Clinical trial NCT03767738
Conditions: Chorioretinal Vascular Disease
Sponsor: Regeneron Pharmaceuticals
Start date: 2018-12-19; Completion date: 2020-08-19
Enrollment: 65 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to determine if the pre-filled syringe (PFS) supports successful preparation and accurate administration of an aflibercept injection.

The secondary objective of the study is to assess ocular safety in the study eye.

Detailed description:

Arms: arm 1: Cohort 1 - Initial patients Cohort 2 - Additional patients
Interventions: intervention 1: Intravitreal Aflibercept Injection (IAI)
Intervention descriptions: intervention 1: IAI prepared and administered with a pre-filled syringe (PFS)

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
VGFTe-OD-1881 Amendment 4 
Regeneron Pharmaceuticals, Inc. 
Page 1 
CONFIDENTIAL 
IND Number:  12462 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A STUDY IN PATIENTS WITH CHORIORETINAL VASCULAR DISEASE 
TO EVALUATE AN AFLIBERCEPT (EYLEA®) PREFILLED SYRINGE 
Compound: 
Aflibercept (EYLEA®) 
Clinical Phase: 
4 
Protocol Number: 
VGFTe-OD-1881 
Protocol Version: 
VGFTe-OD-1881 Amendment 4
Amendment 4 Date of Issue: 
See appended electronic signature page 
Amendment 3 Date of Issue 
15 May 2019 
Amendment 2 Date of Issue: 
29 Jan 2019 
Amendment 1 Date of Issue: 
06 Dec 2018 
Original Date of Issue: 
15 Nov 2018 
Medical/Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
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NCT03767738


Clinical Study Protocol 
 
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AMENDMENT HISTORY 
Amendment 4 
To describe the continuity plan for conducting clinical study activities and study oversight 
activities during the public health emergency due to COVID-19. 
Description of Change 
Brief Rationale 
Section # and Name  
Added language related to the 
COVID-19 pandemic. 
To describe the continuity plan 
for conducting clinical study 
activities and study oversight 
activities during the public 
health emergency due to 
COVID-19. 
Section 8.1 Schedule of Events 
Section 3.3 Risk-Benefit (new 
section) 
Revised the description of the 
diabetic retinopathy indication 
To reflect current approval 
status. 
Section 1  Introduction 
Amendment 3 
The purpose of this amendment is to enroll an additional 35 patients to be treated with the 
aflibercept prefilled syringe (PFS), per health authority request.  The aflibercept PFS to be supplied 
for these additional patients will also represent a presentation intended for commercialization with 
some components originating from a different supplier than the PFS used for the initial 35 patients.  
The initial 35 patients will now be referred to as cohort 1, and the additional 35 patients will be 
called cohort 2. 
Change 
Sections Changed  
Added an additional 35 patients to be enrolled and 
treated with the aflibercept PFS. 
Clinical Study Protocol Synopsis:  Study Design 
Clinical Study Protocol Synopsis:  Population/ 
Sample Size 
Clinical Study Protocol Synopsis:  Statistical Plan 
Section 3.1  Rationale for Study Design 
Section 5.1  Study Description and Duration 
Section 6.1  Number of Patients Planned 
Section 10  Statistical Plan 
Section 10.2  Justification of Sample Size 
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Amendment 2 
The purpose of this amendment is to add a statement that the prefilled syringe (PFS) utilized in 
this study reflects the presentation intended for commercialization, per health authority request. 
Change 
Sections Changed  
Added a statement that the PFS utilized in this study 
reflects the presentation intended for commercialization 
Clinical Study Protocol Synopsis:  
Treatments 
Section 7.1 Investigational and Reference 
Treatments 
Minor editorial correction to Amendment History for 
amendment 1 
Amendment History 
Amendment 1 
The purpose of this administrative amendment is to revise the wording to provide a more general 
description of the prefilled syringe (“externally sterilized” and “tamper-evident tip cap” were 
removed), which will allow for introduction of clinical supply without contradiction in the protocol 
description.  Study design rationale was also clarified, because the study isn’t measuring accuracy 
of the drug administration. 
Change 
Sections Changed  
Removed “externally sterilized” and “tamper-evident tip 
cap” (and associated wording as necessary) 
Clinical Study Protocol Synopsis 
(Treatments:  Study Drug 
Dose/Route/Schedule) 
Section 1 Introduction 
Section 7.1 Investigational and Reference 
Treatments 
Clarified study design rationale 
Section 3.1 Rationale for Study Design 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Study in Patients with Chorioretinal Vascular Disease to Evaluate an 
Aflibercept (EYLEA®) Prefilled Syringe 
Site Locations 
Approximately 2 sites in the United States (US) 
Objectives 
The primary objective of the study is to determine if the prefilled syringe 
(PFS) can be used effectively and safely by retina specialists to administer 
the 2 mg dose of aflibercept. 
The secondary objective of the study is to assess ocular safety in the study 
eye. 
Study Design 
This is a phase 4, single-arm (2-cohort), open-label study in patients with 
chorioretinal 
vascular 
disease 
(neovascular 
age-related 
macular 
degeneration [AMD], diabetic macular edema [DME], retinal vein occlusion 
[RVO], and diabetic retinopathy [DR] in patients with DME) to evaluate 
handling of the aflibercept PFS.  The study consists of a screening period, a 
single aflibercept treatment, and a follow-up period.  The initial 35 patients 
will now be referred to as cohort 1, and the additional 35 patients will be 
called cohort 2. 
After providing informed consent, patients will be assessed for study 
eligibility at the screening visit, up to 2 weeks before the day 1/baseline visit.  
Screening and the day 1/baseline visit can occur on the same day.  Only 
1 eye will be selected as the study eye. 
At the day 1/baseline visit, patients will undergo safety assessments, and 
will then receive a single dose of study drug, prepared (retina specialist 
and/or technician) and administered with the PFS by a retina specialist. 
There is a follow-up period of 28 days with a window of -7 days to +14 days, 
during which patients will be evaluated for safety (ocular adverse events 
[AEs] and all [ocular and non-ocular] serious adverse events [SAEs]). 
Study Duration 
The duration of the study for a patient is approximately 29 days, excluding 
the screening period. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
Approximately 70 patients will be enrolled, 35 patients in each of 2 cohorts, 
at approximately 2 sites in the US. 
 
Target Population: 
The study population will include men or women with treatment-naïve or 
previously-treated neovascular AMD, DME, RVO, or DR with DME, in 
whom treatment with aflibercept is indicated. 
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Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
The drug product is supplied as a sterile aqueous solution for injection in a 
PFS.  The PFSs are single-use 1 mL glass syringes with a luer connection 
for the needle, and are provided in sealed blister packs. 
Each single-dose PFS provides a usable amount to deliver a single dose of 
2 mg aflibercept in a volume of 50 μL, via intravitreal (IVT) injection.  The 
PFS utilized in this study is fully representative of the presentation intended 
for commercialization.  Only 1 eye will be selected as the study eye 
Patients receive a single dose of aflibercept, prepared and administered with 
the PFS, at the day 1/baseline visit. 
Endpoints 
 
 
Primary: 
The primary endpoint in the study is the number of aflibercept injections 
successfully administered utilizing the PFS. 
 
Secondary: 
The secondary endpoint is the ocular safety of aflibercept delivered in the 
PFS.  Safety will be measured by the incidence of ocular AEs and SAEs in 
the study eye. 
Procedures and Assessments 
Ocular safety procedures will include Best Corrected Visual Acuity 
(BCVA) scale, using the 4-meter Early Treatment Diabetic Retinopathy 
Study (ETDRS), intraocular pressure (IOP), slit lamp examination, indirect 
ophthalmoscopy, and spectral domain optical coherence tomography (SD-
OCT). 
Overall safety will be assessed by evaluation of ocular AEs in the study eye, 
and all (ocular and non-ocular) SAEs. 
Statistical Plan 
The sample size of approximately 35 patients per cohort for this study is 
based on US Food and Drug Administration (FDA) advice, and is not 
determined from power analysis. 
The safety analysis set (SAF) includes all enrolled patients who received 
any study drug, and it will be used for all study analyses. 
For continuous variables, descriptive statistics will include the following 
information:  the number of patients reflected in the calculation (n), mean, 
median, standard deviation, minimum, and maximum.  For categorical or 
ordinal data, frequencies and percentages will be displayed for each 
category. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AMD 
Neovascular age-related macular degeneration 
BCVA 
Best Corrected Visual Acuity 
BRVO 
Branch retinal vein occlusion 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRVO 
Central retinal vein occlusion 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy 
EDC 
Electronic data capture 
ETDRS 
Early Treatment Diabetic Retinopathy Scale 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
mCNV 
Myopic choroidal neovascularization 
MedDRA 
Medical Dictionary for Regulatory Activities 
PFS 
Prefilled syringe 
PT 
Preferred term 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAS 
Statistical analysis software 
SD-OCT 
Spectral domain optical coherence tomography 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
US 
United States 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1. 
INTRODUCTION ......................................................................................................11 
2. 
STUDY OBJECTIVES ..............................................................................................11 
2.1. 
Primary Objective .......................................................................................................11 
2.2. 
Secondary Objective ...................................................................................................11 
3. 
RATIONALE .............................................................................................................11 
3.1. 
Rationale for Study Design .........................................................................................11 
3.2. 
Rationale for Dose Selection ......................................................................................12 
3.3. 
Risk-Benefit ................................................................................................................12 
3.3.1. 
COVID-19 Pandemic ..................................................................................................12 
4. 
STUDY VARIABLES................................................................................................12 
4.1. 
Demographic and Baseline Characteristics ................................................................12 
4.2. 
Primary and Secondary Endpoints..............................................................................12 
4.2.1. 
Primary Endpoint ........................................................................................................12 
4.2.2. 
Secondary Endpoint ....................................................................................................12 
5. 
STUDY DESIGN .......................................................................................................12 
5.1. 
Study Description and Duration .................................................................................12 
5.1.1. 
End of Study Definition ..............................................................................................13 
5.2. 
Planned Interim Analysis ............................................................................................13 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............13 
6.1. 
Number of Patients Planned .......................................................................................13 
6.2. 
Study Population .........................................................................................................13 
6.2.1. 
Inclusion Criteria ........................................................................................................13 
6.2.2. 
Exclusion Criteria .......................................................................................................14 
6.3. 
Premature Withdrawal from the Study .......................................................................14 
6.4. 
Replacement of Patients .............................................................................................15 
7. 
STUDY TREATMENTS............................................................................................15 
7.1. 
Investigational and Reference Treatments ..................................................................15 
7.2. 
Dose Modification and Study Treatment Discontinuation Rules ...............................15 
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7.2.1. 
Dose Modification ......................................................................................................15 
7.3. 
Method of Treatment Assignment ..............................................................................15 
7.3.1. 
Masking ......................................................................................................................15 
7.4. 
Treatment Logistics and Accountability .....................................................................15 
7.4.1. 
Packaging, Labeling, and Storage ..............................................................................15 
7.4.2. 
Supply and Disposition of Treatments .......................................................................15 
7.4.3. 
Treatment Accountability ...........................................................................................16 
7.4.4. 
Treatment Compliance ................................................................................................16 
7.5. 
Concomitant Medications and Procedures .................................................................16 
7.5.1. 
Prohibited Medications and Procedures .....................................................................16 
7.5.2. 
Permitted Medications and Procedures ......................................................................16 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................17 
8.1. 
Schedule of Events .....................................................................................................17 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................19 
8.1.2. 
Early Termination Visit ..............................................................................................19 
8.1.3. 
Unscheduled Visits .....................................................................................................19 
8.2. 
Study Procedures ........................................................................................................19 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................19 
8.2.2. 
Ocular Safety Procedures ...........................................................................................19 
8.2.2.1. 
Best Corrected Visual Acuity .....................................................................................19 
8.2.2.2. 
Intraocular Pressure ....................................................................................................19 
8.2.2.3. 
Slit Lamp Examination ...............................................................................................20 
8.2.2.4. 
Indirect Ophthalmoscopy ............................................................................................20 
8.2.2.5. 
Spectral Domain Optical Coherence Tomography .....................................................20 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................20 
9.1. 
Obligations of Investigator .........................................................................................20 
9.2. 
Obligations of Sponsor ...............................................................................................20 
9.3. 
Definitions ..................................................................................................................21 
9.3.1. 
Adverse Event .............................................................................................................21 
9.3.2. 
Serious Adverse Event ................................................................................................21 
9.4. 
Recording and Reporting Adverse Events ..................................................................22 
9.4.1. 
Adverse Events ...........................................................................................................22 
9.4.2. 
Serious Adverse Events ..............................................................................................22 
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9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................22 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................23 
9.4.5. 
Follow-up ....................................................................................................................23 
9.5. 
Evaluation of Severity and Causality .........................................................................23 
9.5.1. 
Evaluation of Severity ................................................................................................23 
9.5.2. 
Evaluation of Causality ...............................................................................................23 
9.6. 
Safety Monitoring .......................................................................................................25 
9.7. 
Investigator Alert Notification ....................................................................................25 
10. 
STATISTICAL PLAN................................................................................................25 
10.1. 
Statistical Hypothesis ..................................................................................................26 
10.2. 
Justification of Sample Size........................................................................................26 
10.3. 
Analysis Sets ...............................................................................................................26 
10.3.1. 
Safety Analysis Set .....................................................................................................26 
10.4. 
Statistical Methods ......................................................................................................26 
10.4.1. 
Patient Disposition ......................................................................................................26 
10.4.2. 
Demography and Baseline Characteristics .................................................................26 
10.4.3. 
Safety Analyses ..........................................................................................................26 
10.4.3.1. 
Adverse Events ...........................................................................................................26 
10.4.3.2. 
Ocular Safety ..............................................................................................................27 
10.4.3.3. 
Treatment Exposure ....................................................................................................27 
10.4.3.4. 
Treatment Compliance ................................................................................................27 
10.5. 
Additional Statistical Data Handling Conventions .....................................................27 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........28 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................28 
11.1. 
Data Management .......................................................................................................28 
11.2. 
Electronic Systems ......................................................................................................28 
12. 
STUDY MONITORING ............................................................................................28 
12.1. 
Monitoring of Study Sites ...........................................................................................28 
12.2. 
Source Document Requirements ................................................................................29 
12.3. 
Case Report Form Requirements ................................................................................29 
13. 
AUDITS AND INSPECTIONS .................................................................................29 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................30 
14.1. 
Good Clinical Practice Statement ...............................................................................30 
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14.2. 
Patient Confidentiality and Data Protection ...............................................................30 
14.3. 
Institutional Review Board .........................................................................................31 
15. 
PROTOCOL AMENDMENTS ..................................................................................31 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................31 
16.1. 
Premature Termination of the Study ...........................................................................31 
16.2. 
Close-out of a Site ......................................................................................................31 
17. 
STUDY DOCUMENTATION ...................................................................................32 
17.1. 
Certification of Accuracy of Data ...............................................................................32 
17.2. 
Retention of Records ..................................................................................................32 
18. 
DATA QUALITY ASSURANCE ..............................................................................32 
19. 
CONFIDENTIALITY ................................................................................................33 
20. 
FINANCING AND INSURANCE .............................................................................33 
21. 
PUBLICATION POLICY ..........................................................................................33 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................34 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................35 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................18 
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1. 
INTRODUCTION 
The efficacy and safety of intravitreal (IVT) aflibercept has been well characterized across multiple 
indications in numerous clinical trials.  Marketing authorizations have been granted for aflibercept 
(EYLEA®, [aflibercept] injection), in over 108 countries for the treatment of patients with 
neovascular “wet” age-related macular degeneration (AMD) including the United States (US), 
countries in the European Union (EU), Japan, and Australia.  Intravitreal aflibercept injection is 
also approved for the treatment of patients with macular edema following central retinal vein 
occlusion (CRVO) in over 104 countries, macular edema following branch retinal vein occlusion 
(BRVO) in over 98 countries, diabetic macular edema (DME) in over 103 countries, and myopic 
choroidal neovascularization (mCNV) in over 95 countries.  In addition to neovascular AMD, 
DME, and retinal vein occlusion (RVO), aflibercept is also approved in the US for the treatment 
of diabetic retinopathy (DR). 
Currently, aflibercept is available as a sterile aqueous solution for injection in single-use, glass 
vials.  Each vial provides a usable amount to deliver a single dose of 2 mg aflibercept in a volume 
of 50 μL.  This configuration requires withdrawal of aflibercept using a 19-gauge × 1½-inch, 5 μM, 
filter needle into a 1 mL syringe.  Prior to injection the filter needle is replaced with 30-gauge × 
½-inch injection needle.  These steps are performed using aseptic technique. 
To minimize the number of manipulations required to prepare the injection, Regeneron has 
developed a single-use 1 mL glass prefilled syringe (PFS).  Each single-dose, PFS provides a 
usable amount to deliver a single dose of 2 mg aflibercept in a volume of 50 μL. 
This study is intended to investigate if the PFS allows for successful preparation and administration 
by retina specialists. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to determine if the PFS can be used effectively and safely by 
retina specialists to administer the 2 mg dose of aflibercept. 
2.2. 
Secondary Objective 
The secondary objective of the study is to assess ocular safety in the study eye. 
3. 
RATIONALE 
3.1. 
Rationale for Study Design 
This study is intended to confirm that the single-dose PFS supports successful preparation and 
administration of an aflibercept injection by retina specialists.  Per regulatory agency feedback, a 
clinical study of at least 30 patients in each of 2 cohorts utilizing each of the proposed commercial 
aflibercept PFS configurations will be conducted. 
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3.2. 
Rationale for Dose Selection 
The dose proposed for this study is the 2 mg dose of aflibercept approved by the Food and Drug 
Administration (FDA) for the treatment of neovascular AMD, RVO, DME, and DR in patients 
with DME. 
3.3. 
Risk-Benefit 
3.3.1. 
COVID-19 Pandemic 
Recognizing that “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on the 
conduct of clinical trials, the Sponsor does not intend to screen any patient in this study in a specific 
location or area until the COVID-19 pandemic is controlled and such that patients can safely 
participate in the study.  Until then, the Sponsor plans to continue to obtain approvals from Health 
Authorities/Ethics Committees (ECs) to enable initiation of study sites for this study, as allowed 
by local laws and regulations. 
4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics including medical and ocular history, and medication history for each 
patient. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary endpoint in the study is the number of aflibercept injections successfully administered 
utilizing the PFS. 
4.2.2. 
Secondary Endpoint 
The secondary endpoint in the study is the ocular safety of aflibercept delivered in the PFS.  Safety 
will be measured by the incidence of ocular adverse events (AEs) and serious adverse events 
(SAEs) in the study eye, through day 29. 
5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This is a phase 4, single2-arm (2-cohort), open-label study in patients with chorioretinal vascular 
disease (neovascular AMD, DME, RVO, and DR in patients with DME) to evaluate use of the 
aflibercept PFS.  The study consists of a screening period, a single aflibercept treatment, and a 
follow-up period through day 29.  The initial 35 patients will now be referred to as cohort 1, and 
the additional 35 patients will be called cohort 2. 
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After providing informed consent, patients will be assessed for study eligibility at the screening 
visit, up to 2 weeks before the day 1/baseline visit.  Screening and the day 1/baseline visit can 
occur on the same day.  Only 1 eye will be selected as the study eye. 
At the day 1/baseline visit, patients will undergo safety assessments, and will then receive a single 
dose of study drug, prepared (retina specialist and/or technician) and administered with the PFS 
by a retina specialist. 
There is a follow-up period of 28 days with a window of -7 days to +14 days, during which patients 
will be evaluated for safety (ocular AEs and all [ocular and non-ocular] SAEs. 
5.1.1. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
5.2. 
Planned Interim Analysis 
No interim analysis is planned. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 70 patients will be enrolled, 35 patients in each of 2 cohorts, at approximately 
2 sites in the US. 
6.2. 
Study Population 
The study population will include men or women with treatment-naïve or previously-treated 
neovascular AMD, DME, RVO, or DR with DME, in whom treatment with aflibercept is indicated. 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Men or women ≥18 years of age who have neovascular AMD, DME, RVO, or DR with 
DME in the study eye 
2. Study eye considered by the retina specialist to be indicated for treatment with aflibercept 
3. Willing and able to comply with clinic visits and study-related procedures 
4. Provide informed consent signed by study patient or legally acceptable representative 
5. Able to understand and complete study-related questionnaires 
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6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Evidence of active infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye 
2. Any active intraocular inflammation or infection in either eye or history of intraocular 
inflammation or infection after past IVT injections with any agent in either eye 
3. History of or any current indication of excessive bleeding and recurrent hemorrhages, 
including any prior excessive intraocular (including subconjunctival) bleeding or 
hemorrhages after IVT injection or intraocular procedures in either eye 
4. Treatment with any IVT injection in the study eye within the 28 days prior to day 1 
5. Intraocular pressure (IOP) >25 mm Hg in the study eye at screening 
6. Count fingers or worse vision in one or both eyes 
7. Use of therapies that are known to be toxic to any ocular tissues (eg, radiation) in either 
eye 
8. Any intraocular surgery in the study eye at any time during the past 3 months 
9. Any prior extended-release therapeutic agent, or ocular drug-release device implantation 
(approved or investigational including steroids) in the study eye 
10. 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 safety 
11. Participation as a patient in any interventional clinical study within the 12 weeks prior to 
day 1 of the study 
12. Current systemic infectious disease or a therapy for active infectious disease 
13. Pregnant or breastfeeding women 
14. Women of childbearing potential* 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential. 
6.3. 
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/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.2. 
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6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
The drug product is supplied as a sterile aqueous solution for injection in a PFS.  The PFS(s) are 
single-use 1 mL glass syringes with a luer connection for the needle, and are provided in sealed 
blister packs. 
Each single-dose PFS provides a usable amount to deliver a single dose of 2 mg aflibercept in a 
volume of 50 μL, via IVT injection.  The PFS(s) utilized in this study are fully representative of 
the presentations intended for commercialization as submitted in the aflibercept IND, Module 
P.2.4 Container Closure System, SN 0810.  Only 1 eye will be selected as the study eye. 
Instructions on dose preparation are provided in the pharmacy manual. 
7.2. 
Dose Modification and Study Treatment Discontinuation Rules 
7.2.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.3. 
Method of Treatment Assignment 
Not applicable, as this is an open-label study without a control group. 
7.3.1. 
Masking 
Not applicable, as this is an open-label study without a control group. 
7.4. 
Treatment Logistics and Accountability 
7.4.1. 
Packaging, Labeling, and Storage 
Open-label study drug will display the product lot number on the label. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
7.4.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed / returned to the sponsor 
or designee. 
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7.4.3. 
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: 
 dispensed to each patient, 
 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. 
7.4.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
7.5. 
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. 
7.5.1. 
Prohibited Medications and Procedures 
Patients may not receive any medications (approved or investigational) for their AMD, DME, 
RVO, or DME with DR in the study eye other than the assigned study treatment (aflibercept) as 
specified in this protocol, unless they have completed the end-of-study (day 29) 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 eye. 
7.5.2. 
Permitted Medications and Procedures 
Standard-of-care treatment will be allowed for any ocular condition in the fellow eye at any time 
during the trial.  At the physician’s discretion, 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 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. 
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8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms.  
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff.  Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted.  All 
temporary mechanisms utilized, and deviations from planned study procedures are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
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Table 1: 
Schedule of Events 
Study Procedure 
Screening1 
Visit 1 
Combined 
Screening/Baseline 
Visit1 
Visit 1/2 
Baseline1 
Visit 2 
 
End of Study 
Visit 3 
Day 
-14 to -1 
1 
1 
29 (-7 to +14 days) 
Screening/Baseline: 
 
 
 
 
Inclusion/exclusion 
X 
X2 
 
 
Informed consent 
X 
X2 
 
 
Medical history 
X 
X2 
 
 
Demographics 
X 
X2 
 
 
Treatment: 
 
 
 
 
Review of concomitant meds 
X 
X2 
X2 
X 
Administer intravitreal aflibercept 
 
X3 
X3 
 
Safety: 
 
 
 
 
Slit lamp examination 
X 
X2 
X2 
X 
Indirect ophthalmoscopy 
X 
X4 
X4 
X 
SD-OCT 
X 
X2 
X2 
X 
ETDRS 4M BCVA 
X 
X2 
X2 
X 
Intraocular Pressure 
X 
X5 
X5 
X 
Adverse events (ocular study eye and all 
serious adverse events) 
X 
X 
X 
X 
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8.1.1. 
Footnotes for the Schedule of Events Table 
1. The screening and baseline visits may be conducted separately (visit 1 and visit 2) or may 
be combined (visit 1/2), but assessments and procedures will not be duplicated. 
2. Must be completed prior to administration of aflibercept. 
3. A single intravitreal injection of aflibercept will be given once on day 1 or as part of the 
combined screening/day 1 visit. 
4. Indirect ophthalmoscopy will be performed pre-dose and immediately after administration 
of study drug (study eye only). 
5. Intraocular pressure will be measured pre-dose and approximately 30 minutes after 
administration of study drug (study eye only). 
8.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study before the end-of-study visit (day 29) will be asked to 
return to the clinic for an early termination visit consisting of the end-of-study assessments 
described in Table 1. 
8.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary for follow-up of AEs, or for any other reason, as warranted. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  medical history and demographics. 
8.2.2. 
Ocular Safety Procedures 
8.2.2.1. 
Best Corrected Visual Acuity 
Visual function of the study eye will be assessed using the 4-meter Early Treatment Diabetic 
Retinopathy Study (ETDRS) scale at time points according to Table 1.  Visual acuity examiners 
must be certified to ensure consistent measurement of Best Corrected Visual Acuity (BCVA). 
Current certification from any study requiring the 4M ETDRS will be accepted.  The patient’s 
BCVA, based on their most recent/current refraction, if they wear glasses or contact lenses, will 
be accepted.  A separate manifest refraction is not required. 
8.2.2.2. 
Intraocular Pressure 
Intraocular pressure of the study eye will be measured using Goldmann applanation tonometry or 
Tono-pen™, at time points according to Table 1.  The same method of IOP measurement must be 
used throughout the study for each individual patient.  Intraocular pressure will be measured pre-
dose (study eye) by the investigator (or designee), and at approximately 30 minutes post-dose 
(study eye) by the investigator (or designee). 
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8.2.2.3. 
Slit Lamp Examination 
Patients’ anterior eye structure and ocular adnexa (study eye) will be examined pre-dose by the 
investigator using a slit lamp (study procedure manual), at time points according to Table 1. 
8.2.2.4. 
Indirect Ophthalmoscopy 
Patients’ posterior pole and peripheral retina in the study eye will be examined pre-dose and 
immediately after administration of study drug (study eye only) by the investigator by indirect 
ophthalmoscopy, at time points according to Table 1. 
8.2.2.5. 
Spectral Domain Optical Coherence Tomography 
Retinal characteristics will be evaluated by the investigator using spectral domain optical 
coherence tomography (SD-OCT), at time points according to Table 1. 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB) all unanticipated 
problems involving risks to patients, according to local regulations.  This may include 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, according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, IRBs as appropriate, and to the investigators.  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected. Any worsening of or new onset of 
symptoms related to (add underlying condition intended to be studied) which occur during the 
screening/washout period prior to study drug administration will be considered expected. 
In addition, the sponsor will report in all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IRBs as appropriate. 
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9.3. 
Definitions 
9.3.1. 
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 pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
 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. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  In-
patient hospitalization is defined as admission to a hospital or an emergency room for 
longer than 24 hours.  Prolongation of existing hospitalization is defined as a hospital 
stay that is longer than was originally anticipated for the event, or is prolonged due to 
the development of a new AE as determined by the investigator or treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one 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). 
Criteria for Serious Sight-Threatening Ocular Adverse Events  
Criteria for serious sight-threatening ocular AEs include the following: 
 Substantial, unexplained vision loss, or an AE that causes substantial vision loss. 
 An AE that requires either surgical or medical intervention to prevent permanent loss 
of vision. 
Criteria for reporting SAEs must be followed for these events.  See Section 9.4 for more 
information on recording and reporting SAEs. 
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9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will record all ocular study eye AEs and any SAEs (ocular and 
systemic) that occur from the time the informed consent is signed until the end of study.  Refer to 
the study reference manual for the procedures to be followed. 
Information on follow-up for AEs is provided in Section 9.4.5. 
9.4.2. 
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 reference 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. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of study or 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. 
 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. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
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), within 24 hours of identification, 
any pregnancy occurring in a female or female partner of a male, 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 that meets the SAE criteria must be reported as an SAE.  
Outcome for all pregnancies should be reported to the sponsor. 
Adverse Events of Special Interest (AESI):  No AESIs have been defined for this study. 
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Refer to the study manual for the procedures to be followed. 
9.4.4. 
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/Study Director within 30 days. 
Refer to the study reference manual for the procedures to be followed. 
9.4.5. 
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. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient 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. 
Moderate:  Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the subject’s health.  Treatment for symptom may be given and/or patient hospitalized. 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the 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 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below.  
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
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 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
 do not reappear or worsen when dosing with study drug is resumed 
 are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
 resolve or improve after discontinuation of study drug  
 reappear or worsen when dosing with study drug  
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
Relationship of AEs to Injection Procedure: 
The relationship of AEs to injection procedure will be assessed by the 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 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
A list of factors to consider in assessing the relationship of AEs to injection procedure, study 
procedure, or background treatment, etc. is provided below.  Please note that this list is not 
exhaustive. 
Is there a reasonable possibility that the event may have been caused by injection procedure? 
No: 
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 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the injection procedure 
 do not reappear or worsen when the injection procedure is resumed 
 are not a suspected response to the injection procedure based upon preclinical data or 
prior clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the injection procedure 
 resolve or improve after discontinuation of study drug or injection procedure 
 reappear or worsen when the injection procedure is resumed 
 are known or suspected to be a response to injection procedure based upon preclinical 
data or prior clinical data 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient 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/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but 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. 
9.7. 
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 reference 
safety information in the Investigator’s Brochure, and has a reasonable suspected causal 
relationship to the study drug). 
10. 
STATISTICAL PLAN 
There will be no formal statistical analyses for this study.  Only descriptive statistics will be 
employed.  Cohort 1 and cohort 2 will be analyzed separately.  There are no plans to either compare 
the individual results from the 2 cohorts, or to analyze the 2 cohorts in a combined manner. 
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10.1. 
Statistical Hypothesis 
There is no statistical hypothesis in this study. 
10.2. 
Justification of Sample Size 
The sample size of approximately 35 patients per cohort for this study is based on FDA advice, 
and is not determined from power analysis. 
10.3. 
Analysis Sets 
10.3.1. 
Safety Analysis Set 
The safety analysis set (SAF) includes all enrolled patients who received any study drug.  
Treatment administration and all clinical safety variables will be analyzed using the SAF. 
10.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean, median, standard deviation, minimum, and 
maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of enrolled patients 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
10.4.3. 
Safety Analyses 
10.4.3.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
 The pretreatment period is defined as the time from signing the informed consent form 
(ICF) to before the first dose of study drug. 
 The treatment period is defined as the day when the single dose of study drug was 
administered. 
 The posttreatment period is defined as the time after administration of the single dose 
of study drug through the day 29 visit. 
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Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (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 will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
presented by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths and other SAEs will be listed and summarized. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized. 
10.4.3.2. Ocular Safety 
In addition to ocular AEs and SAEs in the study eye, IOP measurements will be analyzed 
descriptively at the scheduled visits, including changes from baseline.  All ocular safety parameters 
will be summarized using descriptive statistics.  Information from OCT may also be used to assess 
ocular safety. 
10.4.3.3. Treatment Exposure 
 The number of aflibercept injections successfully administered utilizing the PFS will 
be summarized. 
 The extent of exposure to the investigational drug (characterized according to the 
number of patients exposed) will be detailed in the tables and listings. 
10.4.3.4. Treatment Compliance 
Not applicable, as each patient only receives a single injection. 
10.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
 The baseline assessment is defined as the latest valid pre-dose assessment 
General rules for handling missing data: 
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 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.  
10.6. 
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 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], 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, medications, 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. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 EDC system – data capture 
 Statistical analysis software (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient. 
The investigator must allow study-related monitoring. 
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The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, 
International Council for Harmonisation (ICH) GCP, and all applicable regulatory requirements. 
12.2. 
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. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on paper CRFs within the 
EDC system by trained site personnel.  All required CRFs 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 patient CRF casebook 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. 
13. 
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: 
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 
Providing access to all necessary facilities, study data, and documents for the inspection or audit 
Communicating any information arising from inspection by the regulatory authorities to the 
sponsor immediately 
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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14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
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. 
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. 
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 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. 
14.2. 
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 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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14.3. 
Institutional Review Board 
An appropriately constituted IRB, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB should be informed as soon as possible  
 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. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB-
approved amendment. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
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. 
16.2. 
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:  
 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 
 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  
 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. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
17.2. 
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 obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period 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 (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination. 
18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are summarized.  
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Data Management 
The sponsor is responsible for the data management of this study including quality checking of the 
data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13). 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 12.1). 
All patient data collected during the study will be recorded on paper or electronic CRF unless the 
data are transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for affirming that data entries in the CRF are accurate and correct by electronically 
signing a declaration that accompanies each set of patient final CRF (Section 12.3 and 
Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol:  A Study in Patients with Chorioretinal Vascular Disease to 
Evaluate an Aflibercept (EYLEA®) Prefilled Syringe (PFS) and agree to abide by all provisions 
set forth therein. 
I agree to comply with the current International Council for 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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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: 
A Study in Patients with Chorioretinal Vascular Disease to Evaluate an Aflibercept 
(EYLEA®) Prefilled Syringe 
 
Protocol Number: VGFTe-OD-1881 
Protocol Version: VGFTe-OD-1881 Amendment 4 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
                                        VV-RIM-00107449-1.0 Approved - 01 May 2020 GMT-5:00


Signature Page for VV-RIM-00107449 v1.0
Signature Page for VV-RIM-00107449 v1.0 Approved
ESig Approval
20 13:54:31 GMT+0000
ESig Approval
000
ESig Approval
-2020 13:18:55 GMT+0000
ESig Approval
-2020 14:57:43 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
STATISTICAL ANALYSIS PLAN 
CONFIDENTIAL 
Page 1 of 19 
Title: 
A STUDY IN PATIENTS WITH CHORIORETINAL 
VASCULAR DISEASE TO EVALUATE AN AFLIBERCEPT 
(EYLEA®) PREFILLED SYRINGE (PFS) 
Protocol: 
VGFTe-OD-1881 
Investigational product: 
Intravitreal Aflibercept Injection 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
  
Clinical Trial Manager: 
 
Study Medical Director: 
 
Date: 
01 Feb 2019 
Version: 
1 
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Statistical Analysis Plan 
 
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CONFIDENTIAL  
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for reporting. 
 
 
 
See appended electronic signature page   
I Approve this Document 
 (Author) 
Study Biostatistician 
 
 
 
See appended electronic signature page   
I Approve this Document 
 (Approver) 
Study Medical Director 
 
 
 
See appended electronic signature page   
I Approve this Document 
 (Approver) 
Head of BDM or designee 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................5 
1. 
OVERVIEW .................................................................................................................6 
1.1. 
Background/Rationale ..................................................................................................6 
1.2. 
Study Objectives ...........................................................................................................6 
1.2.1. 
Primary Objectives .......................................................................................................6 
1.2.2. 
Secondary Objectives ...................................................................................................7 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ..................................7 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan ........................................7 
2. 
INVESTIGATION PLAN ............................................................................................8 
2.1. 
Study Design .................................................................................................................8 
3. 
ANALYSIS POPULATIONS ......................................................................................9 
3.1. 
Safety Analysis Set .......................................................................................................9 
4. 
ANALYSIS VARIABLES .........................................................................................10 
4.1. 
Demographic and Baseline Characteristics ................................................................10 
4.2. 
Medical History ..........................................................................................................10 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................10 
4.4. 
Exposure, Compliance, Additional Treatment to Study Treatment ...........................10 
4.5. 
Safety Variables ..........................................................................................................11 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................11 
4.5.2. 
Ocular Safety Measures ..............................................................................................11 
5. 
STATISTICAL METHODS .......................................................................................13 
5.1. 
Demographics, Baseline Characteristics, Medical History, and Prior/ 
Concomitant Medication ............................................................................................13 
5.2. 
Subject Disposition .....................................................................................................13 
5.3. 
Extent of Study Treatment Exposure and Compliance ...............................................13 
5.4. 
Analysis of Safety Data ..............................................................................................14 
5.4.1. 
Adverse Events ...........................................................................................................14 
5.4.2. 
Ocular Safety Measures ..............................................................................................14 
5.4.3. 
Best Corrected Visual Acuity .....................................................................................15 
6. 
DATA CONVENTIONS ............................................................................................16 
6.1. 
Definition of Baseline .................................................................................................16 
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6.2. 
Unscheduled Assessments ..........................................................................................16 
6.3. 
Handling of Patients Who Discontinue ......................................................................16 
6.4. 
Handling of Missing Data ...........................................................................................16 
6.4.1. 
General Rules ..............................................................................................................16 
7. 
INTERIM ANALYSIS ...............................................................................................17 
8. 
SOFTWARE ...............................................................................................................17 
9. 
REFERENCES ...........................................................................................................17 
10. 
APPENDIX.................................................................................................................18 
10.1. 
Schedule of Time and Events: ....................................................................................18 
10.2. 
Intraocular Inflammation: ...........................................................................................18 
 
 
LIST OF TABLES 
Table 1: Schedule of Time and Events ..........................................................................................18 
 
LIST OF FIGURES 
Figure 1: Study Flow Diagram ........................................................................................................8 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse Event 
AMD 
Age-related macular degeneration  
ATC 
Anatomical Therapeutically Chemical 
BCVA 
Best Corrected Visual Acuity 
BRVO 
Branch Retinal Vein Occlusion  
CRF 
Case Report Form 
CRVO 
Central Retinal Vein Occlusion  
DME 
Diabetic Macular Edema 
DR 
Diabetic Retinopathy 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ICH 
International Conference of Harmonization 
IOP 
Intraocular Pressure 
IVT 
Intravitreal 
mCNV 
Myopic Choroidal Neovascularization 
MedDRA 
Medical Dictionary for Regulatory Activities 
(MedDRA) HLT 
High Level Term 
(MedDRA) LLT 
Low Level Term 
(MedDRA) PT 
Preferred Term 
(MedDRA) SOC 
System Organ Class 
PFS 
Prefilled Syringe 
RVO 
Retinal Vein Occlusion  
SAE 
Serious Adverse Event 
SAF  
Safety Analysis set 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-emergent Adverse Event 
WHO 
World Health Organization 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of the study.  The statistical evaluation 
will be done according to the specifications given in the protocol and, if applicable, the 
corresponding amendments. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
technique to be used to confirm that the single-dose Prefilled Syringe (PFS) supports successful 
preparation and accurate administration of an aflibercept injection by retina specialists by using a 
single aflibercept treatment, and a follow-up period through day 29 data from the VGFTe-OD-
1881 study.   
1.1. 
Background/Rationale 
The efficacy and safety of intravitreal (IVT) aflibercept has been well characterized across multiple 
indications in numerous clinical trials. Marketing authorizations have been granted for aflibercept 
(EYLEA®, [aflibercept] injection), in over 108 countries for the treatment of patients with 
neovascular “wet” age-related macular degeneration (AMD) including the United States (US), 
countries in the European Union (EU), Japan, and Australia. Intravitreal aflibercept injection is 
also approved for the treatment of patients with macular edema following central retinal vein 
occlusion (CRVO) in over 104 countries, macular edema following branch retinal vein occlusion 
(BRVO) in over 98 countries, diabetic macular edema (DME) in over 103 countries, and myopic 
choroidal neovascularization (mCNV) in over 95 countries. In addition to neovascular AMD, 
DME, and retinal vein occlusion (RVO), aflibercept is also approved in the US for the treatment 
of diabetic retinopathy (DR) in patients with DME. 
Currently, aflibercept is available as a sterile aqueous solution for injection in single-use, glass 
vials. Each vial provides a usable amount to deliver a single dose of 2 mg aflibercept in a volume 
of 50 μL. This configuration requires withdrawal of aflibercept using a 19-gauge × 1½-inch, 5 μM, 
filter needle into a 1 mL syringe. Prior to injection the filter needle is replaced with 30-gauge × ½-
inch injection needle. These steps are performed using aseptic technique. 
To minimize the number of manipulations required to prepare the injection, Regeneron has 
developed a single-use 1 mL glass PFS that is externally sterilized. Each single-dose, PFS provides 
a usable amount to deliver a single dose of 2 mg aflibercept in a volume of 50 μL. 
This study is intended to investigate if the PFS allows for successful preparation and administration 
by retina specialists. 
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives  
The primary objective of the study is to determine if the PFS can be used effectively and safely 
by retina specialists to administer the 2-mg dose of aflibercept.  
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1.2.2. 
Secondary Objectives 
The secondary objective of the study is to assess ocular safety in the study eye. 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
Not applicable 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan 
Not applicable 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design  
This is a phase 4, single-arm, open-label study in patients with chorioretinal vascular disease 
(neovascular AMD, DME, RVO, and DR in patients with DME) to evaluate handling of the 
aflibercept PFS. The study consists of a screening period, a single aflibercept treatment, and a 
follow-up period through day 29. 
After providing informed consent, patients will be assessed for study eligibility at the screening 
visit, up to 2 weeks before the day 1/baseline visit. Screening and the day 1/baseline visit can 
occur on the same day. Only 1 eye will be selected as the study eye. 
At the day 1/baseline visit, patients will undergo safety assessments, and will then receive a 
single dose of study drug, prepared (retina specialist and/or designee) and administered with the 
PFS by a retina specialist. 
There is a follow-up period of 28 days with a window of -7 days to +14 days, during which 
patients will be evaluated for safety (ocular adverse events (AEs) and all [ocular and non-ocular] 
serious adverse events (SAEs). 
Figure 1: Study Flow Diagram 
 
Screening 
Follow-up 
(Day –14) 
 
(Day 1)/Baseline 
Day 29/ End of Study 
           
 
 
 
 
 
 
Visit 1 
                   Visit 2          
                      Last Visit 
 
  
 
Approximately 35 patients will receive a single dose of study drug based on FDA advice and not 
determined from power analysis.   
 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline 
ICH E9 Statistical Principles for Clinical Trials (1998), the following analysis populations will be 
used for all statistical analysis: 
3.1. 
Safety Analysis Set 
The safety analysis set (SAF) includes all enrolled patients who received study drug. Treatment 
administration and all clinical safety variables will be analyzed using the SAF. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Demographic and baseline assessments to be summarized will include: 
 Age, gender, ethnicity, and race 
 Baseline Intraocular pressure (IOP) 
 Baseline Early Treatment Diabetic Retinopathy Study (ETDRS) letter score 
 Baseline central retinal thickness 
4.2. 
Medical History 
Medical history will be coded according to latest available version of Medical Dictionary for 
Regulatory Activities (MedDRA). 
4.3. 
Pre-Treatment / Concomitant Medication 
Medications taken during the study will be recorded and will be coded to ATC codes according to 
the World Health Organization Drug Dictionary WHO Drug B3 v2018SEP Enhanced (this version 
does not include herbal dictionary). 
Medications will be summarized as follows: 
 Prior medication is defined as medication that was started before and ended before a 
patient received study treatment. 
 Concomitant medication is defined as medications that are ongoing at or begin after the 
study treatment. 
 New medication is defined as medications that began after the start of study treatment. 
The prior, concomitant and new medication will be summarized by ATC class (ATC level 1) and 
subclass (ATC level 2). 
Variables for concomitant medication description and analysis will include Generic name, ATC 
level codes, Indication, Dose/Dose Unit, Frequency, Route, start/end date and study day, Duration, 
Ongoing. 
4.4. 
Exposure, Compliance, Additional Treatment to Study Treatment 
Exposure 
For each patient, the following variables will be used to examine exposure to study treatment for 
the study eye: 
 The number of aflibercept injections successfully administered utilizing the PFS will 
be summarized. 
 The extent of exposure to the investigational drug (characterized according to the 
number of patients exposed) will be detailed in the tables and listings. 
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Compliance 
Not applicable, as each patient only receives a single injection. 
4.5. 
Safety Variables 
 Proportion of Patients with ≥ 10 (mmHg) Increase in Intraocular Pressure from 
Baseline or Pre-dose in Study Eye.  
 Proportion of Patients with Pre-/Post-Injection Intraocular Pressure > 21 (mmHg), ≥ 
25 (mmHg) and 35 ≥ (mmHg) in Study Eye. 
 Proportion of Patients Met IOP Criteria in Any Visit through Day 29 - Study Eye. 
 Change from Baseline in Best Corrected Visual Acuity (BCVA) Score by Visit. 
 Change from Baseline in Central Subfield Thickness by Visit. 
 Mean Change from Baseline for Pre-Injection Intraocular Pressure in Study Eye 
(mmHg). 
4.5.1. 
Adverse Events and Serious Adverse Events 
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. 
AEs will be collected at each visit from the time of informed consent signature until the end of the 
study.  If the patient withdraws from the study during the screening, AEs will be collected up until 
the patient withdraws.  If the patient withdraws at any point after receiving the first dose of study 
medication, AEs will be collected up until 30 days after the last dose of study drug or the 
termination visit, whichever is later. 
AEs will be summarized as: 
 Pre-treatment AE:  Include AEs that occur after the patient has signed the informed 
consent, but prior to Visit 2 (Day 1, date of the patient’s dose of study drug). 
 Treatment-Emergent Adverse Event (TEAE): Treatment-emergent adverse event 
(TEAE) is defined as AE that is observed or reported after study drug and not later than 28 
days after study drug administration. Only worsening, pre-existing AEs and new AEs 
reported during the treatment period (period after study drug) will be collected in the study 
and all TEAEs and AEs will be summarized from Day 1 to Day 29 i.e., through End of 
Study. 
Other variables for AE description and analysis will include AE Verbatim Term, AE start date and 
end date/ongoing and corresponding study day, AE Duration, relationship of AE to study drug, 
relationship of AE to study procedure, seriousness, intensity, action due to AE, treatment of AE 
and outcome.  
4.5.2. 
Ocular Safety Measures 
Variables of analysis for ocular safety measures include during Day 29: 
 Proportion of patients with increased intraocular pressure (IOP): 
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 ≥ 10 mmHg increase in IOP measurement from baseline to any pre-dose 
measurement 
 > 21 mmHg for any pre-dose measurement 
 ≥ 25 mmHg for any pre-dose measurement 
 ≥ 35 mmHg at any time 
Post dose IOP measurement should be the last IOP recorded. 
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Statistical Analysis Plan 
 
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5. 
STATISTICAL METHODS 
All safety variables will be summarized descriptively with appropriate statistics:  categorical 
variables by frequency (absolute and relative frequencies) and continuous variables by sample 
statistics (i.e. mean, standard deviation, minimum, median, quartiles and maximum).  Continuous 
variables will be described by visit and as change from Baseline, if applicable. 
5.1. 
Demographics, Baseline Characteristics, Medical History, and Prior/ 
Concomitant Medication 
Demographic data and baseline characteristics variables described in Section 4.1 will be 
summarized using descriptive statistics for SAF. 
Medical/ocular history is evaluated for SAF by a frequency table, showing number of patients with 
medical history findings by primary system organ class (SOC), high level term (HLT) by MedDRA 
terms. 
Prior/concomitant medication will be summarized by WHO Drug B3 v2018SEP Enhanced (this 
version does not include herbal dictionary) version ATC codes (ATC 3-digit class and ATC 5-
digit subclass) for medication taken during the study.  Separate frequency tables will be displayed 
for patients with prior medications, new medications and concomitant medications by the time 
periods as described in Section 4.3. Concomitant medications will be summarized by Day 1 up to 
Day 29 (End of study). 
5.2. 
Subject Disposition 
The following categories for patient disposition will be summarized descriptively: 
 The total number and percentage of patients received study medication 
 The number and percentage of patients in safety analysis set 
 The total number and percentage of patients who discontinued the study with the 
reasons for discontinuation 
The following listings will be provided to assess the patient disposition: 
 A listing of patients treated but not enrolled and patients enrolled but not treated if 
any 
 A listing of patients who were withdrawn from the study, along with reasons for 
discontinuation 
 Listing of major protocol deviations:  violation of inclusion/exclusion criteria; 
post-enrollment deviations which will impact assessment of endpoints 
5.3. 
Extent of Study Treatment Exposure and Compliance 
The variables for dose exposure described in Section 4.4 will be summarized by frequency for 
study eye in SAF population.   
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5.4. 
Analysis of Safety Data 
The safety variables as described in Section 4.5 will be analyzed on SAF population through Day 
29 after final study database lock. 
5.4.1. 
Adverse Events  
AE summaries will be constructed displaying frequencies and proportions of patients reporting 
AEs within each SOC in decreasing order of total frequency according to the numbers of patients 
reporting the SOC and the AE within the SOC (not number of reports). 
AEs will be classified as Pre-treatment AEs and TEAEs, and will further be summarized by the 
following categories: 
 Ocular AEs in the study eye  
 Ocular AEs in the fellow eye 
 Non-ocular SAEs  
SAEs, drug-related AEs, drug-related SAEs, and TEAEs leading to discontinuation will be 
summarized in the same way as described for TEAE. 
TEAEs leading to permanent treatment discontinuation will be listed and summarized. 
TEAEs in the study eye related to the injection procedure and those related to the study medication 
will be summarized separately. 
An overall summary of the AE profile for aflibercept in this study will be provided.   
Summaries of all TEAEs will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity, presented by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths and other SAEs will also be listed and summarized. 
A listing will be constructed that includes the patient identification, category of AE (ocular study 
eye or fellow eye, non-ocular), AE, MedDRA term, seriousness, severity, causality, elapsed time 
to onset, duration, and outcome. 
Intraocular inflammation will be tabulated and listed. The detailed definition of the preferred 
terms for intraocular inflammation is presented in Appendix 10.2. 
5.4.2. 
Ocular Safety Measures 
Baseline IOP and change from Baseline in IOP to each scheduled assessment visit will be 
summarized with descriptive statistics for study eye and fellow eye.  Assessment of significant 
values or increases will be made and summarized for the proportion of patients with increased 
IOP in the study eye or fellow eye with the categories defined in Section 4.5.2. 
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5.4.3. 
 Best Corrected Visual Acuity  
Baseline BCVA and change from Baseline in BCVA to each scheduled assessment visit will be 
summarized with descriptive statistics for study eye and fellow eye. The listing of summary 
scores for standard Early Treatment Diabetic Retinopathy Study (ETDRS) for study eye will also 
be provided.   
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
6.1. 
Definition of Baseline 
Unless otherwise specified, the Baseline assessment for all measurements will be the last available 
valid measurement taken prior to the administration of investigational product. 
6.2. 
Unscheduled Assessments 
Assessments taken outside of protocol allowable windows will be displayed according to the case 
report form (CRF) assessment recorded by the investigator. 
Unscheduled assessments will not be included in the summaries. 
Early termination visit (ET):  If a subject prematurely discontinues they are asked to come for an 
early termination visit.  Visit based information of this visit will only be used in the tabulation if 
the visit was performed 4 weeks, i.e., 28 days (-7 to +14 days) after baseline visit consisting of 
the end-of-study assessments described in Section 10.1.  ET visits outside this window will not 
be used for analyses and handled in the same way as unscheduled assessments (see above). 
6.3. 
Handling of Patients Who Discontinue 
Patients who discontinue this study will not be replaced. 
6.4. 
Handling of Missing Data  
6.4.1. 
General Rules 
When appropriate, the following rules will be implemented so as not to exclude patients from 
statistical analyses due to missing or incomplete data: 
 AE variables  
For some AEs it is important to determine whether the AE started before or after the first 
active aflibercept injection.  If the AE start date is partially missing, it will be imputed by 
the latest possible date (considering other available data, e.g., stop date) to be conservative. 
 Prior/concomitant medication 
For the tabulation of prior and concomitant medication, partially missing start dates of the 
medication will be imputed by the earliest possible time point, partially missing stop dates 
will be imputed by the latest possible time point. 
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7. 
INTERIM ANALYSIS 
No formal interim analysis is planned. 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
9. 
REFERENCES 
ICH. (1998, February 5). ICH Harmonized tripartite guideline:  Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. 
 
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VGFTe-OD-1881 
Statistical Analysis Plan 
 
01 Feb 2019 
 
CONFIDENTIAL  
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10. 
APPENDIX 
10.1. 
Schedule of Time and Events: 
Table 1: Schedule of Time and Events 
 
10.2. 
Intraocular Inflammation: 
The preferred terms for the definition of intraocular inflammation below are based on MedDRA 
version 21.1. 
 
Intraocular Inflammation 
Preferred term 
Anterior chamber cell 
Anterior chamber fibrin 
Anterior chamber flare 
Anterior chamber inflammation 
Aqueous fibrin 
Autoimmune uveitis 
Chorioretinitis 
Choroiditis 
Cyclitis 
Endophthalmitis 
Eye infection intraocular 
Eye inflammation 
Hypopyon 
Infective iritis 
Infective uveitis 
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Infectious iridocyclitis 
Iridocyclitis 
Iritis 
Non-infectious endophthalmitis 
Non-infective chorioretinitis 
Pseudoendophthalmitis 
Serpiginous choroiditis 
Uveitis 
Vitreal cells 
Vitreous fibrin 
Vitritis 
  
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