Clinical trial NCT03022292
Conditions: Wet Macular Degeneration
Sponsor: University of California, Los Angeles
Start date: 2017-03-30; Completion date: 2020-08-31
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A study investigating the ability of OCTA imaging technology to identify and analyze untreated type 1, 2, and 3 neovascular membrane lesions in treatment naive patients with exudative macular degeneration, as well as investigating the ability of the OCTA imaging technology to evaluate the treatment outcomes of Intravitreal Aflibercept Injection in neovascular lesions associated with macular degeneration.

This study is utilizing a new, FDA approved, non-standard of care technology (OCT-Angiography by Optovue) to image and evaluate the treatment outcomes of using standard of care Intravitreal Aflibercept Injections for their approved use in patients diagnosed with neovascular AMD who are naive to previous Anti-VEGF therapies.

Detailed description:
Prospective study of neovascular AMD subjects with type 1, 2, or 3 neovascularization that have not been treated with prior anti-VEGF therapy. Subjects will be scheduled for intravitreal aflibercept injection (IAI) at baseline, week 4, week 8, week 16, week 24, week 36, and week 48. Additional injections can be administered during the remaining visits on an as needed basis per PI discretion based on the presence of any intraretinal or subretinal fluid on OCT, heme visualized on examination, reduction of BCVA by 5 or more ETDRS letters, or evidence of either increased area, density, or activity of the brush border of the neovascularization on OCT angiography. There will be a minimum of 21 days between subsequent injections. Each subject will therefore receive a minimum of 7 injections and up to a maximum of 13 injections throughout the study period. No injection will be given on the exit visit, week 52. OCT angiography and spectral domain OCT imaging will be performed at baseline and every 4 weeks thereafter

The above procedures are standard of care for neovascular AMD subjects.

As part of this study, these subjects will also undergo imaging of both eyes with OCTA at each visit. This is not standard of Care and is research.

The only procedure that is being performed for research is the OCT-A. The injections and all other procedure are SOC based on physician discretion and clinical need. The investigators will not be modifying the dosage amounts or frequency.

A subgroup of willing subjects will undergo OCT angiography every 2 weeks for the first 12 weeks.

Indocyanine green angiography will be performed at baseline for all subjects to establish baseline subject population characteristics. Fluorescein angiography will be performed at baseline, week 12, and week 52 for efficacy monitoring. Detailed OCT angiography analysis will be performed to identify anatomical and morphological biomarkers of growth progression and disease activity. In addition to qualitative structural and morphological analysis, detailed quantitative OCT angiography analysis of the neovascular lesion using automated or manual capillary density maps and area calculation will be performed at each visit to determine the detailed microvascular response of neovascular complexes to IAI therapy.

Arms: arm 1: Intravitreal injection of aflibercept 2 mg/0.05 ml at baseline, week 4, week 8, week 16, week 24, week 36, and week 48. Additional injections can be administered during the remaining visits on an as needed basis per Primary Investigator (PI) discretion based on the presence of any intraretinal or subretinal fluid on OCT, heme visualized on examination, reduction of BCVA by 5 or more ETDRS letters, or evidence of either increased area, density, or activity of the brush border of the neovascularization on OCT-angiography. There will be a minimum of 21 days between subsequent injections. Each subject will therefore receive a minimum of 7 injections and up to a maximum of 13 injections throughout the study period.
Interventions: intervention 1: Aflibercept Ophthalmic intervention 2: optovue angiovue
Intervention descriptions: intervention 1: IAI given for active exudative macular degeneration (CNV, SRF, PED) per SOC intervention 2: FDA approved Optovue Angiovue will be used to monitor progression and responsiveness of active exudative macular degeneration to IAI.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
NCT03022292 
Clinical Study Protocol 
 
The IAI-OCTA Study 
 
 
 
Compound: 
Intravitreal Aflibercept Injection 
 
 
Study Name: 
The IAI-OCTA Study, or:  
Microvascular structure and morphology 
of neovascular membranes in age related 
macular degeneration (AMD) after 
intravitreal aflibercept injection (IAI) 
therapy using OCT-Angiography Analysis  
 
 
Clinical Phase: 
VI 
 
 
Date of Issue: 
Version 6 January 03, 2018 
 
 
Primary Investigator: 
David Sarraf, MD 
 
 
 
 


 
 
CLINICAL STUDY PROTOCOL SYNOPSIS 
TITLE:   
Micro-vascular structure and morphology of neovascular membranes in age-related macular degeneration (AMD) 
after intravitreal aflibercept injection (IAI) therapy using OCT-Angiography (OCTA).  
TITLE IN LAY TERMS: The IAI-OCTA Study 
SITE LOCATION(S):  
Stein Eye Institute of UCLA 
200 Stein plaza 
Los Angeles, CA 90095 
 
Primary Investigator: David Sarraf, MD 
OBJECTIVE(S):  
To assess and evaluate OCTA technology as an instrument to identify and analyze the growth of untreated type 1, 
2, and 3 neovascular membranes in treatment naïve AMD subjects. 
To assess and evaluate OCTA technology as an instrument to evaluate the treatment outcomes of IAI in 
neovascular lesions in AMD.  
To identify OCTA parameters or biomarkers of neovascular activity after IAI in AMD. 
To better understand the morphology of angiogenesis and arteriogenesis and its response to IAI using OCT 
angiography analysis. 
STUDY DESIGN: 
Prospective clinical trial of AMD subjects with neovascularization (type 1, 2 or 3) that have not been treated with 
prior anti-VEGF therapy in one or both eyes. These subjects will undergo imaging of both eyes with OCT 
angiography at baseline upon entering this study. Subjects will be scheduled for intravitreal aflibercept injections 
(IAI) at baseline, week 4, week 8, week 16 week 24, week 36, and week 48. Additional injections can be 
administered on an as needed basis per Primary Investigator (PI) discretion during the remaining visits. Each 
subject will therefore receive a minimum of 7 injections and up to a maximum of 13 injections throughout the 
study period. There will be no injection at the Exit Visit. OCT angiography and spectral domain OCT imaging will 
be performed at baseline and every 4 weeks thereafter. A subgroup of willing subjects will undergo OCT 
angiography every 2 weeks for the first 12 weeks. Fluorescein and indocyanine angiography, as well as Fundus 
Autofluorescence will be performed at baseline. Fundus Autofluorescence and fluorescein angiography will also be 
performed at week 12 and at week 52 for all subjects. All imaging files for each subject including OCT, OCTA, 
FA and ICG will be forwarded to a reading center (Doheny Image Reading Research Laboratory or DIRRL) for 
evaluation and analysis.  Detailed OCT angiography analysis will be performed to identify anatomical and 
morphological biomarkers of growth progression and disease activity, which may guide treatment in the future and 
may help to develop more effective therapies that may target resistant and recalcitrant neovascular lesions that 
continue to grow, leak, and scar despite maximum intravitreal anti-VEGF therapy. 
  
In addition to qualitative structural and morphological analysis of all neovascular lesions at baseline and follow up, 
detailed quantitative OCT angiographic analysis of the neovascular lesion using automated or manual capillary 
density maps and area calculation will be performed at each visit to determine the detailed microvascular response 
of neovascular complexes to IAI therapy.      
STUDY DURATION: 1 YEAR 
ESTIMATED STUDY COMPLETION DATE: DECEMBER 2018 
POPULATION 
 
Sample Size: 30 subjects.  
 


 
 
 
Target Population: Male and female subjects over the age of 50 with naïve wet macular degeneration in 
one or both eyes. 
 
TREATMENT(S) 
 
Study Drug: Intravitreal aflibercept injection (2 mg/ 0.05 ml) 
 
 
Dose/Route/Schedule: Subjects will be scheduled for intravitreal aflibercept 2mg/ 0.05 ml injection at 
baseline, week 4, week 8,, week 16, week 24, week 36, and week 48. Additional injections can be administered 
during the remaining visits on an as needed basis per PI discretion based on the presence of any intraretinal or 
subretinal fluid on OCT, heme visualized on examination, reduction of BCVA by 5 or more ETDRS letters, or 
evidence of either increased area, density, or activity of the brush border of the neovascularization on OCT-
angiography. There will be a minimum of 21 days between subsequent injections. Each subject will therefore 
receive a minimum of 7injections and up to a maximum of 13 injections throughout the study period. There will be 
no injection at the exit visit, week 52. 
ENDPOINT(S) 
 
Primary: OCT angiography % of neovascular membrane as measured by area of the neovascular lesion 
(in millimeters2) and vessel density (in millimeters-1) at 24 weeks 
 
 
Secondary: Endpoints will be evaluated at 24 weeks and 52 weeks, unless indicated: 
• 
OCT angiography % regression of neovascular membrane as measured by area of the neovascular lesion 
(in millimeters2) and vessel density (in millimeters-1) at 52 weeks 
• 
Mean best corrected visual acuity (BCVA)  
• 
Proportion of patients with gain of ≥5, ≥10, or ≥15 ETDRS letters 
• 
Mean number of injections 
• 
Status of SD OCT intraretinal and subretinal fluid and subretinal hyper-reflective material (SHRM) 
• 
Change in SD OCT central macular thickness, volume of subretinal fluid, volume of SHRM, severity of 
cystoid macular edema, volume of pigment epithelial detachment (PED), and height of PED 
• 
OCT angiography qualitative analysis of the structural microvascular anatomy and morphological 
biomarkers of the neovascular complex including attenuation of the fringe, presence of flow-void areas, 
and changes in vessel looping 
• 
Incidence and severity of ocular and systemic adverse events 
• 
FAF monitoring of atrophy development from baseline to week 12, to week 52 
 
Exploratory: (In subjects participating in the sub-study of serial OCT Angiography during the initial 12 
weeks) 
• 
OCT angiography % regression of neovascular membrane as measured by area of the neovascular lesion 
(in millimeters2) and vessel density (in millimeters-1) during the initial 12 weeks 
• 
OCT angiography qualitative analysis of morphological biomarkers of the neovascular complex including 
attenuation of the fringe, presence of flow-void areas, and changes in vessel looping during the initial 12 
weeks 


 
 
PROCEDURES AND ASSESSMENTS: 
Informed Consent, Inclusion/Exclusion Criteria Assessment, Medical/Surgical/Ocular History review, 
Demographic Information review, Tobacco history review, and Concomitant Medication review, OCT 
Angiography, Spectral Domain OCT, Fluorescein Angiography, Indocyanine Green Angiography imaging, Fundus 
Photography, vital signs at baseline, Best Corrected Visual Acuity Exam, Intraocular Pressure Evaluation, Slit 
Lamp Evaluation, Dilated Fundus Exam, Study Drug Administration, and Post Injection Intraocular Pressure and 
Vision Assessment 
STATISTICAL PLAN: 
Parametric and possibly nonparametric tests may be conducted to calculate for statistical significance in assessing 
the differences of the posterior-treatment values from the baseline values during the first 6 months in comparison 
with the second 6 months of the study, depending on the variables. The significance level to be used is alpha ≤ 
0.05. Statistical analysis will be performed on data from all subjects in this study by the staff statistician, Fei Yu. 


 
 
TABLE OF CONTENTS 
Clinical Study Protocol Synopsis ..................................................................................... 2 
List of Tables ..................................................................................................................... 8 
List of Abbreviations and Definitions of Terms ............................................................. 9 
1. Introduction and Rationale ..................................................................................... 10 
1.1 Introduction .............................................................................................................. 10 
1.2 Rationale .................................................................................................................. 10 
1.2.1 Rationale for Study Design ........................................................................... 10 
1.2.2 Rationale for Dose Selection ........................................................................ 11 
2. Study Objectives....................................................................................................... 11 
2.1 Primary Objective .................................................................................................... 11 
2.2 Secondary Objective(s) ............................................................................................ 11 
2.3 Exploratory Objective(s) .......................................................................................... 11 
3. Study Design ............................................................................................................. 12 
3.1 Study Description and Duration............................................................................... 12 
3.2 Planned Interim Analysis ......................................................................................... 12 
3.3 Study Committees .................................................................................................... 12 
3.3.1 Independent Data Monitoring Committee .................................................... 12 
4. Selection, Withdrawal, and Replacement of Subjects .......................................... 13 
4.1 Number of Subjects Planned .................................................................................... 13 
4.2 Study Population ...................................................................................................... 13 
4.2.1 Inclusion Criteria .......................................................................................... 13 
4.2.2 Exclusion Criteria ......................................................................................... 13 
4.3 Premature Withdrawal from the Study .................................................................... 15 
4.4 Replacement of Subjects .......................................................................................... 15 
5. Study Treatments ..................................................................................................... 15 
5.1 Investigational Treatment ........................................................................................ 15 
5.2 Dose Modification and Stopping Rules ................................................................... 15 
5.2.1 Dose Modification ........................................................................................ 15 
5.2.2 Study Drug Stopping Rules .......................................................................... 15 
5.2.2.1 Reasons for Permanent Discontinuation of Study Drug ........................ 15 
5.3 Treatment Logistics and Accountability .................................................................. 16 
5.3.1 Packaging, Labeling, and Storage ................................................................. 16 


 
 
5.3.2 Supply and Disposition of Treatments .......................................................... 16 
5.3.3 Treatment Accountability ............................................................................. 17 
5.3.4 Treatment Compliance .................................................................................. 17 
5.4 Concomitant Medications and Procedures............................................................... 17 
5.4.1 Permitted Medications and Procedures ......................................................... 17 
5.4.2 Prohibited Medications and Procedures ........................................................ 17 
5.5 Post-Study Treatment............................................................................................... 17 
6. Study Schedule of Events and Visit Descriptions ................................................. 17 
6.1 Schedule of Events ................................................................................................... 17 
6.2 Study Visit Descriptions .......................................................................................... 19 
6.2.1 Screening/Baseline/Day 1 (-14 to 0 days)..................................................... 19 
6.2.2 Week 2 (+/- 7 days), Week 6 (+/- 7 days), Week 10 (+/- 7 days) ................. 19 
6.2.3 Week 4 (+/- 7 days) and Week 8 (+/- 7 days) ............................................... 19 
6.2.4 Week 12 (+/- 7 days) ..................................................................................... 20 
6.2.5 Week 16 (+/- 7 days), Week 24(+/- 7 days), Week 36(+/- 7 days),  and 
Week48 (+/- 7 days) .................................................................................................. 20 
6.2.6 Week 20 (+/- 7 days), Week 28 (+/- 7 days), Week 32 (+/- 7 days), Week 40 
(+/- 7 days)and Week 44 (+/- 7 days) ....................................................................... 21 
6.2.7 End of Study Visit/Early Termination/Week 48 (+/- 7 days) ....................... 21 
6.2.8 Early Termination Visit ................................................................................ 22 
6.2.9 Unscheduled Visits ....................................................................................... 22 
6.3 Study Procedures ..................................................................................................... 22 
6.3.1 Procedures Performed only at the Screening/Baseline Visit ........................ 22 
6.3.1.1 Demographic, Medical History, Tobacco History, and Surgical History 
Review ………………………………………………………………………….22 
6.3.1.2 ICG Imaging .......................................................................................... 22 
6.3.2 Efficacy Procedures ...................................................................................... 22 
6.3.2.1 Visual Acuity ......................................................................................... 22 
6.3.2.2 SD-OCT ................................................................................................. 22 
6.3.2.3 OCT-Angiography ................................................................................. 22 
6.3.2.4 Fluorescein Angiography ....................................................................... 23 
 
6.3.2.5 Fundus Autofluorescence………………………………………………...22 
6.3.3 Safety Procedures .......................................................................................... 23 


 
 
6.3.3.1 Adverse Event Information Collection .................................................. 23 
7. Safety Definitions, Reporting, and Monitoring ..................................................... 23 
7.1 Definitions................................................................................................................ 23 
7.1.1 Adverse Event ............................................................................................... 23 
7.1.2 Serious Adverse Event .................................................................................. 23 
7.2 Recording and Reporting Adverse Events ............................................................... 24 
7.2.1 Deaths ........................................................................................................... 24 
7.2.2 Pregnancy and Other Events that Require Accelerated Reporting ............... 24 
7.2.3 Reporting Adverse Events Leading to Withdrawal from the Study ............. 25 
7.2.4 Abnormal Laboratory, Vital Signs, or Electrocardiogram Results ............... 25 
7.2.5 Follow-up ...................................................................................................... 25 
7.3 Evaluation of Severity and Causality ....................................................................... 26 
7.3.1 Evaluation of Severity ................................................................................... 26 
7.3.2 Evaluation of Causality ................................................................................. 26 
8. Study Variables ........................................................................................................ 26 
8.1 Demographic and Baseline Characteristics ............................................................. 26 
8.2 Primary, Secondary, and Exploratory Endpoints ..................................................... 26 
9. Statistical Plan .......................................................................................................... 27 
9.1 Determination of Sample Size ................................................................................. 27 
9.2 Statistical Methods ................................................................................................... 27 
9.2.1 Demography and Baseline Characteristics ................................................... 27 
9.2.2 Efficacy Analyses ......................................................................................... 27 
9.2.2.1 Primary Efficacy Analysis ..................................................................... 27 
9.2.2.2 Secondary Efficacy Analysis ................................................................. 28 
9.2.2.3 Exploratory Efficacy Analysis ............................................................... 28 
9.2.3 Safety Analysis ............................................................................................. 28 
9.2.3.1 Adverse Events ...................................................................................... 28 
9.2.4 Interim Analysis ............................................................................................ 28 
9.3 Statistical Considerations Surrounding the Premature Termination of a Study ...... 29 
10. Study Monitoring ................................................................................................... 29 
10.1 Source Document Requirements ............................................................................ 29 
10.2 Case Report Form Requirements ........................................................................... 29 
11. Audits and Inspections .......................................................................................... 29 


 
 
12. Ethical and Regulatory Considerations ............................................................... 30 
12.1 Good Clinical Practice Statement .......................................................................... 30 
12.2 Informed Consent................................................................................................... 30 
12.3 Subject Confidentiality and Data Protection.......................................................... 30 
12.4 Institutional Review Board .................................................................................... 30 
13. Protocol Amendments ........................................................................................... 31 
14. Premature Termination of the Study or Close-out of a Site .............................. 31 
14.1 Premature Termination of the Study ...................................................................... 31 
15. Study Documentation ............................................................................................ 31 
15.1 Certification of Accuracy of Data .......................................................................... 31 
15.2 Retention of Records.............................................................................................. 31 
16. References ............................................................................................................... 32 
 
LIST OF TABLES 
Table 1 Schedule of Events............................................................................................ 18 
 
 
 


 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
1. 
INTRODUCTION AND RATIONALE 
1.1 
Introduction 
Neovascular age-related macular degeneration (AMD) is the leading cause of adult 
blindness [1]. While anti-VEGF therapy significantly reduces the rate of severe vision 
loss and may improve vision, subjects with choroidal neovascularization (CNV) continue 
to lose vision long-term and experience an eventual decay in visual acuity [2]. Recent 
advancements in OCT-Angiography (OCTA) have enabled for the first time the ability to 
directly identify and analyze the detailed microvascular structure and morphology of 
neovascular complexes in AMD [3-6]. OCTA utilizes amplitude or phase decorrelation 
technology with high-frequency and dense volumetric scanning to detect red blood cell 
movement and to visualize blood vessels at depth resolved levels throughout the retina 
and choroid [3]. OCTA enables more accurate identification of neovascular lesions 
compared to traditional fluorescein angiography (FA). Historically, FA findings such as 
irregular elevation of the RPE with stippled fluorescence were interpreted to suggest the 
presence of occult choroidal neovascularization (CNV) [7]. As opposed to FA where 
vessel leakage and blurred edges lead one to infer the presence of occult CNV, OCTA 
reveals the vessels themselves and enables more accurate identification of the 
morphology of the neovascular complex and monitoring of its structural response to 
therapy. 
 
OCTA therefore may provide critical information relating to the development and 
progression of neovascularization in AMD and the response of these lesions to anti-
VEGF therapy. Identifying biomarkers of neovascular activity and progression using 
OCTA may provide further guidance and advancement in the management of 
neovascular AMD, may provide better outcome parameters for clinical trials that study 
neovascular AMD therapy, and may permit the development of more effective 
therapeutic agents for neovascular AMD. 
1.2 
Rationale 
1.2.1 
Rationale for Study Design 
Previous clinical trials have not been able to analyze the complex microvascular anatomy 
of the various forms of neovascular lesions in AMD. With the advent of OCTA, we are 
able to directly assess the microvascular morphology and structural architecture of 
neovascular membranes that occur in AMD and assess the responsiveness of these 
neovascular membranes to anti-VEGF therapy [3,7]. Early studies using OCTA in 
neovascular AMD have shown that type 1 and type 2 neovascular membranes continue to 
grow and mature despite continued anti-VEGF therapy and develop a resistant and 
mature core of large dilated feeder vessels that do not respond to any of the approved 
anti-VEGF agents [3,8-11]. Understanding the development and progression in the 
growth of these neovascular membranes and determining the detailed microvascular 
anatomy and structure of these resistant neovascular complexes will spur the 
development of improved therapeutic options that can more efficaciously treat CNV 
leading to better long term visual and anatomic outcomes. In addition it is important to 
identify markers of neovascular activity using OCTA which will better guide therapy in 


 
 
the future and will provide important parameters to be used for future clinical trials 
assessing the efficacy of neovascular AMD therapies. 
1.2.2 
Rationale for Dose Selection 
Intravitreal aflibercept injection 2mg/0.05ml is the standard FDA approved dose that has 
been used in previous Phase III trials and has been shown to be effective [12]. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to assess the % regression of choroidal neovascular 
membrane as measured by area of the neovascular lesion (in millimeters2) and vessel 
density (in millimeters-1) using OCT angiography at 24 weeks while subjects receive IAI 
therapy in follow up.   
2.2 
Secondary Objective(s) 
The secondary objectives of the study are to assess the following at 24 weeks and 52 
weeks, unless indicated: 
• The % regression of choroidal neovascular membrane as measured by area of the 
neovascular lesion (in millimeters2) and vessel density (in millimeters-1) using 
OCT angiography at 52 weeks  
• Mean best corrected visual acuity (BCVA)  
• Proportion of patients with gain of ≥5, ≥10, or ≥15 ETDRS letters 
• Mean number of injections 
• Status of SD OCT intraretinal and subretinal fluid and subretinal hyper-reflective 
material (SHRM) 
• Change in SD OCT central macular thickness, volume of subretinal fluid, volume 
of SHRM, severity of cystoid macular edema, volume of pigment epithelial 
detachment (PED), and height of PED 
• OCT angiography qualitative analysis of the structural microvascular anatomy 
and morphological biomarkers of the neovascular complex including attenuation 
of the fringe, presence of flow-void areas, and changes in vessel looping 
• Incidence and severity of ocular and systemic adverse events 
• FAF monitoring of atrophy development from baseline to week 12, to week 52 
 
2.3 
Exploratory Objective(s)  
The exploratory objectives of the study are to assess the following for subjects 
participating in the sub-study of serial OCT angiography during the initial 12 weeks: 
• OCT angiography % regression of choroidal neovascular membrane as measured 
by area of the neovascular lesion (in millimeters2) and vessel density (in 
millimeters-1) during the initial 12 weeks 
• OCT angiography qualitative analysis of morphological biomarkers of the 
neovascular complex including attenuation of the fringe, presence of flow-void 
areas, and changes in vessel looping during the initial 12 weeks 


 
 
3. 
STUDY DESIGN 
3.1 
Study Description and Duration 
Prospective clinical trial of neovascular AMD subjects with type 1, 2, or 3 
neovascularizationin one or both eyes that have not been treated with prior anti-VEGF 
therapy. These subjects will undergo imaging of both eyes with OCTA at baseline upon 
entering this study. Subjects will be scheduled for intravitreal aflibercept injection (IAI) 
at baseline, week 4, week 8, week 16, week 24, week 36, and week 48. Additional 
injections can be administered during the remaining visits on an as needed basis per PI 
discretion based on the presence of any intraretinal or subretinal fluid on OCT, heme 
visualized on examination, reduction of BCVA by 5 or more ETDRS letters, or evidence 
of either increased area, density, or activity of the brush border of the neovascularization 
on OCT angiography. There will be a minimum of 21 days between subsequent 
injections. Each subject will therefore receive a minimum of 7 injections per enrolled eye 
and up to a maximum of 13 injections throughout the study period per enrolled eye. No 
injection will be given on the exit visit, week 52. OCT angiography and spectral domain 
OCT imaging will be performed at baseline and every 4 weeks thereafter.  
 
A subgroup of willing subjects will undergo OCT angiography every 2 weeks for the first 
12 weeks.  
 
Indocyanine green angiography will be performed at baseline for all subjects to establish 
baseline subject population characteristics. Fluorescein angiography will be performed at 
baseline, week 12, and week 52 for efficacy monitoring. Detailed OCT angiography 
analysis will be performed to identify anatomical and morphological biomarkers of 
growth progression and disease activity. In addition to qualitative structural and 
morphological analysis, detailed quantitative OCT angiography analysis of the 
neovascular lesion using automated or manual capillary density maps and area 
calculation will be performed at each visit to determine the detailed microvascular 
response of neovascular complexes to IAI therapy.  
 
3.2 
Planned Interim Analysis 
There is no planned interim analysis for this study. However, interim analyses may be 
performed in order to summarize preliminary results for the purpose of abstract 
submission for presentation at national or international meetings. Adverse event reports 
from this study may be reviewed and summarized periodically throughout the study to 
ensure the safety of subjects. 
3.3 
Study Committees 
3.3.1 
Independent Data Monitoring Committee 
All imaging files for each subject including OCT, OCTA, FA and ICG will be forwarded 
to a reading center (Doheny Image Reading Research Laboratory or DIRRL) for evaluation 
and analysis. 


 
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS 
4.1 
Number of Subjects Planned 
30 subjects will be included in this study. 
4.2 
Study Population 
Male and female subjects over the age of 50 with treatment-naïve wet macular 
degeneration in one or both eyes. 
4.2.1 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for inclusion in the study: 
1. 
Subject is older than 50 years of age. 
2. 
Subject is willing to participate in the study and able to follow the study criteria 
and protocol. 
3. 
The study eye is treatment naive regarding treatment of neovascular AMD. 
4. 
Subject is willing and able to comply with clinic visits and study-related 
procedures. 
5. 
Subject is able to provide signed informed consent. 
6. 
Subject is able to understand and complete study-related questionnaires. 
7. 
The subject is not currently involved with any other clinical study. 
8. 
Best Corrected Visual Acuity (BCVA) with ETDRS Snellen equivalent of 20/400 
or better and 20/32 or worse in the study eye. 
9. 
Sufficiently clear media (cornea, anterior chamber, lens, vitreous) for OCT, FA 
and fundus photography (FP) in the study eye. 
10. 
Intraocular pressure (IOP) of 25mmHg or less in the study eye, with or without 
use of ocular hypotensive agents. 
11. 
Prior focal corticosteroid treatment is allowed, as long as the study eye is not 
involved. However prior (within 90 days of Day 0) or current systemic 
corticosteroid therapy (oral or intravenous corticosteroid treatment) is not 
permitted.  
4.2.2 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. 
Any prior treatment of neovascular AMD in the eye proposed for enrollment 
including previous anti-vascular endothelial factor (anti-VEGF) therapy, 
photodynamic therapy (PDT), radiation therapy, corticosteroid treatment, surgical 
treatment for CNV, thermal laser treatment, and any other prior intravitreal 
treatment for neovascular AMD (except minerals and vitamins). 
  
2. 
Known serious allergies to aflibercept, fluorescein dye, Indocyanine Green (ICG), 
shellfish, drugs for pupillary dilation, topical anesthetic, or sterilizing solution 
(e.g. Betadine Solution). 
  
3. 
Prior or current systemic anti-VEGF therapy. 
4. 
Pregnant or breast-feeding women. 


 
 
5. 
Sexually active men* or women of childbearing potential** who are unwilling to 
practice adequate contraception during the study (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). 
6. 
Contraindication to pupillary dilation in study eye. 
7. 
Any condition (including inability to read visual acuity charts, or language 
barrier) that may preclude subjects ability to comply with the study protocol and 
requirements. 
8. 
Presence of any advanced systemic condition or end-stage disease, such as 
advanced Alzheimer Syndrome, end-stage cancer, etc., which will likely prevent 
subject from completing study. 
9. 
Previous therapeutic radiation in the region of the study eye. 
10. 
Prior retinal pigment epithelial (RPE) tear in study eye. 
11. 
Prior ocular surgery (except YAG laser capsulotomy) for study within the past 90 
days. 
12. 
Anticipated ocular surgery (except YAG laser capsulotomy) for the next 12 
months. 
13. 
Prior vitrectomy in the study eye. 
14. 
Presence of any causes of CNV and PED other than due to AMD or presence of 
ocular disease other than AMD affecting study eye, i.e. presumed ocular 
histoplasmosis syndrome, android streaks, pathologic myopia (spherical 
equivalent of ≥ -8 diopters of myopia or axial length of ≥ 25mm), choroidal 
rupture, multifocal choroiditis, etc. 
15. 
Presence of any substantial ocular disease (other than the CNV and PED) that 
may compromise vision in the study eye and/or confound interpretation of the 
data; e.g. substantial cataracts, concomitant diabetic retinopathy affecting the 
macula, advanced glaucoma, optic neuritis, optic neuropathy, or atrophy, marked 
macular atrophy, ocular vascular occlusion, history of retinal detachment, uveitis, 
viral or other forms of chorioretinitis, etc.  
16. 
Active ocular infection (i.e., bacterial, viral, parasitic, or fungal) in either eye at 
screening 
17. 
Serous PED without neovascularization and polypoidal choroidal vasculopathy 
(PCV) lesions are excluded in the study eye. 
18. 
PED ≥ 12 disc areas in size. 
19. 
Surface area of submacular hemorrhage >50% of entire PED, if present in the 
study eye. 
20. 
Submacular fibrosis >50% of the entire PED, if present in the study eye.  
*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. 


 
 
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 an 
intercurrent 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 
Intravitreal injection of aflibercept 2 mg/0.05 ml at baseline, week 4, week 8, week 16, 
week 24, week 36, and week48. Additional injections can be administered during the 
remaining visits on an as needed basis per Primary Investigator (PI) discretion based on 
the presence of any intraretinal or subretinal fluid on OCT, heme visualized on 
examination, reduction of BCVA by 5 or more ETDRS letters, or evidence of either 
increased area, density, or activity of the brush border of the neovascularization on OCT-
angiography. There will be a minimum of 21 days between subsequent injections. Each 
subject will therefore receive a minimum of 7 injections and up to a maximum of 13 
injections throughout the study period. 
5.2 
Dose Modification and Stopping Rules 
5.2.1 
Dose Modification 
Dose modification for an individual subject is not allowed. 
5.2.2 
Study Drug Stopping Rules 
5.2.2.1 
Reasons for Permanent Discontinuation of Study Drug 
Subjects have a right to withdraw from the study at any time. 
 
The subject may be withdrawn from the study for any reasons: if it is in the best interest 
of the subject, serious concurrent illnesses, adverse events, or worsening condition. Dr. 


 
 
David Sarraf and staff 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 
• Verteporfin PDT treatment in the study eye 
• Pegaptanib sodium injection in either eye 
• Bevacizumab injection in either eye 
• Ranibizumab injection in either eye 
• 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. 
 
5.3 
Treatment Logistics and Accountability 
5.3.1 
Packaging, Labeling, and Storage 
A medication numbering system will be used in labeling investigational study drug, 
displaying the product lot number on the label. Lists linking medication numbers with 
product lot numbers will be maintained by the Investigational Drug Pharmacy of UCLA 
located at 757 Westwood Plaza, Room B524. 
 
Study drug will be refrigerated at the site at a temperature of 2 to 8ºC; refrigerator 
temperature will be logged daily.  At no time, will product be left unattended or outside 
the control of an individual knowledgeable with regard to product temperature 
requirements. Failure to maintain 2° to 8°C temperature control will likely result in 
unusable product. Moreover, no one will administer product that has not been maintained 
according to temperature requirements. 
5.3.2 
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 opened and unopened vials of study drug will be 
destroyed or returned to Regeneron Pharmaceuticals, Inc. or designee. 


 
 
5.3.3 
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 or returned to Regeneron Pharmaceuticals, Inc. or designee. 
All accountability records will be made available for inspection by regulatory agency 
inspectors. 
5.3.4 
Treatment Compliance 
All drug compliance records will be kept current and will be made available for 
inspection by regulatory agency inspectors.  
 
5.4 
Concomitant Medications and Procedures 
At the screening visit, the subject will be asked to disclose the names of any concomitant 
medications they are taking as well as any medical procedures they have undergone in the 
past. During every subsequent visit, the subject will be asked about any changes to 
medications or new procedures they received between study visits.  
5.4.1 
Permitted Medications and Procedures 
Subjects may continue to take any existing concomitant medications with the exception 
of the prohibited medications and procedures as shown below. Topical eye drops for dry 
eye, controlled glaucoma, or allergic conjunctivitis are permissible. Prior or ongoing 
treatment of the fellow eye with intravitreal aflibercept injection is also permitted. 
5.4.2 
Prohibited Medications and Procedures 
Subjects must not have taken on any oral or intravenous anti-VEGF drugs within 6 
months of study procedures. Subjects must not be on any form of chemotherapy, 
radiation therapy, intravenous corticosteroid drugs within 6 months of study procedures. 
Subjects must not have participated with any other clinical trials within past 6 months.  
5.5 
Post-Study Treatment 
Post study completion, subjects will be released to standard of care clinical treatment and 
observation with a Retina Specialist. Care may be maintained clinically under the PI.  
 
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.


 
 
Table 1 
Schedule of Events 
 
Study Procedure 
Screen/ 
Baseline 
Week 
2 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
 
Wk 
48 
Week 
52Exit/Early 
Termination 
(+/- Day Window) 
-14 to 0 
days 
±7 days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
+7 
days 
±7 days 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study 
Drug 
X 
 
X 
 
X 
 
prn 
X 
prn 
X 
prn 
prn 
X 
prn 
prn 
X 
 
Concomitant Meds 
and Tx 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA Exam 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp 
Evaluation 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dilated Fundus 
Exam 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCT 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT-Angiography 
X 
X* 
X 
X* 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FAF Imaging** 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
FA 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
ICG Imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP, Pre-dose 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-dose VA and 
IOP 
X 
 
X 
 
X 
 
prn 
X 
prn 
X 
prn 
prn 
X 
prn 
prn 
X 
 
*A subgroup of willing subjects will undergo OCTA every 2 weeks for the first 12 weeks.   **For subjects enrolled prior to inclusion of FAF, FAF will be 
performed at next scheduled visit or beginning at Week 12 (whichever is soonest after protocol approval). 


 
 
 
6.2 
Study Visit Descriptions 
6.2.1 
Screening/Baseline/Day 1 (-14 to 0 days) 
After the subject has provided informed consent, the following information will be 
collected: 
 
• Inclusion/exclusion Criteria Review 
• Demographics and Tobacco History 
• Medical history, surgical history, and concurrent illnesses 
• Concomitant medications 
 
The following procedures and assessments will be conducted: 
 
• BCVA Exam  
• IOP Assessment 
• Slit-lamp Examination 
• Dilated Fundus Examination 
• SD-OCT 
• OCT-angiography 
• FAF Imaging 
• Fluorescein Angiography 
• ICG Imaging 
• Study Drug Administration 
• Post Procedure VA and IOP 
6.2.2 
Week 2 (+/- 7 days), Week 6 (+/- 7 days), Week 10 (+/- 7 days) 
The following procedure will be conducted on a subgroup of willing subjects: 
 
• OCT-angiography 
6.2.3 
Week 4 (+/- 7 days) and Week 8 (+/- 7 days) 
The following information will be collected: 
 
• Concomitant medications 
• Adverse Events 
 
The following procedures and assessments will be conducted: 
 
• BCVA Exam 
• IOP Assessment 
• Slit-lamp Examination 
• Dilated Fundus Examination 
• SD-OCT 


 
 
 
• OCT-angiography 
• Study Drug Administration 
• Post Procedure VA and IOP 
6.2.4 
Week 12 (+/- 7 days) 
The following information will be collected: 
 
• Concomitant medications 
• Adverse Events 
 
The following procedures and assessments will be conducted: 
 
• BCVA Exam 
• IOP Assessment 
• Slit-lamp Examination 
• Dilated Fundus Examination 
• SD-OCT 
• OCT-angiography 
• FAF Imaging 
• FA imaging 
 
The following procedures will be conducted on an AS NEEDED basis per PI discretion 
based on the presence of any intraretinal or subretinal fluid on OCT, heme visualized on 
examination, reduction of BCVA by 5 or more ETDRS letters, or evidence of either 
increased area, density, or activity of the brush border of the neovascularization on OCT-
angiography: 
 
• Study Drug Administration 
• Post Procedure VA and IOP 
6.2.5 
Week16 (+/-7 days), Week 24 (+/- 7 days),Week 36 (+/- 7 days), and Week 
48 (+/- 7 days)  
The following information will be collected: 
 
• Concomitant medications 
• Adverse Events 
 
The following procedures and assessments will be conducted: 
 
• BCVA Exam 
• IOP Assessment 
• Slit-lamp Examination 
• Dilated Fundus Examination 
• SD-OCT 


 
 
 
• OCT-angiography 
• Study Drug Administration 
• Post Procedure VA and IOP 
6.2.6 
Week 20 (+/- 7 days), Week 28 (+/- 7 days), Week 32 (+/- 7 days), and 
Week 40 (+/- 7 days), and week 44 (+/- 7days) 
The following information will be collected: 
 
• Concomitant medications 
• Adverse Events 
 
The following procedures and assessments will be conducted: 
 
• BCVA Exam 
• IOP Assessment 
• Slit-lamp Examination 
• Dilated Fundus Examination 
• SD-OCT 
• OCT-angiography 
 
The following procedures will be conducted on an AS NEEDED basis per PI discretion 
based on the presence of any intraretinal or subretinal fluid on OCT, heme visualized on 
examination, reduction of BCVA by 5 or more ETDRS letters, or evidence of either 
increased area, density, or activity of the brush border of the neovascularization on OCT-
angiography: 
 
• Study Drug Administration 
• Post Procedure VA and IOP 
6.2.7 
End of Study Visit/Early Termination/Week 52 (+/- 7 days) 
The following information will be collected: 
 
• Concomitant medications 
• Adverse Events 
 
The following procedures and assessments will be conducted: 
 
• BCVA Exam 
• IOP Assessment 
• Slit-lamp Examination 
• Dilated Fundus Examination 
• SD-OCT 
• OCT-angiography 
• FAF Imaging 


 
 
 
• FA Imaging 
6.2.8 
Early Termination Visit 
Subjects who are withdrawn from the study prior to completion should return to the clinic 
for an early termination evaluation 4 weeks (± 2 weeks) following the last injection/study 
visit for monitoring of all adverse events. The schedule of assessments for early 
termination is the same as that for the final visit. 
6.2.9 
Unscheduled Visits 
All attempts should be made to keep subjects on the study schedule.  Unscheduled visits 
may be necessary to repeat testing following abnormal laboratory results, for follow-up of 
AEs, or for any other reason, as warranted. 
6.3 
Study Procedures 
6.3.1 
Procedures Performed only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study 
eligibility or characterizing the baseline population. 
6.3.1.1 
Demographic, Medical History, Tobacco History, and Surgical History 
Review 
The above listed items will be reviewed with subjects after the informed consent has been 
signed for the purpose of establishing subject population characteristics at baseline.   
6.3.1.2 
ICG Imaging 
ICG imaging will take place at baseline only as a means of establishing baseline subject 
population characteristics. 
6.3.2 
Efficacy Procedures 
6.3.2.1 
Visual Acuity 
BCVA will be assessed on an ETDRS chart at a starting distance of 4 m (performed prior 
to dilating eyes). 
6.3.2.2 
SD-OCT 
Spectral Domain Optical Coherence Tomography will be used every 4 weeks starting at 
Baseline visit for efficacy monitoring. 
6.3.2.3 
OCT-Angiography 
OCT-Angiography will be used every 4 weeks starting at Baseline visit for efficacy 
monitoring. 


 
 
 
6.3.2.4 
Fluorescein Angiography 
Fluorescein angiography will be obtained at Baseline visit, Week 12, and at Study Exit for 
efficacy monitoring. 
6.3.2.5 
Fundus Autofluorescence 
Fundus Autofluorescence will be performed at Baseline, Week 12, and at Study Exit for 
efficacy monitoring.  
6.3.3 
Safety Procedures 
6.3.3.1 
Adverse Event Information Collection 
The investigator (or designee) will record all AEs that occur during the study from baseline 
through End of Study Visit or Early Termination on the AE pages of the case report form 
(CRF).  Information on follow-up for AEs is provided in Section 7.2.5.  Laboratory or vital 
signs abnormalities are to be recorded as AEs as outlined in Section 7.2. 
The definition of an AE and SAE, and information on the determination of severity and 
relationship to treatment are provided in Section 7. 
 
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 which is temporally associated with the use of a study drug, whether or not 
considered related to the study drug.   
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 inpatient hospitalization or prolongation of existing hospitalization.  
Inpatient 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. 
7.2 
Recording and Reporting Adverse Events 
All AEs and SAEs will be recorded on the CRF and in the subject’s source documents.  
Laboratory or vital signs abnormalities will be recorded as AEs only if they are medically 
relevant. 
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 28 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 subject, during the study or within 30 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 Laboratory, Vital Signs, or Electrocardiogram 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. 
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. 
If a laboratory value is considered an AE, its severity will be based on the degree of 
physiological impairment the value indicates.   
7.3.2 
Evaluation of Causality 
The relationship to treatment will be determined by the investigator and reported on the 
CRFand/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. 
8. 
STUDY VARIABLES 
8.1 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (e.g. age, race, weight, height, 
etc.), disease characteristics including medical history, surgical history, and medication 
history for each subject. 
8.2 
Primary, Secondary, and Exploratory Endpoints 
The primary endpoint in the study is the OCT angiography % regression of choroidal 
neovascular membrane as measured by area of the neovascular lesion (in millimeters2) 
and vessel density (in millimeters-1) at 24 weeks. 
 
The following secondary endpoints will be evaluated at 24 weeks and 48 weeks, unless 
indicated: 
• The % regression of choroidal neovascular membrane as measured by area of the 
neovascular lesion (in millimeters2) and vessel density (in millimeters-1) using 
OCT angiography at 48 weeks  


 
 
 
• Mean best corrected visual acuity (BCVA)  
• Proportion of patients with gain of ≥5, ≥10, or ≥15 ETDRS letters 
• Mean number of injections 
• Status of SD OCT intraretinal and subretinal fluid and subretinal hyper-reflective 
material (SHRM) 
• Change in SD OCT central macular thickness, volume of subretinal fluid, volume 
of SHRM, severity of cystoid macular edema, volume of pigment epithelial 
detachment (PED), and height of PED 
• OCT angiography qualitative analysis of the structural microvascular anatomy 
and morphological biomarkers of the neovascular complex including attenuation 
of the fringe, presence of flow-void areas, and changes in vessel looping 
• Incidence and severity of ocular and systemic adverse events 
• FAF monitoring of atrophy development from baseline to week 12, to week 52 
 
The exploratory endpoints for subjects participating in the sub-study of serial OCT 
angiography during the initial 12 weeks are the following: 
• OCT angiography % regression of choroidal neovascular membrane as measured 
by area of the neovascular lesion (in millimeters2) and vessel density (in 
millimeters-1) during the initial 12 weeks 
• OCT angiography qualitative analysis of morphological biomarkers of the 
neovascular complex including attenuation of the fringe, presence of flow-void 
areas, and changes in vessel looping during the initial 12 weeks 
9. 
STATISTICAL PLAN 
9.1 
Determination of Sample Size 
There is no formal sample size calculation for this study. A sample size of 30 subjects is 
chosen, making sure that it is feasible to conduct and complete the study within a 
reasonable time. Data from all enrolled subjects will be analyzed. 
9.2 
Statistical Methods 
9.2.1 
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. 
9.2.2 
Efficacy Analyses 
9.2.2.1 
Primary Efficacy Analysis 
Detailed anatomical descriptions and grading of lesion components in a standardized 
fashion in a reading center setting at baseline and subsequent follow-up visits, including 
changes in % regression of choroidal neovascular membrane at 24 weeks as measured by 
area of the neovascular lesion (in millimeters2) and vessel density (in millimeters-1) using 
OCT angiography while subjects receive IAI therapy in follow up. 


 
 
 
9.2.2.2 
Secondary Efficacy Analysis 
The following will be calculated at 24 weeks and 48 weeks, unless indicated: 
• The % regression of choroidal neovascular membrane as measured by area of the 
neovascular lesion (in millimeters2) and vessel density (in millimeters-1) using 
OCT angiography at 48 weeks  
• Mean best corrected visual acuity (BCVA)  
• Proportion of patients with gain of ≥5, ≥10, or ≥15 ETDRS letters 
• Mean number of injections 
• Status of SD OCT intraretinal and subretinal fluid and subretinal hyper-reflective 
material (SHRM) 
• Change in SD OCT central macular thickness, volume of subretinal fluid, volume 
of SHRM, severity of cystoid macular edema, volume of pigment epithelial 
detachment (PED), and height of PED 
• OCT angiography qualitative analysis of the structural microvascular anatomy 
and morphological biomarkers of the neovascular complex including attenuation 
of the fringe, presence of flow-void areas, and changes in vessel looping 
• Incidence and severity of ocular and systemic adverse events 
• FAF monitoring of atrophy development from baseline to week 12, to week 52 
 
9.2.2.3 
Exploratory Efficacy Analysis 
The following will be calculated for subjects participating in the sub-study of serial OCT 
angiography during the initial 12 weeks: 
• OCT angiography % regression of choroidal neovascular membrane as measured 
by area of the neovascular lesion (in millimeters2) and vessel density (in 
millimeters-1) during the initial 12 weeks 
• OCT angiography qualitative analysis of morphological biomarkers of the 
neovascular complex including attenuation of the fringe, presence of flow-void 
areas, and changes in vessel looping during the initial 12 weeks 
 
9.2.3 
Safety Analysis 
9.2.3.1 
Adverse Events 
Incidence and severity of ocular and systemic safety events through week 48 including: 
worsened acuity > 30 letters, retinal detachment, endophthalmitis, cataract progression, 
vitreous hemorrhage, new PDR or neovascularization of the iris or angle, systemic 
thromboembolic events, deaths, and systemic serious adverse event. 
9.2.4 
Interim Analysis 
Interim analyses may be performed in order to summarize preliminary results for the 
purpose of abstract submission for presentation at national or international meetings. 
Adverse event reports from this study may be reviewed and summarized periodically 
throughout the study to ensure the safety of subjects. 


 
 
 
9.3 
Statistical Considerations Surrounding the Premature Termination of a 
Study 
If the study is terminated prematurely, all data collected and safety parameters will be 
summarized.   
10. 
STUDY MONITORING 
10.1 
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. 
10.2 
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. 
11. 
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. 


 
 
 
12. 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
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. 
12.2 
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. 
12.3 
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.   
12.4 
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 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. 
13. 
PROTOCOL AMENDMENTS 
The investigator will not implement a change in the design or operation of the protocol or 
ICF without an IRB-approved amendment. 
14. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A SITE 
14.1 
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. 
15. 
STUDY DOCUMENTATION 
15.1 
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.  
15.2 
Retention of Records 
The investigator will retain all essential study documents, including ICFs, source 
documents, CRFs, and drug accountability records for at least 15 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. 


 
 
 
16. 
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