A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of Intravitreal Aflibercept Injection in Patients With Moderately Severe to Severe Nonproliferative Diabetic Retinopathy
Phase: PHASE3
Conditions: Nonproliferative Diabetic Retinopathy
Sponsor: Regeneron Pharmaceuticals

IND Number:  12462
EudraCT Number: 2016-002639-14
Regeneron Pharmaceuticals, Inc.
Clinical Study Protocol
A PHASE 3, DOUBLE-MASKED, RANDOMIZED STUDY OF THE 
EFFICACY AND SAFETY OF INTRAVITREAL AFLIBERCEPT 
INJECTION IN PATIENTS WITH MODERATELY SEVERE TO SEVERE 
NONPROLIFERATIVE DIABETIC RETINOPATHY
Compound:
Intravitreal Aflibercept Injection
Clinical Phase:
3
Protocol Number:
VGFTe-OD-1411
Protocol Version:
VGFTe-OD-1411 Amendment 5
Amendment 5 Date of Issue:
See appended electronic signature page
Amendment 4 Date of Issue:
Japan only
Amendment 3 Date of Issue:
20 Oct 2016
Amendment 2 Date of Issue:
12 Feb 2016
Amendment 1 Date of Issue:
22 Dec 2015
Original Date of Issue:
25 Sep 2015
Scientific/Medical Monitor:
Director, Clinical Sciences, Ophthalmology
Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road
Tarrytown, NY 10591
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NCT02718326

Clinical Study Protocol
VGFTe-OD-1411 Amendment 5
Regeneron Pharmaceuticals, Inc.
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CONFIDENTIAL
AMENDMENT HISTORY
Amendment 5
The purpose of this amendment is to change the time point for evaluation of the secondary 
endpoints from week 100 to week 52.
The secondary outcome measures include assessment of parameters associated with the 
prevention of vision threatening complications secondary to diabetic retinopathy, and central-
involved diabetic macular edema (DME).  These secondary outcome measures were to be 
analyzed in an exploratory manner at week 52 and formally tested at week 100.  At week 24, 
these measures were assessed from a safety perspective, and there was a remarkable separation 
between the Intravitreal Aflibercept Injection (IAI) and sham groups.  This separation was highly 
suggestive that IAI has a profound impact on these outcomes in diabetic retinopathy patients.  In 
light of these results, Regeneron feels that it is important to make these data available to the 
diabetic retinopathy community through approved labeling as soon as possible.
Change
Sections Changed 
Change the timepoint for evaluation of the secondary 
endpoints from week 100 to week 52, with additional 
exploratory analysis of the secondary endpoints at 
week 100.
Clinical Study Protocol Synopsis: Endpoints,
Statistical Plan
Figure 1 Study Flow Diagram
Section 8.2 Primary and Secondary 
Variables
Section 9.1 Statistical Hypothesis
Table 4 Significance Levels for Testing 
Secondary Efficacy Endpoints
Section 9.5.2 Efficacy Analyses
Section 9.5.2.1 Analyses of Primary and 
Secondary Efficacy Variables
Amendment 3
The purpose of this amendment is to update exclusion criterion #16 to exclude women who are 
breastfeeding from participation in the study.
Change
Sections Changed 
Exclusion updated: “16. Women who are breastfeeding or 
who have a positive serum hCG/urine pregnancy test at 
the screening or baseline visit”.
Section 4.2.2 Exclusion Criteria (#16)
Added EudraCT Number.
Title Page
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Amendment 2
The purpose of this amendment is to incorporate the following revisions in response to feedback 
from the Food and Drug Administration (FDA) and the Pharmaceuticals and Medical Devices 
Agency (PMDA):
x
Revise the significance levels for testing of the secondary efficacy endpoints, per 
FDA feedback
x
Add a hemoglobin A1c (HbA1c) assessment at week 24, and fundus photography 
(FP) at week 8, per PMDA feedback
Amendment 1
The purpose of this amendment is to incorporate the following changes and clarifications 
following discussions with the FDA:
x
The primary outcome measure of the study will be the proportion of patients who 
have improved by ≥2 steps from baseline in the Diabetic Retinopathy Severity Scale 
(DRSS) score at week 24 in the combined 2Q8 and 2Q16 groups, and at week 52 for 
each group separately.
x
Secondary endpoints have been modified slightly; a few have been separated into 
2 endpoints.
x
The 2Q8 group will transition to a flexible dosing regimen based on the investigator's 
assessment of DRSS score beginning at week 56.
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title
A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of 
Intravitreal Aflibercept Injection in Patients with Moderately Severe to Severe
Nonproliferative Diabetic Retinopathy
Site Locations
Approximately 70 sites.
Objectives
The primary objective of the study is to assess the efficacy of intravitreal (IVT) 
aflibercept compared to sham treatment in the improvement of moderately severe 
to severe nonproliferative diabetic retinopathy (NPDR).
The secondary objectives of the study are:
x
To characterize the safety of IVT aflibercept in patients with moderately 
severe to severe NPDR 
x
To determine if IVT aflibercept will prevent the worsening of diabetic 
retinopathy and reduce the incidence of diabetic macular edema (DME)
x
To determine the anatomic effects of IVT aflibercept in patients with 
moderately severe to severe NPDR.
Study Design
This is a phase 3, double-masked, randomized study of the efficacy and safety of 
IVT aflibercept for the improvement of moderately severe to severe NPDR.
Eligible patients will be enrolled into 1 of 3 treatment groups in a 
1:1:1 randomization scheme, and will be stratified based on their Diabetic 
Retinopathy Severity Scale (DRSS) score (level 47 vs. level 53).  Only 1 eye will 
be selected as the study eye.  The 3 treatment groups will have the following dosing 
regimens from day 1 to week 48:  1) every 8 weeks (2Q8) aflibercept IVT after 5 
initial monthly doses; 2) every 16 weeks (2Q16) aflibercept IVT after 3 initial 
monthly doses and 1 Q8 interval; and 3) sham treatment.  In year 2 (beginning at 
week 56), the 2Q8 group will be treated with a flexible treatment regimen.
The primary outcome measure of the study is the proportion of patients who have 
improved by ≥2 steps from baseline on the DRSS in the combined 2Q8 and 2Q16 
groups at week 24, and in each group separately at week 52.
Patients will be evaluated for efficacy (best corrected visual acuity [BCVA] using 
the 4-meter Early Treatment Diabetic Retinopathy Study [ETDRS] protocol, 
spectral domain optical coherence tomography [SD-OCT], and fluorescein 
angiography [FA]/fundus photography [FP]) and for ocular and systemic safety 
(including ophthalmic exams, visual field testing, and laboratory assessments) 
through week 100.
Patients who develop PDR, anterior segment neovascularization (ASNV), or DME 
in the study eye will qualify for rescue treatment.  If treatment is given, patient data 
will be censored for the primary analysis.
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Intravitreal aflibercept (2 mg) will be made available for patients who have central-
involved DME (CI-DME), PDR or ASNV in the fellow eye at screening (beginning 
on day 1), or are diagnosed during the trial.  
Standard of care treatment (eg, PRP) will also be allowed for patients developing 
PDR in the fellow eye at any time during the trial.
Study Duration
The study duration is 103 weeks, including the screening period.
Population
Sample Size: 
Approximately 360 patients will be enrolled, and with a target enrollment of 
approximately 120 patients in each treatment group (1:1:1 ratio).
Target Population:
The patient population will include men or women with type 1 or 2 diabetes 
mellitus who have moderately severe to severe NPDR (without DME threatening 
the center of the macula), in whom PRP can be safely deferred for at least 
6 months.
For patients who meet eligibility criteria in both eyes, the eye with the most severe 
DRSS score will be selected as the study eye. If both eyes have equivalent scores, 
factors such as ocular dominance and patient preference should be considered in 
making the selection.
Treatments
Study Drug
Dose/Route/Schedu
le:
The investigational product is intravitreal aflibercept injection (IAI), and will be 
administered to the patients by IVT injection.
Study Eye
Patients will be randomly assigned to 1 of 3 treatment groups in a 1:1:1 ratio:
x 2Q8:  aflibercept 2 mg Q8 to week 48 (after 5 initial monthly doses),
followed by a flexible treatment regimen with aflibercept 2 mg to week 96
x 2Q16:  aflibercept 2 mg Q16 to week 96 (after 3 initial monthly doses and 1 
Q8 interval)
x Sham:  sham injections every 4 weeks (Q4) to week 16, followed by sham 
injections Q8 to week 96
To preserve the masking, sham injections will be performed for the 2Q8 and 2Q16 
groups at treatment visits in which patients do not receive an active injection 
through week 96, and at all treatment visits for the sham group from baseline to 
week 96.  Masking will be maintained to the end of the study (week 100).
Endpoints
Primary:
The primary outcome measure of the study is the proportion of patients who have 
improved by ≥2 steps from baseline in the DRSS score at week 24 in the combined 
2Q8 and 2Q16 groups, and at week 52 for each group separately.
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Secondary:
The secondary outcome measures will be tested at week 52 and are as follows:
x
Proportion of patients developing a vision-threatening complication due to 
diabetic retinopathy
Vision-threatening complications are defined as composite outcome of 
PDR (inclusive of patients who have vitreous hemorrhage or tractional 
retinal detachment believed to be due to PDR) and ASNV
o
Note:  ASNV is defined as neovascularization of the iris (at least 2 
cumulative clock hours), and/or definitive neovascularization of 
the iridocorneal angle
x
Proportion of patients who develop CI-DME
x
Time to development of a vision-threatening complication
x
Time to development of CI-DME
x
Proportion of patients who receive PRP, inclusive of patients undergoing 
vitrectomy with endolaser 
x
Area under the curve (AUC) for change in BCVA from baseline
These outcome measures will also be tested at week 100 in an exploratory manner 
for all 3 treatment groups.
Procedures and 
Assessments
Efficacy and safety ocular procedures will include BCVA (ETDRS) and refraction, 
intraocular pressure (IOP), slit lamp examination,
gonioscopy, indirect 
ophthalmoscopy, SD-OCT, FA/FP, and visual field testing (study eye).
Overall safety will be assessed by evaluation of treatment-emergent adverse events 
(TEAEs), physical examinations, electrocardiograms (ECGs), vital signs, and 
clinical safety laboratory tests (hematology, blood chemistry, hemoglobin A1c 
[HbA1c], and urinalysis) at prespecified time points.  
Statistical Plan
The primary efficacy variable is the proportion of patients with a ≥2-step 
improvement from baseline in DRSS score in the study eye at week 24 in the 
combined 2Q8 and 2Q16 groups, and at week 52 for the 2Q8 and 2Q16 groups
separately.  Statistical testing of week 24 and week 52 will be conducted to 
demonstrate the superiority of the aflibercept groups (combined, 2Q8, and 2Q16) to 
the sham group, respectively.
The primary efficacy variable analysis will be conducted on the full analysis set 
(FAS) population.  The primary analysis is a statistical evaluation of superiority of 
3 comparisons (combined aflibercept vs. sham at week 24, aflibercept 2Q8 vs.
sham at week 52, and aflibercept 2Q16 vs. sham at week 52) in respect to the 
primary efficacy variable.
The statistical analysis will be performed using the 
Cochran-Mantel-Haenszel method, stratified by baseline DRSS level (level 47 vs. 
level 53).  Missing or nongradable post-baseline values will be imputed using the 
last observation carried forward (LOCF) procedure. For any patient who receives 
rescue treatment, the measurements after rescue is given will be imputed using the 
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last observation prior to rescue treatment. Baseline values will be carried forward 
if all post-baseline observations are missing or nongradable.
Aflibercept treatment will be considered to be superior to sham if the estimated 
aflibercept group (combined, aflibercept 2Q8, or aflibercept 2Q16) is greater than 
the sham group, and the p-value is less than or equal to or statistically significant at 
a 1.67% level.
A hierarchical testing procedure will be performed for each dose group to compare 
the secondary efficacy variables between the respective aflibercept group and the 
sham group at week 52.
For a sensitivity analysis, the primary efficacy analysis will also be performed 
using all observed measurements (regardless of whether rescue treatment was 
given), and only true missing values will be imputed using the LOCF procedure.  
Baseline values will be carried forward if all post-baseline observations are missing
or nongradeable.
Safety Variables
Safety variables will be summarized on the safety analysis set (SAF) through week 
24 for the combined 2Q8 and 2Q16 group, and the sham group.  Safety data 
accumulated through week 52 and week 100 for each treatment group will be 
summarized at the respective time point.
Summaries of all TEAEs by treatment group, and by ocular study eye, ocular 
fellow eye, and non-ocular TEAEs, will include the number and percentage of 
patients with at least 1 TEAE.  Laboratory test results will be summarized by 
baseline and change from baseline to each scheduled assessment time with 
descriptive statistics. 
Sample Size
Anticipating approximately 41% of patients with a ≥2-step improvement from 
baseline in DRSS score in either the 2Q8 or 2Q16 groups versus 17% in the sham 
group, 102 patients per group are required to detect a difference with a power of 
90% for rejecting the null hypothesis at a 2-sided 1.67% (5%/3) significance level.  
A sample size of 102 patients per group will provide at least 90% power to detect a 
difference between the combined aflibercept group and sham group at week 24, if a
38% response rate is assumed in the combined aflibercept group.  To account for 
about a 15% dropout rate, 120 patients per group will be enrolled.
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TABLE OF CONTENTS
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................13 
1. 
INTRODUCTION AND RATIONALE.....................................................................15 
1.1. 
Introduction.................................................................................................................15 
1.2. 
Rationale.....................................................................................................................16 
1.2.1. 
Rationale for Study Design.........................................................................................16 
1.2.2. 
Rationale for Dose Selection ......................................................................................16 
2. 
STUDY OBJECTIVES ..............................................................................................17 
2.1. 
Primary Objective.......................................................................................................17 
2.2. 
Secondary Objectives .................................................................................................17 
3. 
STUDY DESIGN .......................................................................................................17 
3.1. 
Study Description and Duration .................................................................................17 
3.2. 
Planned Interim Analysis............................................................................................18 
3.3. 
Study Committees.......................................................................................................18 
3.3.1. 
Safety Monitoring Team.............................................................................................18 
3.3.2. 
Other Safety Committee .............................................................................................18 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS..............19 
4.1. 
Number of Patients Planned .......................................................................................19 
4.2. 
Study Population.........................................................................................................19 
4.2.1. 
Inclusion Criteria ........................................................................................................19 
4.2.2. 
Exclusion Criteria.......................................................................................................19 
4.3. 
Premature Withdrawal from the Study.......................................................................21 
4.4. 
Replacement of Patients .............................................................................................21 
5. 
STUDY TREATMENTS............................................................................................21 
5.1. 
Investigational and Reference Treatments..................................................................21 
5.2. 
Rescue Treatment in the Study Eye............................................................................22 
5.3. 
Flexible Treatment in the 2Q8 Group in the Study Eye .............................................22 
5.4. 
Dose Modification and Study Drug Discontinuation Rules .......................................22 
5.4.1. 
Dose Modification ......................................................................................................22 
5.4.2. 
Study Drug Discontinuation .......................................................................................22 
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5.5. 
Method of Treatment Assignment..............................................................................23 
5.5.1. 
Masking ......................................................................................................................23 
5.5.2. 
Emergency Unmasking...............................................................................................25 
5.6. 
Treatment Logistics and Accountability.....................................................................25 
5.6.1. 
Packaging, Labeling, and Storage ..............................................................................25 
5.6.2. 
Supply and Disposition of Treatments .......................................................................25 
5.6.3. 
Treatment Accountability...........................................................................................26 
5.6.4. 
Treatment Compliance................................................................................................26 
5.7. 
Concomitant Medications and Procedures .................................................................26 
5.7.1. 
Prohibited Medications and Procedures .....................................................................26 
5.7.2. 
Permitted Medications and Procedures ......................................................................27 
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS.........................27 
6.1. 
Schedule of Events .....................................................................................................27 
6.2. 
Study Visit Descriptions.............................................................................................33 
6.2.1. 
Early Termination Visit ..............................................................................................33 
6.2.2. 
Unscheduled Visits .....................................................................................................33 
6.3. 
Study Procedures ........................................................................................................33 
6.3.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................33 
6.3.2. 
Ocular Procedures (Efficacy and Safety) ...................................................................33 
6.3.2.1. 
Best Corrected Visual Acuity.....................................................................................33 
6.3.2.2. 
Intraocular Pressure ....................................................................................................33 
6.3.2.3. 
Slit Lamp Examination...............................................................................................33 
6.3.2.4. 
Gonioscopy.................................................................................................................34 
6.3.2.5. 
Indirect Ophthalmoscopy............................................................................................34 
6.3.2.6. 
Fundus Photography/Fluorescein Angiography .........................................................34 
6.3.2.7. 
Spectral Domain Optical Coherence Tomography.....................................................34 
6.3.2.8. 
Visual Field Testing....................................................................................................35 
6.3.3. 
Safety Procedures (Non-Ocular).................................................................................35 
6.3.3.1. 
Vital Signs ..................................................................................................................35 
6.3.3.2. 
Physical Examination .................................................................................................35 
6.3.3.3. 
Electrocardiogram.......................................................................................................35 
6.3.3.4. 
Laboratory Testing......................................................................................................35 
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6.3.4. 
Anti-Drug Antibody Procedures.................................................................................37 
6.3.4.1. 
Anti-Drug Antibody Measurements and Samples......................................................37 
 
 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................37 
7.1. 
Definitions ..................................................................................................................37 
7.1.1. 
Adverse Event.............................................................................................................37 
7.1.2. 
Serious Adverse Event................................................................................................38 
7.2. 
Recording and Reporting Adverse Events..................................................................38 
7.2.1. 
Adverse Events ...........................................................................................................38 
7.2.2. 
Serious Adverse Events ..............................................................................................39 
7.2.3. 
Other Events that Require Accelerated Reporting......................................................39 
7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study...........................40 
7.2.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results.............................40 
7.2.6. 
Follow-up....................................................................................................................40 
7.3. 
Evaluation of Severity and Causality .........................................................................40 
7.3.1. 
Evaluation of Severity ................................................................................................40 
7.3.2. 
Evaluation of Causality...............................................................................................41 
7.4. 
Safety Monitoring.......................................................................................................41 
7.5. 
Investigator Alert Notification....................................................................................42 
8. 
STUDY VARIABLES................................................................................................42 
8.1. 
Demographic and Baseline Characteristics ................................................................42 
8.2. 
Primary and Secondary Variables ..............................................................................42 
8.3. 
Additional Variables...................................................................................................43 
9. 
STATISTICAL PLAN................................................................................................43 
9.1. 
Statistical Hypothesis..................................................................................................43 
9.2. 
Justification of Sample Size........................................................................................44 
9.3. 
Analysis Sets...............................................................................................................45 
9.3.1. 
Efficacy Analysis Sets ................................................................................................45 
9.3.2. 
Safety Analysis Set.....................................................................................................45 
9.4. 
Patient Disposition......................................................................................................45 
9.5. 
Statistical Methods......................................................................................................45 
9.5.1. 
Demography and Baseline Characteristics .................................................................46 
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9.5.2. 
Efficacy Analyses .......................................................................................................46 
9.5.2.1. 
Analyses of Primary and Secondary Efficacy Variables............................................46 
9.5.2.2. 
Analyses of Additional Efficacy Variables ................................................................48 
9.5.3. 
Safety Analysis ...........................................................................................................49 
9.5.3.1. 
Adverse Events ...........................................................................................................49 
9.5.3.2. 
Ocular Safety ..............................................................................................................50 
9.5.3.3. 
Other Safety................................................................................................................50 
9.5.3.4. 
Treatment Exposure....................................................................................................50 
9.5.3.5. 
Treatment Compliance................................................................................................50 
9.6. 
Interim Analysis..........................................................................................................50 
9.7. 
Additional Statistical Data Handling Conventions.....................................................51 
9.8. 
Statistical Considerations Surrounding the Premature Termination of a Study.........51 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS.....................................52 
10.1. 
Data Management.......................................................................................................52 
10.2. 
Electronic Systems......................................................................................................52 
11. 
STUDY MONITORING ............................................................................................52 
11.1. 
Monitoring of Study Sites...........................................................................................52 
11.2. 
Source Document Requirements ................................................................................52 
11.3. 
Case Report Form Requirements................................................................................53 
12. 
AUDITS AND INSPECTIONS .................................................................................53 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS..........................................54 
13.1. 
Good Clinical Practice Statement...............................................................................54 
13.2. 
Informed Consent .......................................................................................................54 
13.3. 
Patient Confidentiality and Data Protection ...............................................................54 
13.4. 
Institutional Review Board.........................................................................................55 
14. 
PROTOCOL AMENDMENTS..................................................................................55 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE............................................................................................................................55 
15.1. 
Premature Termination of the Study...........................................................................55 
15.2. 
Close-out of a Site ......................................................................................................55 
16. 
STUDY DOCUMENTATION...................................................................................56 
16.1. 
Certification of Accuracy of Data...............................................................................56 
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16.2. 
Retention of Records ..................................................................................................56 
17. 
CONFIDENTIALITY ................................................................................................56 
18. 
FINANCING AND INSURANCE.............................................................................57 
19. 
PUBLICATION POLICY ..........................................................................................57 
20. 
REFERENCES ...........................................................................................................58 
21. 
INVESTIGATOR’S AGREEMENT..........................................................................59 
APPENDIX 1. OPTICAL COHERENCE TOMOGRAPHY - ANGIOGRAPHY 
SUB-STUDY..............................................................................................................60 
APPENDIX 2. FACTORS TO CONSIDER IN ASSESSING THE RELATIONSHIP 
OF ADVERSE EVENTS TO STUDY DRUG OR INJECTION 
PROCEDURE.............................................................................................................61 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS.....................................................62 
LIST OF TABLES
Table 1: 
Responsibilities of the Masked and Unmasked Personnel .........................................24 
Table 2: 
Schedule of Events – Year 1.......................................................................................28 
Table 3: 
Schedule of Events – Year 2.......................................................................................31 
Table 4: 
Significance Levels for Testing Secondary Efficacy Endpoints ................................44 
LIST OF FIGURES
Figure 1: 
Study Flow Diagram...................................................................................................18 
LIST OF APPENDICES
Appendix 1. Optical Coherence tomography - Angiography Sub-study ....................................60 
Appendix 2. Factors to Consider in Assessing the Relationship of Adverse Events to 
Study Drug or Injection Procedure.............................................................................61 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
2Q4
2 mg every 4 weeks
2Q8
2 mg every 8 weeks
2Q16
2 mg every 16 weeks
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Argus
Pharmacovigilance and clinical safety software system
ASNV
Anterior segment neovascularization
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BCVA
Best corrected visual acuity
BUN
Blood urea nitrogen
CI-DME
Central-involved DME
CPK
Creatine phosphokinase
CRF
Case report form (electronic or paper)
DME
Diabetic macular edema
DRSS
Diabetic Retinopathy Severity Scale
ECG
Electrocardiogram
EDC
Electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
Fluorescein angiography
FAS
Full analysis set
FP
Fundus photography
GCP
Good Clinical Practice
HbA1c
Hemoglobin A1c
IAI
Intravitreal aflibercept injection
ICF
Informed consent form
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
IOP
Intraocular pressure
IVT
Intravitreal
IVRS
Interactive voice response system
IWRS
Interactive web response system
LDH
Lactate dehydrogenase
LOCF
Last observation carried forward
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MedDRA
Medical Dictionary for Regulatory Activities
NPDR
Nonproliferative diabetic retinopathy
OCT
Optical coherence tomography
PCSV
Potentially clinically significant value
PDR
Proliferative diabetic retinopathy
PRP
Panretinal photocoagulation
PT
Preferred term
RBC
Red blood cell
Regeneron
Regeneron Pharmaceuticals, Inc.
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SD-OCT
Spectral Domain Optical Coherence Tomography
SMT
Safety monitoring team
SOC
System organ class
TEAE
Treatment-emergent adverse event
VA
Visual acuity
VEGF
Vascular endothelial growth factor
WBC
White blood cell
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1.
INTRODUCTION AND RATIONALE
1.1.
Introduction
Diabetes mellitus and its complications are a worldwide health epidemic that is expected to 
increase.  In 2013, the World Health Organization estimated that 347 million people had diabetes 
and this number has been projected to increase to 366 million by 2030 and potentially more if 
rates of obesity continue to increase (Wild 2004).  Despite early intervention programs and better 
methods of glycemic control, morbidity and mortality as a consequence of diabetes, including 
diabetic retinopathy, are expected to rise.  Diabetic retinopathy is microvascular damage to the 
blood vessels in the retina, and it can progress to vision-threatening stages including proliferative 
diabetic retinopathy (PDR), where new vessels that are susceptible to hemorrhage grow initially 
from the retina and/or optic disc and extend beyond the internal limiting membrane, and diabetic 
macular edema (DME), where fluid accumulates disrupting the macular architecture and 
function.  Although there are treatments for DME (eg, anti-vascular endothelial growth factor 
[VEGF] agents), there is a significant unmet medical need for the treatment of diabetic 
retinopathy. More advanced retinopathy (proliferative) is often treated with panretinal 
photocoagulation (PRP).  Although PRP may stop the progression of a proliferative disease, it is 
inherently destructive to the retina and, therefore, likely to cause visual symptoms such as visual 
field defects, reduced contrast sensitivity, and impaired night and color vision, and can also lead 
to exacerbation of macular edema (Bressler 2011).
There is currently no treatment for 
nonproliferative diabetic retinopathy (NPDR), and patients are observed until disease progresses 
sufficiently to warrant PRP.
Intravitreal (IVT) anti-VEGF therapy is currently the standard of care treatment for DME, and it 
has proven to be generally safe and effective in patients with DME.  In the phase 3 VISTA and 
VIVID studies of EYLEA® (aflibercept, known in the scientific literature and in clinical studies 
as VEGF Trap-Eye or intravitreal aflibercept injection [IAI]), patients treated with either 
aflibercept 2 mg every 4 weeks (2Q4) or aflibercept 2 mg every 8 weeks (2Q8) (following 
5 initial monthly doses) regimens gained 11.5 and 10.7 letters, respectively, in best corrected 
visual acuity (BCVA) at week 52 (data on file).  Similar visual acuity (VA) gains were seen in 
the RISE and RIDE studies of 0.3 and 0.5 mg Lucentis given monthly (Brown 2013).
In addition to the effect on vision, improvements in diabetic retinopathy as measured by the 
Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale 
(DRSS) were demonstrated in studies of EYLEA and Lucentis.  In the VISTA and VIVID 
studies, the proportion of patients showing a ≥2-step improvement in DRSS at week 52 for the 
2Q4 and 2Q8 groups was 33.8% and 29.1% (VISTA) and 33.3% and 27.7% (VIVID), 
respectively (Korobelnik 2014).  In order to confirm that these results would be consistent for a 
population with moderately severe to severe NPDR at baseline, a subgroup analysis was 
performed in patients with a baseline DRSS score of level 47 or 53.  In this subgroup, as with the 
entire population, consistently more patients in the aflibercept groups had a ≥2-step improvement 
in DRSS (2Q4 = 49.6%, 2Q8 = 43.9%), as compared to the laser group (16.7%) (data on file).  It 
is also worth noting that the proportion of patients with ≥2-step improvement in DRSS both in 
the subgroup and the overall population at week 52 was similar at the earlier time point of 
week 24.
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Despite advances in treatment for DME, there are currently no approved treatments for NPDR in 
patients without DME, leaving patients at risk for the development of DME and/or PDR.  Based 
on the evidence from the VISTA and VIVID studies in patients with DME showing that EYLEA 
(in addition to treating macular edema) also improves the underlying diabetic retinopathy, we 
propose to investigate EYLEA in patients with moderately severe to severe NPDR who do not 
have DME by assessing the proportion of patients who improve by at least 2 steps on the DRSS.
This phase 3 study will assess the efficacy and safety of IVT aflibercept in patients with 
moderately severe to severe NPDR.
Additional background information on the study drug can be found in the Investigator’s 
Brochure.
1.2.
Rationale
1.2.1.
Rationale for Study Design 
Patients with severe NPDR may have 20/20 vision and therefore experience no symptoms of 
their advancing disease.  However, profound vision loss can occur acutely if the fragile, leaky 
vessels develop and either bleed into the vitreous cavity or cause retinal traction and/or 
detachment (Bressler 2011).  Therefore, slowing or halting the worsening of disease will 
minimize or completely avert these severe, often irreversible, effects on vision in a patient
population for which there are no approved, or generally accepted, therapies.
The most comprehensive grading scale that has been developed for diabetic retinopathy was 
derived from the ETDRS.  This was a landmark study that established the value of laser 
photocoagulation in managing diabetic retinopathy.  From this study, a systematic grading scale, 
the DRSS, was derived to predict progression from NPDR to PDR.
Based on the evidence from the VISTA and VIVID studies showing that aflibercept, in addition 
to treating macular edema, also improves the underlying diabetic retinopathy in patients with 
severe NPDR, this study is designed to assess the superiority of aflibercept when compared to 
sham in treating patients with moderately severe to severe NPDR, by assessing the proportion of 
patients who improve by at least 2 steps on the DRSS.  In the VISTA and VIVID studies, the 
2Q8 interval was shown to be effective in improving the DRSS score in patients with macular 
edema.  However, as patients with moderately severe to severe NPDR who do not have 
concurrent DME are unlikely to be experiencing vision loss, a longer interval between physician 
visits and injections would be preferable.  Therefore, a dosing regimen with a longer interval will 
be tested (aflibercept 2 mg every 16 weeks [2Q16]) in the current study, along with the 2Q8 
regimen.
1.2.2.
Rationale for Dose Selection
The 2 mg dose of aflibercept is the same as the currently marketed dose of EYLEA and was used 
in the phase 3 DME studies, where improvement in underlying diabetic retinopathy was 
demonstrated.
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2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is to assess the efficacy of IVT aflibercept compared to sham 
treatment in the improvement of moderately severe to severe NPDR.
2.2.
Secondary Objectives
The secondary objectives of the study are:
x
To characterize the safety of IVT aflibercept in patients with moderately severe to 
severe NPDR 
x
To determine if IVT aflibercept will prevent the worsening of diabetic retinopathy 
and reduce the incidence of DME
x
To determine the anatomic effects of IVT aflibercept in patients with moderately 
severe to severe NPDR
3.
STUDY DESIGN
3.1.
Study Description and Duration
This is a phase 3, double-masked, randomized study of the efficacy and safety of IVT aflibercept 
for the improvement of moderately severe to severe NPDR.
After providing informed consent, patients will be assessed for study eligibility at the screening 
visit, up to 3 weeks before day 1/baseline.  At the day 1/baseline visit, patients will undergo 
safety assessments prior to receiving the first dose of study drug.
Eligible patients will be enrolled into 1 of 3 treatment groups in a 1:1:1 randomization scheme, 
and will be stratified based on their DRSS score (level 47 vs. level 53). Only 1 eye will be 
selected as the study eye. The 3 treatment groups will have the following dosing regimens from 
day 1 to week 48: 1) 2Q8 aflibercept IVT after 5 initial monthly doses; 2) 2Q16 aflibercept IVT 
after 3 initial monthly doses and 1 8-week interval; and 3) sham treatment (see section 5.1). In 
year 2 (beginning at week 56), the 2Q8 group will be treated with a flexible treatment regimen
(see section 5.3).
The primary outcome measure of the study is the proportion of patients who have improved by 
≥2 steps from baseline on the DRSS in the combined 2Q8 and 2Q16 groups at week 24, and in 
each group separately at week 52.  Patients will be evaluated for efficacy (BCVA using the 
4-meter ETDRS protocol, spectral domain optical coherence tomography [SD-OCT], and 
fluorescein angiography [FA]/fundus photography [FP]) and for ocular and systemic safety 
(including ophthalmic exams, visual field testing, and laboratory assessments) through week 100 
(Figure 1).
Patients who develop PDR, anterior segment neovascularization (ASNV), or DME will qualify 
for rescue treatment (see section 5.2).  If treatment is given, patient data will be censored for the 
primary analysis.
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Figure 1:
Study Flow Diagram
Screening
Treatment
(Day –21)
(Day –1)
(Day 1)
Week 24
Week 52
Week 100
Visit 1
Baseline/Visit 2
Primary Outcome
Measure (2Q8 & 2Q16 
combined)
Visit 7
Primary (2Q8 & 
2Q16 separately)
and Secondary 
Outcome Measures
Visit 11
End of Study
Visit 18
3.2.
Planned Interim Analysis
No formal interim analysis is planned.
3.3.
Study Committees 
3.3.1.
Safety Monitoring Team
A safety monitoring team (SMT) at Regeneron will meet at scheduled times during the study to 
review masked safety data.  These data may include, but are not limited to:
x
Treatment-emergent adverse events (TEAEs) that result in an early study withdrawal
x
Serious adverse events (SAEs)
x
Fatal events
x
Identified and potential risks for IVT aflibercept
Appropriate action, if needed, will be taken based upon these reviews and in consultation with 
the medical monitor.
3.3.2.
Other Safety Committee
Potential arterial thrombotic events will be evaluated by a masked adjudication committee 
according to criteria formerly applied and published by the Anti-Platelet Trialists’ Collaboration 
prior 
to 
database 
unmasking 
(Antithrombotic 
Trialists' 
Collaboration 
1994; 
Antithrombotic Trialists' Collaboration 2002).  An arterial thrombotic event is defined as a 
nonfatal myocardial infarction, nonfatal ischemic stroke, nonfatal hemorrhagic stroke, or death 
resulting from vascular or unknown causes.  Additional details regarding data to be collected can 
be found in the study procedure manual.
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4.
SELECTION, WITHDRAWAL, AND REPLACEMENT OF
PATIENTS
4.1.
Number of Patients Planned
Approximately 360 patients will be enrolled in approximately 70 sites, with a target enrollment 
of approximately 120 patients in each treatment group.
4.2.
Study Population
The patient population will include men or women with type 1 or 2 diabetes mellitus who have 
moderately severe to severe NPDR (without DME threatening the center of the macula), in 
whom PRP can be safely deferred for at least 6 months.
For patients who meet eligibility criteria in both eyes, the eye with the most severe DRSS score 
will be selected as the study eye. If both eyes have equivalent scores, factors such as ocular 
dominance and patient preference should be considered in making the selection.
4.2.1.
Inclusion Criteria
A patient must meet the following criteria at screening and at day 1 to be eligible for inclusion in 
the study:
1. Men or women ≥18 years of age with type 1 or 2 diabetes mellitus who have moderately 
severe to severe NPDR (DRSS levels 47 or 53), confirmed by the central reading center, 
in whom PRP can be safely deferred for at least 6 months per the investigator
2. BCVA ETDRS letter score in the study eye of ≥69 letters (approximate Snellen 
equivalent of 20/40 or better)
3. Willing and able to comply with clinic visits and study-related procedures
4. Provide signed informed consent
4.2.2.
Exclusion Criteria
A patient who meets any of the following criteria at either the screening visit or at day 1 will be 
excluded from the study:
1. Presence of DME threatening the center of the macula (within 1,000 microns of the 
foveal center) in the study eye
2. Evidence of retinal neovascularization on clinical examination or FA
3. Any prior focal or grid laser photocoagulation (within 1,000 microns of the foveal center) 
or any prior PRP in the study eye
4. Any prior systemic anti-VEGF treatment or IVT anti-VEGF treatment in the study eye
5. Any prior intraocular steroid injection in the study eye
6. History of vitreoretinal surgery in the study eye
7. Intraocular pressure (IOP) ≥25 mm Hg in the study eye
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8. Evidence of active infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye
9. Any intraocular inflammation or infection in either eye within 3 months of the screening 
visit
10. Current ASNV, vitreous hemorrhage, or tractional retinal detachment visible at the 
screening assessments in the study eye
11. Ocular media of insufficient quality to obtain fundus and optical coherence tomography 
(OCT) images in the study eye
12. Hemoglobin A1c (HbA1c) >12%, or if HbA1c is ≤12%, diabetes mellitus is uncontrolled
in the opinion of the investigator
13. Uncontrolled blood pressure (defined as systolic >160 mm Hg or diastolic >95 mm Hg 
while patient is sitting)
14. History of cerebrovascular accident or myocardial infarction within 180 days of day 1
15. Renal failure, dialysis, or history of renal transplant
16. Women who are breastfeeding or who have a positive serum hCG/urine pregnancy test at 
the screening or baseline visit
17. Any concurrent ocular condition in the study eye which, in the opinion of the 
investigator, could either increase the risk to the patient beyond what is to be expected 
from standard procedures of IVT injections, or which otherwise may interfere with the 
injection procedure or with evaluation of efficacy or safety
18. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that might affect interpretation of the 
results of the study or render the patient at high risk for treatment complications
19. Participation as a patient in any interventional clinical study within the 12 weeks prior to 
day 1 of the study
20. Sexually active men* or women of childbearing potential** who are unwilling to 
practice adequate contraception prior to the initial dose/start of the first treatment, during 
the study, and for at least 3 months after the last dose.  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; 
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 childbearing potential.  Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation.
21. Patients who are on systemic anti-VEGF treatment (ie, bevacizumab, ziv-aflibercept) for 
oncology treatment (if a patient requires systemic anti-VEGF treatment during the study, 
the patient will be withdrawn)
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4.3.
Premature Withdrawal from the Study
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion.
The investigator and sponsor have the right to withdraw a patient 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 patients should be avoided.
Patients who withdraw prematurely from the study will be asked to complete study assessments 
per section 6.2.1.
4.4.
Replacement of Patients
Patients prematurely discontinued from the study will not be replaced.
5.
STUDY TREATMENTS
5.1.
Investigational and Reference Treatments 
The investigational product is IAI, which will be supplied in sterile, sealed, 3 mL, single-use 
vials, each with a “withdrawable” volume of approximately 50 μL (0.05 mL) at a concentration 
of 40 mg/mL.
The injection volume will be 50 μL (0.05 mL) and will be administered to the patients by IVT 
injection.  Only 1 eye will be selected as the study eye.
Study Eye
Patients will be randomly assigned to 1 of 3 treatment groups in a 1:1:1 ratio:
x
2Q8: aflibercept 2 mg Q8 to week 48 (after 5 initial monthly doses), followed by a 
flexible treatment regimen with aflibercept 2 mg to week 96
x
2Q16: aflibercept 2 mg Q16 to week 96 (after 3 initial monthly doses and 1 8-week 
interval)
x
Sham: sham injections Q4 to week 16, followed by sham injections Q8 to week 96
Masking will be maintained to the end of the study (week 100).  To preserve the masking, sham 
injections will be performed for the 2Q8 and 2Q16 groups at treatment visits in which patients do 
not receive an active injection through week 96, and at all treatment visits for the sham group 
from baseline to week 96.  Instructions on dose preparation are provided in the pharmacy 
manual.
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5.2.
Rescue Treatment in the Study Eye
Patients who develop PDR, ASNV, or central-involved DME (CI-DME) in the study eye may be 
treated, if deemed appropriate by the masked physician.  For any of these complications, an FP 
must be performed before rescue treatment is given.
Patients who develop CI-DME may receive IVT aflibercept (refer to EYLEA USPI 2015) or 
laser photocoagulation, and will no longer receive their randomized treatment.  Rescue treatment 
may be given by the masked or unmasked physician.
Patients who develop PDR and/or ASNV may receive PRP or vitrectomy with endolaser, if 
necessary, but will remain on their randomized treatment schedule. Panretinal photocoagulation 
or surgical intervention may be performed by either the masked or unmasked physician.
In 
addition, 1 injection of aflibercept may be given, which must be administered by the unmasked 
physician.
If treatment for DME, ASNV, or PDR is given, patient data will be censored from the time of 
treatment for the primary analysis.
5.3.
Flexible Treatment in the 2Q8 Group in the Study Eye
Beginning at week 56, patients randomized to the 2Q8 group will receive aflibercept using a 
flexible treatment regimen.  An injection will be given at each visit unless a patient has reached 
Level 35 or better (mild NPDR) on the DRSS (as determined by the masked investigator), at 
which point treatment will be deferred (and a sham injection given). Level 35 can be clinically 
defined as microaneurysms plus venous loops, hard exudates, cotton wool spots, and/or mild 
retinal hemorrhages (less than present in ETDRS standard photograph 2a in up to 3 quadrants 
[see also study procedure manual]).
The determination whether Level 35 or better has been 
reached will be assessed by the masked investigator at each visit on FP.
To maintain masking, all treatment groups will be assessed (using FP) for flexible treatment 
criteria from week 56 to week 96, but the 2Q16 group will continue to receive treatment every 
16 weeks and the sham group will continue to receive sham injections at every visit.
5.4.
Dose Modification and Study Drug Discontinuation Rules
5.4.1.
Dose Modification
Dose modification for an individual patient is not allowed.
5.4.2.
Study Drug Discontinuation
Patients who permanently discontinue from study drug and who do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits per the visit schedule.
Patients who opt to withdraw from the study will be asked to complete study assessments, per 
section 6.2.1.
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5.5.
Method of Treatment Assignment
Approximately 360 patients will be randomized in a 1:1:1 ratio to receive either aflibercept 2Q8, 
aflibercept 2Q16, or sham according to a central randomization scheme provided by an 
interactive voice response system (IVRS)/interactive web response system (IWRS) to the 
designated study pharmacist (or qualified designee).  Randomization will be stratified according 
to the patient’s DRSS level (level 47 vs. level 53 at the screening visit).
5.5.1.
Masking
To preserve the masking, sham injections will be performed for the 2Q8 and 2Q16 groups at
treatment visits in which patients do not receive an active injection through week 96; sham 
injections will be performed at all treatment visits for the sham group from baseline to week 96. 
Weeks 52 and 100 are nontreatment visits.
A masked physician will be assigned to do the following:  1) assess AEs, and 2) perform the 
masked assessment of efficacy.  A separate, unmasked physician will administer treatment in the 
study eye (ie, perform study drug injection or sham injection) (Table 1).
The unmasked physician or designee will not have any role in the study beyond the receipt, 
tracking, preparation, destruction, administration of study drug, and assessing safety during the 
observation period following study drug administration. The masked physician will determine if 
a patient has developed DME, ASNV, or PDR in the study eye, and will be responsible for 
recommending treatment, which will be administered by the unmasked physician. Once it has 
been determined that a patient has progressed to DME, ASNV, or PDR, treatment may be given 
by either the masked or unmasked physician.  Beginning at week 56, the masked physician will 
assess whether a patient has a DRSS Level 35 or better in the study eye using FP, to determine 
the need for flexible treatment. The unmasked physician will administer sham or active treatment 
per protocol.
Every effort must be made to ensure that all other study site personnel other than those 
designated as unmasked remain masked to treatment assignment.
Masked and unmasked roles will be assumed for the entire study, and switching from an 
unmasked to a masked role after the first patient is randomized at a site is not permitted.  Any 
deviation to the roles above must first be approved by the sponsor.  This must be properly 
documented before any patients are treated, and the Site Signature and Delegation Log must be 
maintained as new personnel are added to the study team.
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Table 1:
Responsibilities of the Masked and Unmasked Personnel
Masked or Unmasked Personnel
x Performs all screening procedures up until randomization
x Assesses inclusion/exclusion criteria
x Obtains medical/ophthalmic history
x Obtains informed consent
x Collects samples for laboratory testing and antibody sampling 
x Performs electrocardiograms (ECGs) and transfers to reading center
x Administers rescue treatment once the need for rescue has been determined by the masked 
investigator (physician only)
Masked Personnel
x Determines if a patient has developed DME, ASNV, or PDR in the study eye and 
recommends treatment (physician only)
x Assesses AEs, including severity and relationship 
x Assesses efficacy
x Performs ophthalmic examinations, including IOP, at all study visits (except post-dose 
examinations immediately after treatment)
x Evaluates all safety, including review of images for safety concerns (except those 
immediately after IVT injection) 
x May perform fellow eye injections at any unscheduled visits where only the fellow eye is 
treated
x Tests refraction and BCVA (no exceptions will be granted)
x Performs Humphrey Visual Field test
x Performs and assesses OCT, FP, and FA images and transfers them to reading centers
x Assesses need for flexible treatment during year 2
Unmasked Personnel
x Coordinates randomization 
x Performs receipt and accountability of study drug
x Performs study drug (IAI) or sham injection (study eye)
x Performs fellow eye injection (if treatment is administered bilaterally/in conjunction with 
study eye treatment)
x Observes safety at the end of the observation period (approximately 30 minutes following 
study treatment)
x Checks IOP post-dose (study eye) before the end of the approximately 30-minute 
observation period
x Checks indirect ophthalmoscopy post-dose (study eye)
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After the week 24 and week 52 analyses, study reports will be issued that will indicate the 
efficacy outcomes up to week 24 and week 52, respectively.  All patients and study personnel 
who were masked through week 24 and week 52 will remain masked to the individual patient 
treatment assignments even after the issuance of each study report, respectively.
5.5.2.
Emergency Unmasking 
Unmasking of treatment assignment for a patient may be necessary due to a medical emergency 
or any other significant medical event (eg, pregnancy).
x
If unmasking is required:

Only the investigator will make the decision to unmask the treatment assignment.

Only the affected patient will be unmasked.

Unmasking of the treatment assignment must be performed via the IVRS; manual 
unmasking (ie, via the designated unmasked staff at the study site) will not be 
permitted

The investigator will notify Regeneron and/or designee before unmasking the patient, 
whenever possible
If emergency unmasking is required and the IVRS is not available, only the Regeneron Head of 
Pharmacovigilance and Risk Management or designee will unmask the patient and provide the 
treatment assignment to the investigator.
5.6.
Treatment Logistics and Accountability
  
 
  
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5.6.3.
Treatment Accountability
All drug accountability records must be kept current.
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication
x
dispensed to each patient,
x
returned from each patient (if applicable), and
x
disposed of at the site or returned to the sponsor or designee.
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study.
Drug accountability will be also performed for aflibercept administered in the fellow eye.
5.6.4.
Treatment Compliance
All drug compliance records must be kept current and must be made available for inspection by 
the sponsor and regulatory agency inspectors.
5.7.
Concomitant Medications and Procedures
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication.  This includes medications that were started before the study 
and are ongoing during the study.
If a pretreatment concomitant medication is administered in the study eye before injection (eg, 
antibiotic or anesthetic), it must be administered for both active and sham treatment.
5.7.1.
Prohibited Medications and Procedures 
Patients may not receive any medications (approved or investigational) for their diabetic 
retinopathy in the study eye other than the assigned study treatment (aflibercept or sham) as 
specified in this protocol, unless they have developed PDR, ASNV, or DME (in which case they 
may be treated as indicated in section 5.2) or completed the end of study (week 100) visit 
assessments.  This includes medications administered locally (eg, IVT, topical, juxtascleral or 
periorbital routes), as well as those administered systemically, with the intent of treating the 
study and/or fellow eye.
Aflibercept will be provided for fellow eye use (see section 5.7.2); other anti-VEGF agents will 
not be allowed.
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5.7.2.
Permitted Medications and Procedures
Fellow Eye
Intravitreal aflibercept (2 mg) will be made available for patients who have CI-DME, PDR or 
ASNV in the fellow eye at study start (beginning on day 1), or are diagnosed during the trial 
(refer to EYLEA USPI 2015).
Standard of care treatment (eg, PRP) will also be allowed for patients developing PDR in the 
fellow eye at any time during the trial.
The patient’s fellow eye may receive treatment on the same day as the study eye or at an 
unscheduled visit.  All fellow eye treatments must be recorded on the electronic case report form 
(CRF) as a concomitant medication and/or procedure for the fellow eye.  The fellow eye will not 
be considered an additional study eye.  Patients who receive treatment for the fellow eye will not 
be required to be withdrawn from the study.  Safety of the fellow eye will be monitored and all 
AEs will be collected.  Other conditions in the fellow eye may be treated with approved 
therapies.
Any other medications that are considered necessary for the patient’s welfare, and that are not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of the 
investigator.
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 2 and Table 3.
Additional details for the exploratory OCT-angiography sub-study are provided in Appendix 1.
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Table 2:
Schedule of Events – Year 1
Screening 
Visit 1
Baseline 
Visit 2
Year 1 Treatment Period
Study Procedure
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 111
Week
--
0
4
8
12
16
24
32
40
48
52
Day
(visit window)
-21 to -1
1
29
± 7 days
57
± 7 days
85
± 7 days
113
± 7 days
169
± 7 days
225
± 7 days
281
± 7 days
337
± 7 days
365
± 10 days
Screening/Baseline:
Informed consent
X
Inclusion/exclusion
X
X
Medical and ophthalmic history
X
Demographics
X
Randomization
X
Treatment:
Review of concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Administer IVT aflibercept (IAI) or 
sham2
X
X
X
X
X
X
X
X
X
Ocular Assessments:
BCVA (ETDRS) and refraction
X
X
X
X
X
X
X
X
X
X
X
Slit lamp examination 
X
X
X
X
X
X
X
X
X
X
X
Gonioscopy3
X
X
X
X
X
Intraocular pressure4
X
X
X
X
X
X
X
X
X
X
X
Indirect ophthalmoscopy5
X
X
X
X
X
X
X
X
X
X
X
SD-OCT
X
X
X
X
X
X
X
X
X
X
X
FA & FP6
X
X7
X
X
X
X
Visual field testing (study eye)8
X9
X
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Screening 
Visit 1
Baseline 
Visit 2
Year 1 Treatment Period
Study Procedure
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 111
Week
--
0
4
8
12
16
24
32
40
48
52
Day
(visit window)
-21 to -1
1
29
± 7 days
57
± 7 days
85
± 7 days
113
± 7 days
169
± 7 days
225
± 7 days
281
± 7 days
337
± 7 days
365
± 10 days
Non-Ocular Assessments:
Physical examination
X10
Vital signs11
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
Adverse events12
X
X
X
X
X
X
X
X
X
X
X
Laboratory Testing:13
Hematology, blood chemistry, 
urinalysis, Vitamin D and HbA1c14
X
X15
X
Pregnancy test, women of 
childbearing potential16
serum
urine
urine
urine
urine
urine
urine
urine
urine
urine
Anti-aflibercept antibody samples17
X
X
1.
Patients who are withdrawn from the study before week 52/visit 11 will be asked to return to the clinic to complete the visit 11 assessments.
2.
Patients will receive either IAI or sham injections given by the unmasked investigator, depending on the assigned treatment group.
3.
Gonioscopy in the study eye only.
4.
Intraocular pressure will be measured pre-dose (bilateral) and approximately 30 minutes after administration of study drug on days when study drug/sham is 
administered (study eye only).
5.
Indirect ophthalmoscopy will be performed pre-dose (bilateral) and immediately after administration of study drug on days when study drug is administered 
(study eye only).
6.
An FP must be performed once a patient has been diagnosed with PDR, ASNV, or CI-DME in the study eye, and before rescue treatment is given. For sites 
that will capture FA images on the Optos® Ultra-Widefield Imaging system, axial length must be measured in both eyes at baseline using any appropriate 
method.
7.
Only FP at week 8.
8.
Only sites that have access to Humphrey Visual Field will perform visual field testing at the indicated visits. 
9.
May be performed at visit 1 or visit 2.
10. Including height and weight.
11. Vital signs (body temperature, blood pressure, and heart rate) will be measured after the patient has been sitting for 5 minutes.
12. Adverse events will be collected from the time the informed consent form (ICF) is signed until early termination or the end of study visit.  If a patient 
withdraws from the study, ongoing AEs will be followed to the end of study visit or until the patient withdraws consent. 
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13. All samples collected for laboratory assessments will be obtained prior to administration of study drug.
14. At visits at which FA is performed, urinalysis samples will be collected before FA in order to avoid false elevations in urine protein values. Vitamin D will 
be tested at visit 1 (screening) only.
15. Sampling only for HbA1c.
16. For women of childbearing potential, a negative screening serum pregnancy test and urine pregnancy test on day 1 are required before randomization. All 
women of childbearing potential will have a urine pregnancy test at each treatment visit starting at visit 2 (day 1); a negative urine pregnancy test is required 
before treatment is administered (randomized treatment, rescue treatment with IAI, or fellow eye treatment with IAI).
17. All ADA samples must be collected prior to administration of study drug on days when study drug is administered.
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Table 3:
Schedule of Events – Year 2
Study Procedure
Visit 12
Visit 13
Visit 14
Visit 15
Visit 16
Visit 17
Visit 18/End 
of Study1
Week
56
64
72
80
88
96
100
Day
(visit window)
393
± 7 days
449
± 7 days
505
± 7 days
561
± 7 days
617
± 7 days
673
± 7 days
701
± 10 days
Treatment:
Review of concomitant medications
X
X
X
X
X
X
X
Administer IVT aflibercept (IAI) or sham2
X
X
X
X
X
X
Ocular Assessments:
BCVA (ETDRS) and refraction
X
X
X
X
X
X
X
Slit lamp examination
X
X
X
X
X
X
X
Gonioscopy3
X
X
X
Intraocular pressure4
X
X
X
X
X
X
X
Indirect ophthalmoscopy5
X
X
X
X
X
X
X
SD-OCT
X
X
X
X
X
X
X
FP6
X
X
X
X
X
X
X
FA7
X
X
X
Visual field testing (study eye)8
X
Non-Ocular Assessments:
Vital signs9
X
X
X
X
X
X
X
ECG
X
Adverse events10
X
X
X
X
X
X
X
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Study Procedure
Visit 12
Visit 13
Visit 14
Visit 15
Visit 16
Visit 17
Visit 18/End 
of Study1
Week
56
64
72
80
88
96
100
Day
(visit window)
393
± 7 days
449
± 7 days
505
± 7 days
561
± 7 days
617
± 7 days
673
± 7 days
701
± 10 days
Laboratory Testing:11
Hematology, blood chemistry, urinalysis, 
Vitamin D, and HbA1c12
X
Pregnancy test, women of childbearing 
potential13
urine
urine
urine
urine
urine
urine
urine
Anti-aflibercept antibody samples14
X
1.
Patients who are withdrawn from the study after week 52/visit 11 will be asked to return to the clinic for week 100/visit 18 assessments.
2.
Patients will receive either IAI or sham injections given by the unmasked investigator, depending on the assigned treatment group.
3.
Gonioscopy in the study eye only.
4.
Intraocular pressure will be measured pre-dose (bilateral) and approximately 30 minutes after administration of study drug on days when study drug/sham is 
administered (study eye only).
5.
Indirect ophthalmoscopy will be performed pre-dose (bilateral) and immediately after administration of study drug on days when study drug is administered 
(study eye only).
6.
An FP must also be performed once a patient has been diagnosed with PDR, ASNV, or CI-DME in the study eye, and before rescue treatment is given.
7.
For sites that will capture FA images on the Optos® Ultra-Widefield Imaging system, axial length must be measured in both eyes at baseline using any 
appropriate method.
8.
Only sites that have access to Humphrey Visual Field will perform visual field testing at the indicated visits.
9.
Vital signs (body temperature, blood pressure, and heart rate) will be measured after the patient has been sitting for 5 minutes.
10. Adverse events will be collected from the time the ICF is signed until early termination or the end of study visit.  If a patient withdraws from the study, 
ongoing AEs will be followed to the end of study visit or until the patient withdraws consent.
11. All samples collected for laboratory assessments should be obtained prior to administration of study drug.
12. At visits at which FA is performed, urinalysis samples will be collected before FA in order to avoid false elevations in urine protein values. Vitamin D will 
be tested at visit 18 (week 100) only.
13. All women of childbearing potential will have a urine pregnancy test at each treatment visit starting at visit 2 (day 1).  A negative urine pregnancy test is 
required before treatment is administered (randomized treatment, rescue treatment with IAI, or fellow eye treatment with IAI)
14. All ADA samples must be collected prior to administration of study drug on days when study drug is administered.
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6.2.
Study Visit Descriptions
6.2.1.
Early Termination Visit
Patients who are withdrawn from the study before week 52/visit 11 will be asked to return to the 
clinic to complete the visit 11 assessments, as described in Table 2. Patients who are withdrawn 
from the study after week 52/visit 11 will be asked to return to the clinic for week 100/visit 18 
assessments, as described in Table 3.
6.2.2.
Unscheduled Visits
All attempts should be made to keep patients on the study schedule.  However, unscheduled 
visits may be necessary to evaluate or repeat testing following abnormal laboratory results, for 
follow-up of AEs, for rescue treatment for the study eye, for treatment of the fellow eye, or for 
any other reason, as warranted.
6.3.
Study Procedures
6.3.1.
Procedures Performed Only at the Screening/Baseline Visit
For women of childbearing potential, a negative serum pregnancy test at screening is required for 
eligibility.
6.3.2.
Ocular Procedures (Efficacy and Safety)
6.3.2.1.
Best Corrected Visual Acuity 
Visual function of the study eye and the fellow eye will be assessed using the ETDRS protocol 
(The Early Treatment Diabetic Retinopathy Study Group 1985) at 4 meters at each study visit, as 
specified in Table 2 and Table 3.  Visual acuity examiners must be certified to ensure consistent 
measurement of BCVA.  The VA examiner must remain masked to treatment assignment.  Best 
corrected visual acuity should be done before any other ocular procedures are performed.  A 
detailed protocol for conducting VA testing and refraction can be found in the study procedure 
manual.
6.3.2.2.
Intraocular Pressure
Intraocular pressure of the study eye will be measured at every visit using Goldmann applanation 
tonometry or Tono-pen™, as specified in Table 2 and Table 3.  The same method of IOP 
measurement must be used throughout the study for each individual patient.  Intraocular pressure 
will be measured pre-dose (bilateral) by the masked physician (or designee), and at 
approximately 30 minutes post-dose (study eye) by the unmasked physician (or designee).
6.3.2.3.
Slit Lamp Examination
Patients’ anterior eye structure and ocular adnexa will be examined bilaterally pre-dose at each 
study visit using a slit lamp (study procedure manual) by the masked investigator, as specified in 
Table 2 and Table 3.
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6.3.2.4.
Gonioscopy
Patients will be evaluated for the development of neovascularization of the iridocorneal angle by 
gonioscopy in conjunction with slit lamp biomicroscopy. The examination should be performed 
in the study eye only before the application of mydriatic agents, as specified in Table 2 and 
Table 3, or if frank rubeosis is present.
6.3.2.5.
Indirect Ophthalmoscopy 
Patients’ posterior pole and peripheral retina will be examined by indirect ophthalmoscopy at
each study visit pre-dose (bilateral) by the masked investigator and post-dose (study eye) by the 
unmasked investigator, as specified in Table 2 and Table 3.  Post-dose evaluation must be 
performed immediately after injection (active drug or sham).
6.3.2.6.
Fundus Photography/Fluorescein Angiography
The anatomical state of the retinal vasculature and the DRSS level will be evaluated by FA and 
FP as specified in Table 2 and Table 3.
The study eye will be the transit eye. Fundus 
photography and FA will be captured and transmitted to an independent reading center for both 
eyes.
An FP must be performed once a patient has been diagnosed with PDR, ASNV, or CI-DME in 
the study eye, and before rescue treatment is given.
Fundus and angiographic images will be sent to an independent reading center where images will 
be read by masked readers.  All FPs and FAs will be archived at the site as part of the source 
documentation.  Photographers must be certified by the reading center to ensure consistency and 
quality in image acquisition.  Every effort will be made to ensure that all photographers at the 
site remain masked to treatment assignment.  A detailed protocol for image acquisition and 
transmission can be found in the study procedure manual.
For sites that will capture FA images on the Optos® Ultra-Widefield Imaging system, axial 
length must be measured in both eyes at baseline using any appropriate method.
6.3.2.7.
Spectral Domain Optical Coherence Tomography
Retinal characteristics will be evaluated at every visit using SD-OCT.  Images will be captured 
and transmitted for both eyes.  Images will be sent to an independent reading center where they 
will be read by masked readers.  All OCTs will be electronically archived at the study sites as 
part of the source documentation.  Optical coherence tomography technicians must be certified 
by the reading center to ensure consistency and quality in image acquisition.  Every effort will be 
made to ensure that OCT technicians at the study site remain masked to treatment assignment.  A 
detailed protocol for acceptable OCT machines and OCT image acquisition/transmission can be 
found in the study procedure manual.
Details on an optional sub-study evaluating an exploratory OCT-angiography procedure are 
provided in Appendix 1.
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6.3.2.8.
Visual Field Testing
Visual field testing will be assessed in the study eye using the Humphrey Visual Field Analyzer 
by sites who have access to this machine, at visits specified in Table 2 and Table 3.  The first 
visual field testing may be performed at either visit 1 or visit 2. Technicians must be certified to 
ensure consistency and quality testing procedures. Every effort will be made to ensure that visual 
field technicians at the study site remain masked to treatment assignment. A detailed protocol 
for visual field testing can be found in the study procedure manual.
6.3.3.
Safety Procedures (Non-Ocular)
6.3.3.1.
Vital Signs
Vital signs, including body temperature, blood pressure, and heart rate will be collected pre-dose 
at time points according to Table 2 and Table 3.  Vital sign measurements will be taken once the 
patient has been sitting down for 5 minutes.
6.3.3.2.
Physical Examination
A physical examination, including height and weight, will be performed at the screening visit.
6.3.3.3.
Electrocardiogram
A standard 12-lead ECG measurement will be measured at visits specified in Table 2 and 
Table 3.  Heart rate will be recorded from the ventricular rate and the PR, QRS, RR and QT 
intervals will be recorded.  The ECG strips or report will be retained with the source 
documentation.  Electrocardiograms will be forwarded to a central reader.
6.3.3.4.
Laboratory Testing 
Hematology, blood chemistry, urinalysis, HbA1c, and pregnancy testing samples will be 
analyzed by a central laboratory.  All samples collected for laboratory assessments will be 
obtained prior to administration of study drug.  At visits at which FA is performed, urinalysis 
samples must be collected before FA to avoid false elevations in urine protein values.  Detailed 
instructions for blood sample collection are in the laboratory manual provided to study sites.
Samples for laboratory testing will be collected at time points according to Table 2 and Table 3.  
Tests will include:
Blood Chemistry
Sodium
Total protein, serum
Total bilirubin
Potassium
Creatinine
Total cholesterol
Chloride
Blood urea nitrogen (BUN)
Uric acid
Carbon dioxide
Aspartate aminotransferase (AST)
Creatine phosphokinase (CPK)
Calcium
Alanine aminotransferase (ALT)
Glucose
Alkaline phosphatase
Albumin
Lactate dehydrogenase (LDH)
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Hematology
Hemoglobin
Differential:
Hematocrit
Neutrophils
Red blood cells (RBCs)
Lymphocytes
White blood cells (WBCs)
Monocytes
Red cell indices
Basophils
Platelet count
Eosinophils
Urinalysis
Color
Urine protein:creatinine ratio
RBC
Clarity
Glucose
Hyaline and other casts
Creatinine
Blood
Bacteria
pH
Bilirubin
Epithelial cells
Specific gravity
Leukocyte esterase
Crystals
Ketones
Nitrite
Yeast
Protein
WBC
Other Laboratory Tests
Hemoglobin A1c and Vitamin D will be measured at time points according to Table 2 and 
Table 3.
Women of childbearing potential must have the outcome of their serum pregnancy test before 
randomization.  They should continue to be tested for pregnancy (urine pregnancy test) during 
the study at every treatment visit.  For patients on an IAI rescue regimen, or those being treated 
with IAI in the fellow eye, urine pregnancy test should be done before each dose.
Abnormal Laboratory Values and Laboratory Adverse Events
x
All laboratory values must be reviewed by the masked investigator or authorized 
designee.
x
Significantly abnormal tests must be repeated to confirm the nature and degree of the 
abnormality.  When necessary, appropriate ancillary investigations should be 
initiated.  If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the medical 
monitor must be consulted.
x
The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the masked investigator.
Criteria for reporting laboratory values as an AE are provided in section 7.2.5.
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6.3.4.
Anti-Drug Antibody Procedures
6.3.4.1.
Anti-Drug Antibody Measurements and Samples
Samples for anti-drug antibody (ADA) assessment will be collected at time points listed in 
Table 2 and Table 3.  Samples should be collected prior to the administration of study drug.  
Samples collected for ADA measurements may be used for exploratory analysis or to investigate 
unexpected AEs.
  
7.
SAFETY DEFINITIONS, REPORTING, AND MONITORING
7.1.
Definitions
7.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient 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 (ie, any clinically significant change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of the study drug.
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7.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:
x
Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger).
x
Is life-threatening – in the view of the investigator, the patient 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.
x
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.
x
Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).
x
Is a congenital anomaly/birth defect
x
Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or
may require intervention to prevent 1 of the other serious outcomes listed above 
(eg, 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).
An ocular important medical event may include the following:
x
An AE that requires either surgical or medical intervention to prevent permanent loss 
of vision
x
Substantial, unexplained vision loss or an AE that causes substantial vision loss
7.2.
Recording and Reporting Adverse Events
7.2.1.
Adverse Events
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study.  Refer to the study procedure manual for the procedures to be 
followed.
Information on follow-up for AEs is provided in section 7.2.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in section 7.2.5.
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7.2.2.
Serious Adverse Events
All SAEs, regardless of assessment of causal relationship to study drug must be reported to the 
sponsor (or designee) within 24 hours.  Refer to the study procedure manual for the procedure to 
be followed.
Information not available at the time of the initial report must be documented in a follow-up 
report.  Substantiating data such as relevant hospital or medical records and diagnostic test 
reports may also be requested.
The investigator must promptly report to the Institutional Review Board (IRB) all unanticipated 
problems involving risks to patients.  This includes death from any cause and all SAEs related to 
the use of the study drug.  It is recommended that all SAEs be reported to the IRB, regardless of 
assessed causality.
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply:
x
SAE with an onset within 30 days of the end of study/early termination visit - the
SAE will be reported to the sponsor.  The investigator should make every effort to 
obtain follow-up information on the outcome until the event is considered chronic 
and/or stable.
x
SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable.
7.2.3.
Other Events that Require Accelerated Reporting
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event:
Symptomatic Overdose of Study Drug:
Accidental or intentional overdose of at least 
2 times the intended dose of study drug within the intended therapeutic 
window, if associated with an AE,
Pregnancy:
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), by telephone within 
24 hours of identification, any pregnancy occurring in a female patient or
female partner of a male patient, during the study or within 90 days of the last 
dose of study drug.  Any complication of pregnancy affecting a female study 
patient or female partner of a male study patient, and/or fetus and/or newborn 
must be reported as an SAE.
Refer to the study procedure manual for the procedures to be followed.
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7.2.4.
Reporting Adverse Events Leading to Withdrawal from the Study
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days.
Refer to the study procedure manual for the procedures to be followed.
7.2.5.
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include:
x
the test result is associated with accompanying symptoms, and/or
x
the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or
x
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
Contact the medical monitor in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria.
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.
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in section 7.3.1.
7.2.6.
Follow-up
Adverse event information will be collected until the patient’s last study visit.
Serious adverse event information will be collected 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 AEs will be graded according to the following scale:
x
Mild:
Does not interfere in a significant manner with the patient’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 patient.
x
Moderate: Produces some impairment of functioning but is not hazardous to health.  
It is uncomfortable or an embarrassment.  Treatment for symptom may be needed.
x
Severe:
Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health.  Treatment for symptom may be given and/or 
patient hospitalized.
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7.3.2.
Evaluation of Causality
Relationship of AEs to Study Drug:
The relationship of AEs to study drug will be assessed by the masked investigator, and will be a 
clinical decision based on all available information.  The following question will be addressed:
Is there a reasonable possibility that the AE may have been caused by the study drug?
The possible answers are:
Not Related:
There is no reasonable possibility that the event may have been caused by 
the study drug
Related:
There is a reasonable possibility that the event may have been caused by 
the study drug
For a list of factors to consider in assessing the relationship of AEs to study drug, see 
Appendix 2.
The sponsor will request information to justify the causality assessment of SAEs, as needed.
Relationship of AEs to Injection Procedure:
The relationship of AEs to injection procedure will be assessed by the masked investigator, and 
will be a clinical decision based on all available information.  The following question will be 
addressed:
Is there a reasonable possibility that the AE may have been caused by the injection procedure?
The possible answers are:
Not Related:
There is no reasonable possibility that the event may have been caused by 
the injection procedure
Related:
There is a reasonable possibility that the event may have been caused by 
the injection procedure
For a list of factors to consider in assessing the relationship of AEs to the injection procedure, 
see Appendix 2.
The sponsor will request information to justify the causality assessment of SAEs, as needed.
7.4.
Safety Monitoring
The investigator will monitor the safety of study patients at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The medical monitor will have primary responsibility for 
the emerging safety profile of the compound.  The study monitor will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; Biostatistics and Data 
Management).  Safety monitoring will be performed on an ongoing basis (eg, individual review 
of SAEs) and on a periodic cumulative aggregate basis.
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7.5.
Investigator Alert Notification
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the 
Investigator’s Brochure, and has a reasonable suspected causal relationship to the 
medicinal/study drug).
8.
STUDY VARIABLES
8.1.
Demographic and Baseline Characteristics
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics including medical history, and medication history for each patient.
8.2.
Primary and Secondary Variables
The primary outcome measure of the study is the proportion of patients who have improved by 
≥2 steps from baseline in the DRSS score at week 24 in the combined 2Q8 and 2Q16 groups, and 
at week 52 for each group separately.
The secondary outcome measures will be tested at week 52 and are as follows:
x
Proportion of patients developing a vision-threatening complication due to diabetic 
retinopathy
Vision-threatening complications are defined as composite outcome of PDR 
(inclusive of patients who have vitreous hemorrhage or tractional retinal detachment 
believed to be due to PDR) and ASNV

Note: ASNV is defined as neovascularization of the iris (at least 2 cumulative 
clock hours), and/or definitive neovascularization of the iridocorneal angle
x
Proportion of patients who develop CI-DME
x
Time to development of a vision-threatening complication
x
Time to development of CI-DME
x
Proportion of patients who receive PRP, inclusive of patients undergoing vitrectomy 
with endolaser 
x
Area under the curve (AUC) for change in BCVA from baseline
See section 9.5.2.1 for hierarchy of endpoints to be tested.  These outcome measures will also be 
tested at week 100 in an exploratory manner for all 3 treatment groups. 
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8.3.
Additional Variables
The additional outcome measures in the study are:
x
Time to first improvement of ≥2 steps from baseline in the DRSS score through week 52
and week 100
x
Proportion of patients with ≥2-step improvement from baseline in the DRSS score at 
week 100
x
Proportion of patients with ≥2-step worsening from baseline in the DRSS score at 
week 52 and at week 100
x
Proportion of patients with ≥3-step worsening from baseline in the DRSS score at 
week 52 and at week 100
x
Proportion of patients with ≥3-step improvement from baseline in the DRSS score at 
week 52 and at week 100
x
Proportion of patients who receive vitrectomy through week 52 and through week 100
x
Change in central retinal thickness from baseline at week 52 and at week 100
x
Change in mean deviation on visual field testing from baseline at week 52 and at 
week 100
x
Change in BCVA from baseline at week 52 and week 100
x
Proportion of patients who have gained or lost ≥5, ≥10, or ≥15 letters from baseline at 
week 52 and at week 100
x
The proportion of patients who are equal to or better than 20/20 or equal to or better than 
20/40 at week 52 and at week 100
The following additional variables will be tested only at the week 24 time point:
x
Change in BCVA from baseline at week 24 
x
AUC for change in BCVA from baseline at week 24 
x
Proportion of patients who have lost ≥5, ≥10, or ≥15 letters from baseline at week 24
9.
STATISTICAL PLAN
This section provides the basis for the SAP for the study.  Analysis variables are listed in 
section 8.
9.1.
Statistical Hypothesis
This study will examine the following hypotheses for the primary efficacy variable regarding the 
proportion of patients with a ≥2-step improvement from baseline in DRSS score in the study eye 
at week 24 in the combined 2Q8 and 2Q16 groups, and at week 52 for the 2Q8 and 2Q16 groups 
separately.  Statistical testing of week 24 and week 52 will be conducted to demonstrate the 
superiority of the aflibercept groups (combined, 2Q8, and 2Q16) to the sham group, respectively.
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For each test, let pt (and pc) be the true proportion of patients with a ≥2-step improvement from 
baseline in DRSS score at week 24 for the combined 2Q8 and 2Q16 groups, and at week 52 for 
the 2Q8 and 2Q16 groups separately (and the sham group, pc).
The following hypotheses will be tested:
H0: pt = pc versus H1: pt ≠ pc
To control the family-wise type I error rate of 5%, primary efficacy endpoints for the combined 
group (week 24) and endpoints for the 2Q8 and 2Q16 groups (week 52) will be tested separately 
at the significance level of α = 1.67% (5%/3).  Secondary efficacy endpoints at week 52 will be 
tested for the 2Q8 and 2Q16 groups by the hierarchical testing procedure at the significance level 
for the different scenarios indicated in Table 4.
Table 4:
Significance Levels for Testing Secondary Efficacy Endpoints
Scenario
1
2
3
4
5
6
7
Combined Group at Week 
24 Positive?
X
X
X
X
2Q8 Group at Week 52 
Positive?
X
X
X
X
2Q16 Group at Week 52 
Positive?
X
X
X
X
Significance level 
for secondary endpoints
0.05
0.033
0.033
0.033
0.0167
0.0167
Significance level for 
Testing for 2Q8 Group at 
week 52
0.025
0.033
0.0167
0.0167
Significance level for 
Testing for 2Q16 at week 52
0.025
0.033
0.0167
0.0167
9.2.
Justification of Sample Size
Anticipating approximately 41% of patients with a ≥2-step improvement from baseline in DRSS 
score in either the 2Q8 or 2Q16 groups versus 17% in the sham group, 102 patients per group are 
required to detect a difference with a power of 90% for rejecting the null hypothesis at a 2-sided 
1.67% (5%/3) significance level.  A sample size of 102 patients per group will provide at least 
90% power to detect a difference between the combined aflibercept group and sham group at 
week 24, if a 38% response rate is assumed in the combined aflibercept group. The assumption 
of the proportions for the aflibercept group and sham group is based on VIVID and VISTA data 
at a given time point.  To account for about a 15% dropout rate, 120 patients per group will be 
enrolled. 
The sample size calculation was computed using the Chi square test (continuity corrected) from 
the commercial software nQuery nTerm 7.0.
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9.3.
Analysis Sets
9.3.1.
Efficacy Analysis Sets
Full analysis set (FAS):  The FAS will include all randomized patients who received any study 
treatment.  The analysis on the FAS will be performed according to the treatment assigned at 
baseline (as randomized).
9.3.2.
Safety Analysis Set
The safety analysis set (SAF) includes all randomized patients who received any study treatment 
(active or sham); it is based on the randomized treatment.  Treatment compliance/administration 
and all clinical safety variables will be analyzed using the SAF.
9.4.
Patient Disposition
The following will be provided:
x
The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF
x
The total number of randomized patients:  received a randomization number
x
The total number of patients in each analysis set
x
The total number of patients who discontinued the study, and the reasons for 
discontinuation
x
A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized
x
A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation
9.5.
Statistical Methods
The statistical methods summarized in this section outline the plan for data analysis of this study.  
A final and complete SAP will be provided prior to the unmasking of the data.
Unless stated otherwise, all variables will be analyzed descriptively with appropriate statistical 
methods:  continuous variables by sample statistics (ie, mean, standard deviation, median, 
quartiles, minimum, and maximum), and categorical variables by frequencies and percentages.
All statistical analyses will be performed using Statistical Analysis System (SAS); the version 
used will be specified in the SAP.
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9.5.1.
Demography and Baseline Characteristics
Demographic variables and baseline characteristics will be summarized by treatment group and 
pooled aflibercept treatment groups for the FAS and SAF, depending on the type of data, as 
described in section 9.5.  Medical history will be coded by Medical Dictionary for Regulatory 
Activities (MedDRA®) codes, and prior and concomitant medications by Anatomical Therapeutic 
Chemical (ATC) codes (World Health Organization Drug Dictionary).  No formal comparison 
between treatment groups will be conducted.
Demographic and baseline characteristics will be summarized descriptively by treatment group.
9.5.2.
Efficacy Analyses
Efficacy analyses of all efficacy variables defined in section 8.2 will be conducted using the FAS 
population.  Missing values will be imputed with post-baseline values during the ontreatment 
period by using the last observation carry forward (LOCF) procedure.
For any patient who 
receives rescue treatment, measurements after rescue is given will be imputed using the last 
observation prior to rescue treatment.
The primary endpoint analysis for the study will be conducted at 2 time points (week 24 for the 
combined 2Q8 and 2Q16 groups, and week 52 for the 2Q8 and 2Q16 groups separately).  Each 
of the primary efficacy analyses will be tested at the 1.67% (5%/3) significance level to control 
for multiplicity.
The secondary endpoints described in section 8.2 for both groups (2Q8 and 2Q16) will be tested 
in a hierarchical manner at week 52, as described in section 9.1.
Primary Efficacy Analysis for the Combined 2Q8 and 2Q16 Groups at Week 24 
This analysis will be conducted on the FAS and will include the primary efficacy endpoint at 
week 24 for the combined 2Q8 and 2Q16 groups only.
Primary Efficacy Analysis for the 2Q8 and 2Q16 Groups at Week 52 
This analysis will be conducted on the FAS and will include the primary efficacy endpoint at 
week 52 for the 2Q8 and 2Q16 groups separately.
9.5.2.1.
Analyses of Primary and Secondary Efficacy Variables
Primary Efficacy Variable
The primary efficacy variable analysis will be conducted on the FAS population. The primary 
analysis is a statistical evaluation of superiority of 3 comparisons (combined aflibercept vs. sham 
at week 24, aflibercept 2Q8 vs. sham at week 52, and aflibercept 2Q16 vs. sham at week 52) in 
respect to the primary efficacy variable (see section 8.2). The statistical analysis will be 
performed using the Cochran-Mantel-Haenszel method, stratified by baseline DRSS level (level 
47 vs. level 53). Missing or nongradable post-baseline values will be imputed using the LOCF 
procedure.
For any patient who receives rescue treatment, the measurements after rescue is 
given will be imputed using the last observation prior to rescue treatment. Baseline values will 
be carried forward if all post-baseline observations are missing or nongradable.
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Aflibercept treatment will be considered to be superior to sham if the estimated aflibercept group
(combined, aflibercept 2Q8, or aflibercept 2Q16) is greater than the sham group, and the p-value 
is less than or equal to or statistically significant at a 1.67% level.
As stated above, for the primary efficacy analysis, any patient who receives rescue treatment in 
the study eye will have all efficacy measurements collected after rescue treatment is imputed 
using the last observation prior to such treatment. For a sensitivity analysis, the primary efficacy 
analysis will also be performed using all observed measurements (regardless of whether rescue 
treatment was given), and only true missing values will be imputed using the LOCF procedure. 
Baseline values will be carried forward if all post-baseline observations are missing or 
nongradable.
Secondary Efficacy Variables
If at least one of the aflibercept groups is shown to be superior to sham in the primary variable, 
additional comparisons will be made for this aflibercept group with respect to the secondary 
variables at week 52, using the significance level specified in section 9.1.
A hierarchical testing procedure will be performed for each dose group to compare the secondary 
variables between the respective aflibercept group and sham in the following order:
x
2Q8 secondary endpoints at week 52

Proportion of patients developing a vision-threatening complication due to 
diabetic retinopathy

Proportion of patients who develop CI-DME

Time to development of a vision-threatening complication

Time to development of CI-DME

Proportion of patients who receive PRP, inclusive of patients undergoing 
vitrectomy with endolaser 

AUC for change in BCVA from baseline
x
2Q16 secondary endpoints at week 52

Proportion of patients developing a vision-threatening complication due to 
diabetic retinopathy

Proportion of patients who develop CI-DME

Time to development of a vision-threatening complication

Time to development of CI-DME

Proportion of patients who receive PRP, inclusive of patients undergoing 
vitrectomy with endolaser 

AUC for change in BCVA from baseline
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The p-values at week 52 for the secondary endpoints will be reported for all comparisons 
between the aflibercept groups and the sham group; however, a superiority claim can be made 
for a given endpoint only if all preceding endpoint comparisons in the hierarchy are shown to be 
statistically significant at a significance level specified in section 9.1. The hierarchical method 
ensures the overall type I error rate of 5% for this study, with multiplicity adjustment for primary 
and secondary endpoint analyses.
All endpoints will also be analyzed descriptively at week 100 in an exploratory manner. 
The analysis of proportion variables will be done using the same methodology as for the analyses 
of the primary efficacy variable described in this section.
For continuous variables (ie, BCVA), an analysis of covariance (ANCOVA) model with baseline 
measurements of the continuous variable as covariates and treatment and baseline DRSS score 
(level 47 vs. level 53) stratification as fixed factors will be used for the endpoint. The pair-wise 
comparisons of each aflibercept group versus sham will be done in the ANCOVA model. In 
addition, 2-sided 95% confidence intervals for the difference of each aflibercept group minus 
sham will be calculated.
Time to first vision-threatening complication (composite of PDR [inclusive of patients who have 
vitreous hemorrhage or tractional retinal detachment believed to be due to PDR] and ASNV) will 
be analyzed using the Kaplan-Meier estimates. A log-rank test will be performed, comparing 
sham with the aflibercept groups, as well as 2-sided 95% confidence intervals for the time to first 
vision-threatening complication for the difference of each comparison group. 
Time to 
development of CI-DME will be analyzed similarly.
Similar to the analysis of the primary endpoint, any patient who receives rescue treatment in the 
study eye will have all efficacy measurements collected after rescue treatment imputed using the 
last observation prior to such treatment.  For a sensitivity analysis, the primary efficacy analysis 
will also be performed using all observed measurements (regardless of whether rescue treatment 
was given) and only true missing values will be imputed using the LOCF procedure.  Baseline
values will be carried forward if all post-baseline observations are missing.
Analyses of the primary and secondary endpoints may also be performed on subsets of the FAS, 
such as patients who have developed CI-DME, PDR, or patients who have had a vitrectomy.  
Such subsets will be defined in the SAP.
9.5.2.2.
Analyses of Additional Efficacy Variables
All additional efficacy variables (see section 8.3) will be analyzed descriptively.  In addition, the 
primary and secondary variables will be also analyzed descriptively at week 100.  These 
descriptive analyses may include statistical tests on the proportion for the efficacy variables, in 
the same way as described for the primary and secondary efficacy variable analyses (see 
section 9.5.2.1).
The analysis of categorical variables will be done using the same methodology used for the 
analysis of the primary efficacy variable described in section 9.5.2.1. Analyses of continuous 
variables (eg, central retinal thickness, median deviation on visual field) will use a 2-way 
ANCOVA main effects models with treatment group and baseline DRSS (level 47 vs. level 53) 
stratification as fixed factors and baseline assessment of the efficacy outcome measure as a 
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covariate. The pairwise comparisons of each aflibercept treatment group versus sham will be 
done in these models by corresponding CONTRAST statements and a point-estimate.  A 2-sided
95% confidence interval for the treatment difference of each aflibercept treatment group minus 
sham will be calculated.
9.5.3.
Safety Analysis
Safety variables will be summarized on the SAF through week 24 for the combined 2Q8 and 
2Q16 group, and the sham group.  Safety data accumulated through week 52 and week 100 for 
each treatment group will be summarized at the respective time point.
9.5.3.1.
Adverse Events
Definitions
For safety variables, 3 observation periods are defined:
x
The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug.
x
The treatment period is defined as the day from first dose of study drug to the last 
dose of study drug.
x
The post-treatment period is defined as the time after the last dose of study drug 
A TEAE is defined as an event (or an exacerbation of a preexisting event during the treatment 
period) that is observed or reported after the first administration of study drug, and no later than 
30 days after last administration of study drug (active or sham injection).
Analysis
All AEs reported in this study will be coded using the currently available version of the 
MedDRA.  Coding will be to lowest level terms.  The verbatim text, the preferred term (PT), and 
the primary system organ class (SOC) will be listed.
Summaries of all TEAEs by treatment group, and by ocular study eye, ocular fellow eye, and 
non-ocular TEAEs, will include:
x
The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT
x
TEAEs by severity (according to the grading scale outlined in section 7.3.1),
presented by SOC and PT
x
TEAEs by relationship to drug or injection procedures (related, not related), presented 
by SOC and PT
Deaths and other SAEs will be listed and summarized by treatment group.
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group.
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9.5.3.2.
Ocular Safety
Ocular safety variables (eg, IOP measurements) will be analyzed descriptively at their scheduled 
visit, including changes from baseline.  All ocular safety parameters will be summarized using 
descriptive statistics.  Information from OCT, FP, and FA may also be used to assess ocular 
safety.
9.5.3.3.
Other Safety
Vital Signs
Vital signs (body temperature, blood pressure, and heart rate) will be summarized by baseline 
and change from baseline to each scheduled assessment time with descriptive statistics.
Laboratory Tests
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics.
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest.
Listings will be provided with flags indicating the out of laboratory range values.
9.5.3.4.
Treatment Exposure
Exposure to study drug will be examined for each patient.  The total number of treatments 
administered to each patient and the duration of treatment will be analyzed and summarized 
using descriptive statistics by treatment group in the SAF and FAS populations.
9.5.3.5.
Treatment Compliance
Compliance with protocol-defined study medication will be calculated as follows:
Treatment compliance = (number of received injections [active or sham] through a given 
week)/(number of planned injections [active or sham] during the period of participation in the 
study through the given week) x 100%.
The 24-week treatment period is defined as the period from day 1 to week 16 (visit 6; last study 
treatment visit) plus 28 days.  For all treatment groups, the 52-week treatment period is defined 
as the period from day 1 to week 48 (visit 10/last study treatment visit), and the 100-week 
treatment period is defined as the period from day 1 to week 96 (visit 17/last study treatment 
visit) plus 28 days. Sham injections will be counted as planned treatment.
9.6.
Interim Analysis
No formal interim analysis is planned.  
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9.7.
Additional Statistical Data Handling Conventions
The following analysis and data conventions will be followed:
Definition of baseline: 
x
The baseline assessment is defined as the latest valid pre-dose assessment
General rules for handling missing data:
x
Rules for handling missing data for efficacy assessments will use LOCF for patients in 
analysis populations as described.  Additional details will be provided in the SAP.
x
If the start date of an AE or concomitant medication is incomplete or missing, it will be 
assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed; 
otherwise, the missing day or month by the first day or the first month will be imputed. 
x
No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made.
Visit windows:
x
Assessments taken outside of protocol allowable windows will be displayed according to 
the CRF assessment recorded by the investigator.
Unscheduled assessments:
x
Extra assessments (laboratory data or vital signs associated with nonprotocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries.  If more than 1 laboratory value is available for a given visit, 
the first observation will be used in summaries and all observations will be presented in 
listings.
9.8.
Statistical Considerations Surrounding the Premature Termination 
of a Study
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in section 15.1.
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10.
DATA MANAGEMENT AND ELECTRONIC SYSTEMS
10.1.
Data Management 
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 
Regeneron.
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history/ophthalmic 
history) will be done using internationally recognized and accepted dictionaries.
The CRF data for this study will be collected with an electronic data capture (EDC) tool, 
Medidata RAVE.
10.2.
Electronic Systems
Electronic systems that may be used to process and/or collect data in this study will include the 
following:
x
IVRS/IWRS system – randomization, study drug supply
x
EDC system – data capture
x
SAS – statistical review and analysis
x
Argus – a pharmacovigilance and clinical safety software system
11.
STUDY MONITORING
11.1.
Monitoring of Study Sites
The study monitor and/or designee (eg, contract research organization monitor) will visit each 
site prior to enrollment of the first patient, and periodically during the study.  In accordance with 
ICH guidelines, the monitor will compare the CRF entries with the appropriate source 
documents.  Additional review may include, but is not limited to, patient ICFs, documentation of 
patient 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 must 
be provided to the sponsor upon request.
11.2.
Source Document Requirements
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents).
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source 
documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities.
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11.3.
Case Report Form Requirements
Study data obtained in the course of the clinical study will be recorded on electronic CRFs by 
trained site personnel.  A CRF must be completed for each and every patient enrolled in the 
study.  After review of the clinical data for each patient, the investigator must provide an 
electronic signature.  A copy of each CRF page is to be retained by the investigator as part of the 
study record and must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities.
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit 
trail, which is part of the system.  For corrections made via data queries, a reason for any 
alteration must be provided.
12.
AUDITS AND INSPECTIONS
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for:
x
Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection
x
Providing access to all necessary facilities, study data, and documents for the 
inspection or audit
x
Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately
x
Taking all appropriate measures requested by the sponsor 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 addition, representatives of the sponsor may observe the conduct of any aspect of 
the clinical study or its supporting activities both within and outside of the investigator's 
institution.
In all instances, the confidentiality of the data must be respected.
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13.
ETHICAL AND REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice Statement
It is the responsibility of both the sponsor and 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 GCP and applicable 
regulatory requirements.
13.2.
Informed Consent
The principles of informed consent are described in ICH guidelines for GCP.
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB.  A copy of the IRB-approved ICF and documentation of 
approval must be provided to the sponsor before study drug will be shipped to the study site.
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient 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 patient
in language that he/she can understand.  The ICF should be signed and dated by the patient and 
by the investigator or authorized designee who reviewed the ICF with the patient.
x
Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF.
x
Patients 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 must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the patient.
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient.
13.3.
Patient Confidentiality and Data Protection
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by their initials and a patient
identification number, only, on CRFs or other documents submitted to the sponsor.  Documents 
that will not be submitted to the sponsor (eg, signed ICF) must be kept in strict confidence.
The patient's and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party.
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13.4.
Institutional Review Board 
An appropriately constituted IRB, as described in ICH guidelines for GCP, must review and 
approve:
x
The protocol, ICF, and any other materials to be provided to the patients
(eg, advertising) before any patient may be enrolled in the study
x
Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB should be informed as soon as possible
x
Ongoing studies on an annual basis or at intervals appropriate to the degree of risk
In addition, the IRB should be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical study.
A copy of the IRB approval letter with a current list of the IRB members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should 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) must be kept on file by the investigator.
14.
PROTOCOL AMENDMENTS
The sponsor may not implement a change in the design or operation of the protocol or ICF 
without an IRB-approved amendment.
15.
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE
15.1.
Premature Termination of the Study
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing.
15.2.
Close-out of a Site
The sponsor and the investigator have the right to close-out a site prematurely.
Investigator’s Decision
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at 
least 30 days’ notice.  The final decision should be made through mutual agreement with the 
sponsor.  Both parties will arrange the close-out procedures after review and consultation.
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Sponsor’s Decision
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others: 
x
The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time
x
The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines 
x
The total number of patients required for the study are enrolled earlier than expected
In all cases, the appropriate IRB and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the patients’ 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 must be signed 
by the investigator.  This certification form accompanies each set of CRFs.  The signed form will 
be provided to the sponsor with the final set of CRFs for each patient.
16.2.
Retention of Records
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of 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.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  
Records must be destroyed in a manner that ensures confidentiality.
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination.
17.
CONFIDENTIALITY
Confidentiality of information is provided as a separate agreement.
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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
Antithrombotic Trialists’ Collaboration. Collaborative overview of randomized trial of 
antiplatelet therapy – II: Maintenance of vascular graft or arterial patency by antiplatelet therapy.  
Br Med J 1994; 308:168-171.
Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of
antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk 
patients. Br Med J 2002; 324:71-86.
Bressler, NM, Beck RW, and Ferris FL, 3rd, Panretinal photocoagulation for proliferative 
diabetic retinopathy. The New England journal of medicine, 2011. 365(16):  1520-6.
Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al; RIDE and RISE 
Research Group.  Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 
36-month results from two phase III trials: RISE and RIDE.  Ophthalmology. 2013 
Oct;120(10):2013-22.
Early Treatment Diabetic Retinopathy Study research group.  Photocoagulation for diabetic 
macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 
1985 Dec;103(12):1796-806.
EYLEA® (aflibercept) Injection, United States Prescribing Information, Revised July 2015.
Korobelnik, J. F., Do, D. V., Schmidt-Erfurth, U., Boyer, D. S., Holz, F. G., Heier, J. S., et al. 
(2014). Intravitreal aflibercept for diabetic macular edema. Ophthalmology 121, 2247-54
Wild S, Roglic G, Green A, Sicree R, King H.  Global prevalence of diabetes: estimates for the 
year 2000 and projections for 2030.  Diabetes Care. 2004 May;27(5):1047-53.
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21.
INVESTIGATOR’S AGREEMENT
I have read the attached protocol:  A Phase 3, Double-Masked, Randomized Study of the 
Efficacy and Safety of Intravitreal Aflibercept Injection in Patients with Moderately Severe to 
Severe Nonproliferative Diabetic Retinopathy, and agree to abide by all provisions set forth 
therein.
I agree to comply with the current International Conference on Harmonisation Guideline for 
Good Clinical Practice and the laws, rules, regulations, and guidelines of the community, 
country, state, or locality relating to the conduct of the clinical study.
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a 
partnership in which the sponsor is involved.  I will immediately disclose it in writing to the 
sponsor if any person who is involved in the study is debarred, or if any proceeding for 
debarment is pending, or, to the best of my knowledge, threatened.
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor.
(Signature of Investigator)
(Date)
(Printed Name)
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APPENDIX 1.
OPTICAL COHERENCE 
TOMOGRAPHY - ANGIOGRAPHY SUB-STUDY
This is an exploratory study for OCT-angiography conducted as a sub-study to protocol 
VGFTe-OD-1411.  Investigational sites that are participating in VGFTe-OD-1411 may choose to 
participate in this optional, exploratory OCT-angiography sub-study.  In order to participate, 
sites must have the Optovue Angio-vue system installed.
A.
OCT-Angiography Sub-study Objective
The objective of this sub-study is to explore the use of OCT-angiography to monitor vascular 
leak and other disease characteristics in patients with diabetic retinopathy treated with aflibercept 
versus sham.  Since OCT-angiography has the ability to image vessels based on fluid flow 
characteristics, and more accurately, delineate the vascular layers, it may provide additional 
information related to treatment response beyond that achievable with standard OCT imaging.
B.
Number of Patients and Sites
Patients will be enrolled at the investigator’s discretion at sites that have access to the Optovue 
Angio-vue system.  There will be no cap on the number of patients or sites that may participate.
C.
Timing of OCT-Angiography
Optical coherence tomography-angiography will be performed approximately quarterly at the 
time points indicated in Table 1 and Table 2, in conjunction with the scheduled study visits for 
the main study.
Table 1:
Schedule of Events (OCT-Angiography) – Year 1
Screening 
Visit 1
Year 1 Treatment Period
Study Procedure
Visit 5
Visit 7
Visit 9
Visit 11
Week
--
12
24
40
52
Day
(visit window)
-21 to -1
85
± 7 days
169
± 7 days
281
± 7 days
365
± 10 
days
Signed Informed Consent
X
Optical Coherence Tomography - Angiography
X
X
X
X
X
Table 2:
Schedule of Events (OCT-Angiography) – Year 2
Study Procedure
Visit 13
Visit 15
Visit 18/End 
of Study
Week
64
80
100
Day
(visit window)
449
± 7 days
561
± 7 days
701
± 10 days
Optical Coherence Tomography - Angiography
X
X
X
Detailed instructions for image collection and transmission will be provided in the study 
procedure manual.
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APPENDIX 2.
FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG OR INJECTION PROCEDURE
Is there a reasonable possibility that the event may have been caused by the study drug or 
injection procedure?
No:
x
due to external causes such as environmental factors or other treatment(s) being 
administered
x
due to the patient’s disease state or clinical condition
x
do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug or injection procedure
x
do not reappear or worsen when dosing with study drug or injection procedure is 
resumed
x
are not a known response to the study drug or injection procedure based upon 
preclinical data or prior clinical data
Yes:
x
could not be explained by environmental factors or other treatment(s) being 
administered
x
could not be explained by the patient’s disease state or clinical condition
x
follow a reasonable temporal sequence following the time of administration of the 
dose of study drug or injection procedure
x
resolve or improve after discontinuation of study drug or injection procedure
x
reappear or worsen when dosing with study drug or injection procedure is resumed
x
are known to be a response to the study drug or injection procedure based upon 
preclinical data or prior clinical data
NOTE: This list is not exhaustive.
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician)
To the best of my knowledge, this report accurately describes the conduct of the study and the 
data generated.
Study Title:
A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of
Intravitreal Aflibercept Injection in Patients with Moderately Severe to Severe 
Nonproliferative Diabetic Retinopathy
Protocol Number:
VGFTe-OD-1411
Protocol Version: 
VGFTe-OD-1411 Amendment 5
See appended electronic signature page
Sponsor’s Responsible Scientific/Medical Monitor
See appended electronic signature page
Sponsor’s Responsible Regulatory Representative
See appended electronic signature page
Sponsor’s Responsible Clinical Study Team Lead
See appended electronic signature page
Sponsor’s Responsible Biostatistician
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