC on an annual basis or at intervals appropriate to 
the degree of risk.  
In addition, the IRB will be informed of any event likely to affect the safety of subjects or the 
continued conduct of the clinical study. 
A copy of the IRB approval letter will be sent to Regeneron prior to shipment of drug supplies to 
the investigator.  The approval letter will include the study number and title, the documents 
reviewed, and the date of the review. 
Records of the IRB review and approval of all study documents (including approval of ongoing 
studies) will be kept on file by the investigator. 
14. 
PROTOCOL AMENDMENTS 
The investigator will not implement a change in the design or operation of the protocol or ICF 
without an IRB-approved amendment. 

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15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A SITE 
15.1 
Premature Termination of the Study 
The investigator will notify Regeneron of a desire to close-out a site in writing, providing 
approximately 30 days’ notice.  The final decision will be made through mutual agreement with 
Regeneron.  Both parties will arrange the close-out procedures after review and consultation. 
In all cases, the appropriate IRB and Health Authorities will be informed according to applicable 
regulatory requirements, and adequate consideration will be given to the protection of the subjects’ 
interests. 
16. 
STUDY DOCUMENTATION 
16.1 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs will be signed 
by the investigator.  This certification form accompanies each set of CRFs.  
16.2 
Retention of Records 
The investigator will retain all essential study documents, including ICFs, source documents, 
CRFs, and drug accountability records for at least 10 years following the completion or 
discontinuation of the study, or longer if a longer period is required by relevant regulatory 
authorities.  Records will be destroyed in a manner that ensures confidentiality. 
17. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
18. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
19. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 

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20. 
REFERENCES 
1. Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among 
adults in the United States. Arch Ophthalmol 2004;122:477–485. 
 
2. Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in 
the United States. Arch Ophthalmol 2004;122:564–572. 
 
3. Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 
1988;32(6):375–413. 
 
4. Age-related Eye Disease Study Research Group.  Risk factors for the incidence of advanced 
age-related macular degeneration in the age-related eye disease study (AREDS)- AREDS 
Report No. 19.  Ophthalmology 2005; 112(4):533-539. 
 
5. Barbazetto IA, Saroj N, Shapiro H, Wong P, Ho AC, Freund KB. Incidence of new choroidal 
neovascularization in fellow eyes of patients treated in the MARINA and ANCHOR trials.  Am 
J Ophthalmol. 2010 Jun;149(6):939-946. 
 
6. Lujan BJ, Zhengrong L, Hopkins JJ.  Comparison of spectral domain (SD-OCT) and 
fluorescein angiography (FA) conversion rates in fellow eyes of harbor patients.  AAO  2012 
Joint Meeting Poster # PO241. Chicago, IL, November 10-13th. 
 
7. Age-related Eye Disease Study Research Group.  A randomized, placebo-controlled, clinical 
trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-
related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 
2001;119: 1416–36. 

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APPENDIX A - Paxos CheckupTM Application Procedures 
21. 
APPENDIX A 
PAXOS CHECKUPTM APPLICATION PROCEDURES 
21.1 
For the Practice Sites 
Practice sites will be trained by DigiSight Technologies, Inc. prior to subject enrollment so 
that staff are certified to: 
• Register monitoring subjects on the Paxos CheckupTM app 
• Configure subject test sequence (Acuity and Amsler) and frequency (bi-weekly) 
• Prepare subjects for home monitoring (“onboarding”) 
• Review monitoring data for testing compliance and vision alerts 
• Respond per study protocol to vision alerts 
 
Physicians and staff will also be registered on the DigiSight system (required to review 
patient monitoring information), and practices configured (so that data sharing between 
physicians and staff may occur) prior to study start. 
21.2 
For the Subject 
Once subjects have been enrolled in the monitoring sub-study, they will be registered and 
“onboarded” by site staff following procedures documented in: 
How to Register New Patients 
How to Prepare New Patients for Home Vision Monitoring 
The onboarding process will be accomplished during the subject’s baseline visit, when 
subject is not dilated. 
Following the baseline visit, the subject will monitor at home, running “My Test Sequence” 
to do his/her Acuity and Amsler tests at least twice per week.  Optimally, subject will test 
around the same time of day and in the same conditions, but this is not required. 
Subject will be reminded if he/she fails to test at least twice per week, and must respond to 
any reminders, or instructions from the app to re-test, promptly. 
Failure to maintain testing compliance will be grounds for removal from the sub-study, at 
the site physician’s determination. 
Because monitoring data must flow to the practices in real time, subjects using devices 
without cell service which require network connectivity (for example, iPods and certain 
iPads) must ensure that they are connected (for example, via WiFi) when testing.  If the 
subject cannot maintain connectivity reliably during the study, this may be grounds for 
removal from the sub-study, at the site physician’s determination. 
If the subject receives a vision alert on his/her testing device, he/she should follow the 
instructions from the application and call his/her physician’s office to discuss promptly.  If 
he/she feels the alert was generated by a testing error, he/she should make this clear to the 
office at the time of discussion. 

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Please note that the subject should NEVER WAIT TO CONTACT HIS/HER PHYSICIAN 
IF HE/SHE EXPERIENCES A CHANGE IN HIS/HER VISION because of something 
learned in connection with the app, nor should he/she assume that a vision alert received 
in the app necessarily corresponds to a significant event in the progression of his/her 
disease, but must follow study protocol and contact the office when a vision alert is 
received. 
If the subject requires technical support on any issue having to do with the Paxos 
CheckupTM application or www.digisight.net website for the duration of the sub-study, 
he/she may contact info@digisight.net or call (650) 223-5560 to receive timely technical 
support. 
If the subject requires help with any non-technical (medical) issues for the duration of the 
sub-study, he/she should contact his/her physician or physician’s office. 
If a loaner device is used for the duration of the study, it will be returned to DigiSight 
Technologies, Inc. at the subject’s exit or withdrawal.