A Randomized, Double-Masked, Active-Controlled Phase 2/3 Study of the Efficacy and Safety of High-Dose Aflibercept in Patients With Diabetic Macular Edema
Phase: PHASE2
Conditions: Diabetic Macular Edema, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus
Sponsor: Regeneron Pharmaceuticals

EudraCT Number: 2019-003643-30 
IND Number: 12462  
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-MASKED, ACTIVE-CONTROLLED 
PHASE 2/3 STUDY OF THE EFFICACY AND SAFETY OF HIGH-DOSE 
AFLIBERCEPT IN PATIENTS WITH DIABETIC MACULAR EDEMA 
Compound: 
High-dose aflibercept 
Study Name: 
PHOTON 
Clinical Phase: 
2/3 
Protocol Number: 
VGFTe-HD-DME-1934  
Protocol Version: 
VGFTe-HD-DME-1934 Amendment 6 
Amendment 6 
See appended electronic signature page 
Amendment 5 Date of Issue 
14 Sep 2022 
Amendment 4 Date of Issue 
28 Apr 2022 
Amendment 3 Date of Issue: 
07 May 2020 
Amendment 2 Date of Issue: 
14 Feb 2020 
Amendment 1 Date of Issue: 
06 Dec 2019 
Original Date of Issue: 
16 Oct 2019 
Medical /Study Director: 
  
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
VV-RIM-00179129-4.0 Approved - 27 Feb 2023 GMT-5:00
NCT04429503

Clinical Study Protocol 
 
VGFTe-HD-DME-1934 Amendment 6 
Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
 
 
 
 
 
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VGFTe-HD-DME-1934 Amendment 6 
 
Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 6 
The primary purpose of this amendment is to extend contraception requirements based on 
proposed aflibercept HD labeling language updates. 
Description of Change 
Brief Rationale 
Section # and Name 
Update the length of 
time contraception is 
required after study drug 
dosing. 
To align with the proposed HD labeling 
update, which 
 the time 
contraception is needed after the last study 
drug dose, based on the following: the 
recommended duration of contraception 
following the last intravitreal dose 
increased from 3 months for 2 mg 
aflibercept to 
 for HD aflibercept. 
The 3-month duration of contraception for 
the 2-mg dose was based on the time 
required for all patients to reach the lower 
limit of quantitation (LLOQ) of free 
aflibercept in plasma 
 plus a 
conservative 1-month buffer. For HD 
aflibercept, the population PK model-
predicted time for 99% of patients to reach 
the LLOQ of free aflibercept in plasma is 
 Applying the same 1-month 
buffer utilized for 2-mg aflibercept, the 
recommended duration of contraception 
for HD aflibercept is 
 
Section 7.2.2 Exclusion 
Criteria (# 36) 
 
 
 
Clarifying the timing for investigator 
decision if shortening dosing interval 
outside of shortening criteria.  
Section 6.1 Study Description 
and Design 
Updated a reference. 
The title of the referred to study was 
inadvertently deleted in the last version of 
the protocol. 
Section 11.1 Statistical 
Hypothesis 
 
 
 
 
 
 
The addition of this text provides 
clarification to the clinics for the treatment 
of DME in the study eye between these 
visits. 
Section 9.1.3 
 
 
 
Removal of text from 
sections for patients in 
China.  
This text was removed due to the fact that 
no sites were opened in China for this 
study, and therefore, no patients were 
enrolled. 
Section 9.2.4 Drug 
Concentration and 
Measurements 
Section 9.2.5 
Immunogenicity 
Measurements and Samples 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name 
Section 9.2.6 Future 
Biomedical Research 
(Optional) 
Section 9.2.6.1 
Pharmacogenomic Analysis 
(Optional) 
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CONFIDENTIAL 
Amendment 5 
 
 
 
 
 
Description of Change 
Brief Rationale 
Section # and Name 
 
 
 
  
 
 
 
 
 
Clinical Study Protocol Synopsis 
Study Design 
Study Duration 
Section 1 Introduction 
Section 3.3 Risk-Benefit 
Section 4.1.3 Additional Secondary 
Endpoints 
Section 4.1.4 Exploratory Endpoints 
Section 6.1 Study Description and 
Duration 
Figure 1 Study Flow Diagram 
Figure 3 
 
 
Section 6.1.1  End of Study Definition 
Section 6.2 Planned Interim Analysis 
Section 6.3.3 Independent Data 
Monitoring Committee 
Section 7.1 Number of Patients Planned 
Section 7.2.1 Inclusion Criteria 
Section 7.3 Premature Withdrawal from 
the Study 
Section 8.1 Investigational and 
Reference Treatments 
Section 8.5 Masking 
Section 9.1.3 
 
 
Table 4 
 
 
Section 9.1.3.1 
 
 
 
Section 9.1.4 Early Termination Visit 
Section 9.2.2 Ocular Study Procedures 
(Efficacy and Safety) 
Section 9.2.3.4  Laboratory Testing 
Section 10.1.1 General Guidelines 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Section 11.5 Interim Analysis 
Section 13.2.1 
 
 
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Description of Change 
Brief Rationale 
Section # and Name 
Minor template updates, in 
addition to minor edits and 
formatting changes. 
Throughout 
Throughout 
 
Amendment 4 
The primary purpose for this amendment is to simplify and extend the confirmatory testing 
hierarchy:  
To remove the initial Bonferroni-based split of the overall significance level (which had been 
introduced originally to allow simultaneous testing of the 2 hypotheses (8 mg aflibercept every 
12 weeks [HDq12] vs 2 mg aflibercept every 8 weeks [2q8] and 8 mg aflibercept every 16 weeks 
[HDq16] vs 2q8) of the primary endpoint at a significance level of 0.0125 [1-sided] each) and to 
assign the full significance level of 0.025 (1-sided) to the first hypothesis (HDq12 vs 2q8). The 
reason for this change is to adjust the testing sequence to the perceived clinical probability of 
success, ie, since HDq12 is more likely to succeed than HDq16 (due to the higher dosing frequency 
after the loading phase).  
1. To remove the subsequent splitting of the remaining alpha levels between 2 hypotheses, 
and replace it by a simpler hierarchical testing procedure in both the global statistical 
analysis plan (G-SAP) and the statistical analysis plan for EMA and PMDA (EP-SAP). 
This change allows sequential testing of hypotheses at the full significance level after 
successful rejection of the hypotheses which are ranked higher in the hierarchy. The reason 
for this change is to prioritize testing of hypotheses which are deemed to be clinically more 
relevant. 
2. To allow formal statistical testing for superiority of the change from baseline in best 
corrected visual acuity (BCVA) at week 48 (and week 60, in the EP-SAP only) that 
controls the overall family-wise type 1 error. The formal statistical testing for superiority 
is added at the end of the revised testing hierarchy. Hence the testing hierarchy is extended. 
3. To remove the endpoint of “Proportion of patients without retinal fluid at the foveal center 
at week 12” as a key secondary endpoint in the testing hierarchy (it remains as a secondary 
endpoint assessed at week 48). Based on recent data from another, completed study, it was 
determined that week 12 is not a reasonable time point to assess this endpoint. Analysis of 
this endpoint will be more informative at week 48 after a year of treatment. 
Of note, the updated confirmatory testing hierarchy still controls the overall family-wise type 1 
error at 0.025 level (1-sided). These changes will be implemented after the end of enrollment but 
before database lock and before any unmasking occurs.  
The following table outlines the changes made to the protocol and the affected sections: 
 
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Description of Change 
Brief Rationale 
Section # and Name 
Replaced the figures of 
sequentially rejective 
graphical procedure for G-
SAP and EP-SAP by a 
hierarchical testing 
procedure  
Mixed model repeated 
measurements (MMRM) 
updated to remove the 
random effect, variable “b,” 
and some index updates 
were made to the model 
equation 
Replace sequentially rejective 
graphical procedure by a 
hierarchical testing procedure 
Removed random effect, 
variable “b,” to avoid over 
parameterization 
Clinical Study Protocol Synopsis, 
Statistical Plan 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Section 11.4.4 Control of Multiplicity 
Figure 3: Hypothesis Testing (removed) 
 
Updated the power for 
primary endpoint 
hypotheses based on 
hierarchical testing 
procedure 
To clarify the power of 
primary endpoint hypotheses 
based on hierarchical testing 
procedure without alpha split 
Clinical Study Protocol Synopsis, 
Statistical Plan 
Section 11.2 Justification of Sample 
Size 
Removed key secondary 
endpoint regarding 
proportion of patients 
without fluid at foveal 
center at week 12 (it 
remains as a secondary EP 
at week 48)  
Based on recent data from 
another, completed study, it 
was determined that week 12 
is not a reasonable time point 
to assess this endpoint. 
Analysis of this endpoint is 
will be more informative at 
week 48 after a year of 
treatment.  
Clinical Study Protocol Synopsis, 
Endpoint 
Clinical Study Protocol Synopsis , 
Statistical Plan 
Section 4.1.2 Key Secondary Endpoints 
Figure 1 Study Flow Diagram 
Section 11.1 Statistical Hypothesis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Added superiority testing 
for the endpoint of mean 
change in BCVA to the end 
of the statistical testing 
hierarchy 
To control the type I error 
when formally testing for 
superiority in BCVA. 
Clinical Study Protocol Synopsis, 
Statistical Plan 
Section 4.1.4 Exploratory Endpoints 
Section 11.1 Statistical Hypothesis 
Section 11.4.4 Control of Multiplicity 
Table 5 The Testing Order of 
Hierarchical Testing Procedure in G-
SAP and EP-SAP (new) 
Updated definition of FAS 
to include randomized, 
treated patients  
To exclude from analysis 
patients randomized in error 
and not treated 
Section 11.3.1 Efficacy Analysis Sets 
Updated the definition of 
treatment-related TEAEs 
To ensure that AEs are 
analyzed appropriately as 
treatment emergent 
Section 11.4.5.1 Adverse Events 
Removed the following 
exploratory endpoint “fluid 
on spectral domain optical 
coherence tomography” 
This exploratory endpoint is 
covered by other secondary 
and exploratory endpoints. 
Section 4.1.4 Exploratory Endpoints 
 
Minor edits and formatting 
changes. 
Minor edits and formatting 
changes. 
Throughout 
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Amendment 3 
The primary purposes for this amendment are to clarify the machine-specific values for central 
retinal thickness (CRT; measured on spectral domain optical coherence tomography [SD-OCT]) 
defined in the inclusion criteria for the reading center’s determination of eligibility, and to describe 
the continuity plan for conducting clinical study activities and study oversight activities during the 
public health emergency due to Coronavirus Disease 2019 (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 3.3 Risk-Benefit 
Section 9.1.1 Schedule of 
Events for the Study 
Updated the figure for the 
dosing schedule. 
To show that sham injections are not 
administered at week 96. 
Figure 2 Dosing Schedule 
Inclusion criterion #2 updated 
to clarify the machine-specific 
values for CRT on SD-OCT 
for the reading center to 
determine eligibility. 
While 320 µm is accurate, it is specific 
for the Spectralis machine, while 300 
µm is the equivalent for the Cirrus and 
other commercially available 
machines. 
Section 7.2.1 Inclusion 
Criteria (#2) 
Updated urine pregnancy 
testing in the Schedule of 
Events tables.  Also clarified 
wording in Study Procedures. 
To reflect that a urine pregnancy test 
should be performed at all visits except 
optional visit 4.1 and the end of study 
visit. 
Table 2 Schedule of Events 
Section 9.2.3.4 Laboratory 
Testing (Other Laboratory 
Tests) 
Amendment 2  
The primary purpose of this amendment is to update details of the study design, combining rescue 
treatment with Dose Regimen Modification (DRM) assessments in both year 1 and year 2.  Patients 
in the HDq12 and HDq16 groups will now be eligible for a rescue regimen (8 mg aflibercept every 
8 weeks) beginning at week 16. 
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Change and Rationale for Change 
Sections Changed  
Updates to the dose regimen modification (DRM) 
criteria to incorporate a rescue regimen defining criteria 
to allow high-dose aflibercept every 8 weeks for the 
HDq12 and HDq16 groups, beginning at week 16. 
Clinical Study Protocol Synopsis: 
Treatments 
Clinical Study Protocol Synopsis: Statistical 
Plan 
Section 6.1 Study Description and Duration 
Section 8.2 Rescue Treatment 
Table 2 Schedule of Events 
Section 9.1.1.1 Footnotes for the Schedule of 
Events, footnote 6 
Section 11.4.5.3 Treatment Exposure 
Exploratory endpoints for best corrected visual acuity 
(BCVA) were added.  As treatment before week 48 and 
week 60 are less synchronized due to the modifications 
introduced for the dose regimen modifications (DRMs), 
it is now important to assess these additional/earlier 
endpoints before week 48. 
Section 4.1.4 Exploratory Endpoints 
Inclusion criteria updated to include patients with 
BCVA of 24 to 78 letters to better align with clinical 
practice patterns. 
Section 7.2.1 Inclusion Criteria (#3) 
Minor additions to the exclusion criteria regarding 
intraocular surgery prior to screening and other 
systemic disease. 
Section 7.2.2 Exclusion Criteria (#9, #20, 
#21, #26) 
Updates to the masking sections to clarify roles of the 
masked and unmasked investigators regarding rescue 
treatment. 
Section 8.5 Masking 
Table 1 Responsibilities of the Masked and 
Unmasked Personnel 
Section 9.2.2.6 Best Corrected Visual Acuity 
Addition of assessment of causality to aflibercept 2mg 
for patients receiving injections in the fellow eye. 
Section 8.8.1 Prohibited Medications and 
Procedures 
Section 10.2.4 Causality 
Window for pharmacokinetic (PK) assessments 
clarified 
Section 9.1.2 Schedule of Events for the 
Dense PK Substudy 
Clarification of expectation for early termination visit 
in order to be consistent across studies in the 
development program for HD aflibercept. 
Section 9.1.3 Early Termination Visit 
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Change and Rationale for Change 
Sections Changed  
Clarification of the method of obtaining ultra-widefield 
angiography and color photography images. 
Section 9.2.2.4 Fundus 
Photography/Fluorescein Angiography 
Section 9.1.1.1 Footnotes for the Schedule of 
Events, footnotes 10 and 11 
Clarification that a paper questionnaire will be used. 
Section 9.2.2.7 Quality of Life Questionnaire 
Section 12.1.2 Electronic Systems 
Clarifications of expectations for pharmacokinetic and 
anti-drug antibody (ADA) samples and the future 
biomedical research (FBR) study in China. 
Section 9.2.4 Drug Concentration and 
Measurements 
Section 9.2.5 Immunogenicity 
Measurements and Samples 
Section 9.2.6 Future Biomedical Research 
(Optional) 
Clarification of reference used for assessment of 
expectedness for safety reporting for 2 mg aflibercept. 
Section 10.4 Notifying Health Authorities, 
Institutional Review Board /Ethics 
Committee, and Investigators 
Efficacy analysis estimands are further clarified 
Minor correction in statistical models. 
Section 11.4.3 Efficacy Analyses 
Section 11.4.3.1 Primary Efficacy Analysis 
Editorial change in description of dosing groups and 
randomization scheme 
Synopsis, Study Design 
Section 6.1 Study Description and Duration 
Section 7.1 Number of Patients Planned 
Minor edits and formatting changes. 
Throughout 
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Amendment 1  
The purpose of this amendment is to address feedback received from European Union (EU) 
regulatory agencies as part of the Voluntary Harmonisation Procedure (VHP).  The requested 
revisions include:  addition of information on criteria for study and study drug discontinuation, 
specification that collection of adverse events (AEs) and serious adverse events (SAEs) will begin 
at the time of informed consent, clarification on assessment of laboratory values as AEs, 
clarification of some of the statistical considerations, and other minor revisions as requested. 
Change 
Sections Changed  
Minor update to the definition of abstinence to include 
reference to “The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the subject” 
and the definition of post-menopausal to include 
“amenorrhoeic for at least 12 months without an 
alternative medical cause.” 
Section 7.2.2 Exclusion Criteria (#32f) 
Addition of specific criteria for discontinuation of 
treatment in individual patients. 
Section 8.3.2 Study and Study Drug 
Discontinuation 
Update to indicate that AEs will be collected from the 
time of informed consent form (ICF) signing rather than 
from the time of first dose. 
Section 10.1.1 General Guidelines 
Addition of reference to Sections 9.2.3.4 and 10.1.1, 
which provide additional information to the investigator 
regarding the assessment and reporting of laboratory 
values as AEs. 
Section 10.2.3 Severity 
Addition of language regarding the rationale for the 4-
letter non-inferiority margin 
Section 11.1 Statistical Hypothesis 
Corrections to the equations in the statistical section 
(MMRM analysis model) 
Section 11.4.3.1 Primary Efficacy Analysis 
Addition of definition of pretreatment period 
Section 11.4.5.1 Adverse Events 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
2q8 
2 mg aflibercept every 8 weeks 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AOBP 
Automated office blood pressure 
APTC 
Anti-Platelet Trialists’ Collaboration 
AST 
Aspartate aminotransferase 
ATE 
Arteriothromboembolic event 
BCVA 
Best corrected visual acuity 
BP 
Blood pressure 
BRVO 
Branch retinal vein occlusion 
BUN 
Blood urea nitrogen 
CMH 
Cochran-Mantel-Haenszel method 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRT 
Central retinal thickness 
CRVO 
Central retinal vein occlusion 
CSME 
Clinically significant macular edema 
DME 
Diabetic macular edema 
DBP 
Diastolic blood pressure 
DR 
Diabetic retinopathy 
DRCR 
Diabetic Retinopathy Clinical Research 
DRM 
Dose regimen modification 
DRSS 
Diabetic Retinopathy Severity Scale 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
 
 
EMA 
European Medicines Agency 
EOS 
End of study 
EP-SAP 
Statistical Analysis Plan for EMA and PMDA  
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ETDRS 
Early Treatment Diabetic Retinopathy Study 
 
 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
FP 
Fundus photography 
GCP 
Good Clinical Practice 
G-SAP 
Global statistical analysis plan 
HbA1c 
Hemoglobin A1c 
HD 
High-dose aflibercept  
HDq12 
8 mg aflibercept every 12 weeks  
HDq16 
8 mg aflibercept every 16 weeks 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRF 
Intraretinal fluid 
IV 
Intravenous 
IVT 
Intravitreal 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
mCNV 
Myopic choroidal neovascularization 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measurements 
NAb 
Neutralizing antibody 
nAMD 
Neovascular age-related macular degeneration 
NB 
New Baseline 
NEI VFQ-25 
National Eye Institute Visual Function Questionnaire-25 
NI 
Non-inferiority 
OCT 
Optical coherence tomography 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
Per protocol set 
PT 
Preferred term 
QoL 
Quality of life 
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RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SBP 
Systolic blood pressure 
SC 
Steering committee 
SD-OCT 
Spectral domain optical coherence tomography 
SOC 
System organ class 
SRF 
Subretinal fluid 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................12 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................21 
1. 
INTRODUCTION ......................................................................................................24 
2. 
STUDY OBJECTIVES ..............................................................................................26 
2.1. 
Primary Objective .......................................................................................................26 
2.2. 
Secondary Objectives .................................................................................................26 
2.3. 
Exploratory Objectives ...............................................................................................26 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................27 
3.1. 
Hypotheses ..................................................................................................................27 
3.2. 
Rationale .....................................................................................................................27 
3.2.1. 
Rationale for Study Design .........................................................................................27 
3.2.2. 
Rationale for Dose Selection ......................................................................................27 
3.3. 
Risk-Benefit ................................................................................................................28 
4. 
ENDPOINTS ..............................................................................................................30 
4.1. 
Primary and Secondary Endpoints..............................................................................30 
4.1.1. 
Primary Endpoint ........................................................................................................30 
4.1.2. 
Key Secondary Endpoints ...........................................................................................30 
4.1.3. 
Additional Secondary Endpoints ................................................................................30 
4.1.4. 
Exploratory Endpoints ................................................................................................30 
5. 
STUDY VARIABLES................................................................................................32 
5.1. 
Demographic and Baseline Characteristics ................................................................32 
5.2. 
Efficacy Variables ......................................................................................................32 
5.3. 
Safety Variables ..........................................................................................................32 
5.4. 
Pharmacokinetic Variables .........................................................................................32 
5.5. 
Immunogenicity Variables ..........................................................................................32 
6. 
STUDY DESIGN .......................................................................................................33 
6.1. 
Study Description and Duration .................................................................................33 
6.1.1. 
End of Study Definition ..............................................................................................38 
6.2. 
Planned Interim Analysis ............................................................................................38 
6.3. 
Study Committees .......................................................................................................38 
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6.3.1. 
Study Steering Committee ..........................................................................................38 
6.3.2. 
Anti-Platelet Trialists Collaboration Adjudication Committee ..................................38 
6.3.3. 
Independent Data Monitoring Committee ..................................................................39 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............40 
7.1. 
Number of Patients Planned .......................................................................................40 
7.2. 
Study Population .........................................................................................................40 
7.2.1. 
Inclusion Criteria ........................................................................................................40 
7.2.2. 
Exclusion Criteria .......................................................................................................40 
7.3. 
Premature Withdrawal from the Study .......................................................................43 
7.4. 
Replacement of Patients .............................................................................................43 
8. 
STUDY TREATMENTS............................................................................................44 
8.1. 
Investigational and Reference Treatments ..................................................................44 
8.2. 
Rescue Treatment .......................................................................................................44 
8.3. 
Dosing Modification and Study Treatment Discontinuation Rules ............................44 
8.3.1. 
Dosing Modification ...................................................................................................44 
8.3.2. 
Study and Study Drug Discontinuation ......................................................................44 
8.4. 
Method of Treatment Assignment ..............................................................................45 
8.5. 
Masking ......................................................................................................................45 
8.6. 
Emergency Unmasking ...............................................................................................47 
8.7. 
Treatment Logistics and Accountability .....................................................................48 
8.7.1. 
Packaging, Labeling, and Storage ..............................................................................48 
8.7.2. 
Supply and Disposition of Treatments .......................................................................48 
8.7.3. 
Treatment Accountability ...........................................................................................48 
8.7.4. 
Treatment Compliance ................................................................................................48 
8.8. 
Concomitant Medications and Procedures .................................................................48 
8.8.1. 
Prohibited Medications and Procedures .....................................................................49 
8.8.2. 
Permitted Medications and Procedures ......................................................................49 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................49 
9.1. 
Schedule of Events .....................................................................................................49 
9.1.1. 
Schedule of Events for the Study ................................................................................49 
9.1.1.1. 
Footnotes for the Schedule of Events Table ...............................................................54 
9.1.2. 
Schedule of Events for the Dense PK Substudy .........................................................55 
9.1.2.1. 
Footnotes for the Dense PK Substudy Schedule of Events Table 3 ...........................55 
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9.1.3. 
 ...............................................................56 
 
..............................59 
9.1.4. 
Early Termination Visit ..............................................................................................60 
9.1.5. 
Unscheduled Visits .....................................................................................................60 
9.2. 
Study Procedures ........................................................................................................60 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................60 
9.2.2. 
Ocular Study Procedures (Efficacy and Safety) .........................................................60 
9.2.2.1. 
Intraocular Pressure ....................................................................................................61 
9.2.2.2. 
Slit Lamp Examination ...............................................................................................61 
9.2.2.3. 
Indirect Ophthalmoscopy ............................................................................................61 
9.2.2.4. 
Fundus Photography/Fluorescein Angiography .........................................................61 
9.2.2.5. 
Spectral Domain Optical Coherence Tomography .....................................................61 
9.2.2.6. 
Best Corrected Visual Acuity .....................................................................................62 
9.2.2.7. 
Quality of Life Questionnaire .....................................................................................62 
9.2.3. 
Safety Procedures (non-ocular) ..................................................................................62 
9.2.3.1. 
Vital Signs ..................................................................................................................62 
9.2.3.2. 
Physical Examination .................................................................................................62 
9.2.3.3. 
Electrocardiogram .......................................................................................................62 
9.2.3.4. 
Laboratory Testing ......................................................................................................62 
9.2.4. 
Drug Concentration and Measurements .....................................................................64 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................64 
9.2.6. 
Future Biomedical Research (Optional) .....................................................................64 
9.2.6.1. 
Pharmacogenomic Analysis (Optional) ......................................................................64 
10. 
SAFETY EVALUATION AND REPORTING .........................................................65 
10.1. 
Recording and Reporting Adverse Events ..................................................................65 
10.1.1. 
General Guidelines .....................................................................................................65 
10.1.2. 
Reporting Procedure ...................................................................................................66 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................66 
10.2. 
Definitions ..................................................................................................................66 
10.2.1. 
Adverse Event .............................................................................................................66 
10.2.2. 
Serious Adverse Event ................................................................................................67 
10.2.3. 
Severity .......................................................................................................................67 
10.2.4. 
Causality .....................................................................................................................68 
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10.3. 
Safety Monitoring .......................................................................................................69 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................70 
11. 
STATISTICAL PLAN................................................................................................71 
11.1. 
Statistical Hypothesis ..................................................................................................71 
11.2. 
Justification of Sample Size........................................................................................72 
11.3. 
Analysis Sets ...............................................................................................................73 
11.3.1. 
Efficacy Analysis Sets ................................................................................................73 
11.3.2. 
Safety Analysis Set .....................................................................................................73 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................73 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................73 
11.4. 
Statistical Methods ......................................................................................................74 
11.4.1. 
Patient Disposition ......................................................................................................74 
11.4.2. 
Demography and Baseline Characteristics .................................................................74 
11.4.3. 
Efficacy Analyses .......................................................................................................74 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................75 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................76 
11.4.4. 
Control of Multiplicity ................................................................................................76 
11.4.5. 
Safety Analysis ...........................................................................................................77 
11.4.5.1. 
Adverse Events ...........................................................................................................77 
11.4.5.2. 
Other Safety ................................................................................................................78 
11.4.5.3. 
Treatment Exposure ....................................................................................................78 
11.4.5.4. 
Treatment Compliance ................................................................................................78 
11.4.6. 
Pharmacokinetics ........................................................................................................78 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................78 
11.4.6.2. 
Pharmacokinetics/Pharmacodynamics Analyses ........................................................79 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................79 
11.5. 
Interim Analysis ..........................................................................................................80 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........80 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................81 
12.1. 
Data Management and Electronic Systems ................................................................81 
12.1.1. 
Data Management .......................................................................................................81 
12.1.2. 
Electronic Systems ......................................................................................................81 
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12.2. 
Study Monitoring ........................................................................................................81 
12.2.1. 
Monitoring of Study Sites ...........................................................................................81 
12.2.2. 
Source Document Requirements ................................................................................82 
12.2.3. 
Case Report Form Requirements ................................................................................82 
12.3. 
Audits and Inspections ................................................................................................82 
12.4. 
Study Documentation .................................................................................................83 
12.4.1. 
Certification of Accuracy of Data ...............................................................................83 
12.4.2. 
Retention of Records ..................................................................................................83 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................84 
13.1. 
Good Clinical Practice Statement ...............................................................................84 
13.2. 
Informed Consent .......................................................................................................84 
 
................................................................84 
13.3. 
Patients Confidentiality and Data Protection ..............................................................84 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................85 
13.5. 
Clinical Study Data Transparency ..............................................................................85 
14. 
PROTOCOL AMENDMENTS ..................................................................................85 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................86 
15.1. 
Premature Termination of the Study ...........................................................................86 
15.2. 
Close-out of a Site ......................................................................................................86 
16. 
CONFIDENTIALITY ................................................................................................86 
17. 
FINANCING AND INSURANCE .............................................................................86 
18. 
PUBLICATION POLICY ..........................................................................................86 
19. 
REFERENCES ...........................................................................................................87 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................90 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................91 
 
LIST OF TABLES 
Table 1: 
Responsibilities of the Masked and Unmasked Personnel .........................................47 
Table 2: 
Schedule of Events .....................................................................................................50 
Table 3: 
Schedule of Events: (Dense PK Substudy) .................................................................55 
 
 ...........................................................57 
Table 5: 
The Testing Order of Hierarchical Testing Procedure in G-SAP and EP-SAP ..........77 
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LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................34 
Figure 2: 
Dosing Schedule .........................................................................................................34 
 
 ..............................................................35 
 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Masked, Active-Controlled Phase 2/3 Study of the 
Efficacy and Safety of High-Dose Aflibercept in Patients with Diabetic 
Macular Edema   
Site Location(s) 
 
Principal Investigator 
Approximately 180 clinical study sites in North America, Europe, and Asia.  
(to be determined)  
Objective(s) 
The primary objective of the study is to determine if treatment with high-
dose aflibercept (HD) at intervals of 12 or 16 weeks provides noninferior 
best-corrected visual acuity (BCVA) compared to 2 mg aflibercept dosed 
every 8 weeks.   
The secondary objectives of the study are: 
• 
to determine the effect of HD vs. 2 mg aflibercept on anatomic and 
other visual measures of response 
• 
to evaluate the safety, immunogenicity and pharmacokinetics (PK) 
of HD.  
Exploratory objectives of the study are: 
• 
to determine the effect of HD vs. 2 mg aflibercept on additional 
anatomic measures of response 
• 
to study molecular drivers of diabetic macular edema (DME) or 
related diseases, the mechanism of action of afIibercept, and the 
vascular endothelial growth factor (VEGF) pathway. 
Study Design 
Phase 2/3, multi-center, randomized, double-masked study in patients with 
DME involving the center of the macula to investigate the efficacy and 
safety of HD versus 2 mg aflibercept. 
Approximately 640 eligible patients randomized into 3 treatment groups in 
a 1:2:1 ratio to the following 3 treatment groups: 1) 2q8: 2 mg aflibercept 
every 8 weeks, following 5 initial monthly doses (n=160), 2) HDq12: HD 
aflibercept every 12 weeks, following 3 initial monthly doses (n=320), 
3) HDq16: HD aflibercept every 16 weeks following 3 initial monthly doses 
(n=160).  
Approximately 24 patients will be included in a dense PK substudy (n=8 per 
group, with half Japanese and half non-Japanese per group). In all patients, 
blood samples for measurement of drug concentrations (PK) and anti-drug 
antibody (ADA) will be obtained prior to the first treatment and at 
prespecified time points throughout the course of the study. In addition, a 
DNA sample will be collected from those who sign the informed consent 
form (ICF) for the optional genomic substudy.   
 
 
 
 
Study Duration 
The study duration for a patient during the initial phase of the study is 
approximately 96 weeks; 
 
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End of Study Definition 
The end of study (EOS) is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
Sample size is approximately 640 patients. 
 
Target Population: 
Patients with DME involving the center of the macula 
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
High-dose aflibercept (8 mg) given by intravitreal injection in extended-
dose intervals (every 12 or 16 weeks) following 3 initial monthly injections 
according to study group.  Dosing regimen modifications (DRMs) are 
permitted based on clinical criteria defined in the protocol. 
 
Reference Drug 
 
Dose/Route/Schedule: 
Aflibercept 2 mg given by intravitreal injection every 8 weeks following 
5 initial monthly doses.   
Endpoints 
 
 
Primary: 
Change from baseline in BCVA at week 48. 
 
Secondary: 
The key secondary efficacy endpoints are: 
• 
Proportion of patients with a ≥2 step improvement in the Diabetic 
Retinopathy Severity Scale (DRSS) at week 48 
• 
Change from baseline in BCVA at week 60  
Procedures and Assessments 
Efficacy procedures:  ocular examination including BCVA (Early Treatment 
Diabetic Retinopathy Study [ETDRS]) and refraction, intraocular pressure 
(IOP), slit lamp examination, indirect ophthalmoscopy, fluorescein 
angiography (FA), fundus photography (FP), spectral domain optical 
coherence tomography (SD-OCT), OCT angiography (OCTA), National 
Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25). Safety 
procedures: ophthalmic exams, physical examination, vital signs, 
electrocardiogram (ECG), adverse events, laboratory and immunogenicity 
assessments. Pharmacokinetic and genomic substudies will be conducted. 
Statistical Plan 
The sample size calculation is based on testing 2 primary hypotheses for 
non-inferiority (NI) of HDq12 vs. 2q8 (control) and HDq16 vs. 2q8 (control) 
with respect to the primary endpoint of change from baseline in BCVA at 
week 48.  The NI margin is set at 4 letters for each of the primary hypotheses.   
Under the original testing strategy (prior to Amendment 4), assuming a 
standard deviation of 9.07 letters for each treatment group, and dropout rate 
of 19%, a sample size of 160 per treatment group based on two-sample t-
test will provide ≥90% power for each pairwise comparison.  Sample size in 
the HDq12 group is doubled to meet regulatory requirements for the safety 
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database.  Therefore, the study sample size is estimated for a total of 640 
patients (160, 320, and 160 for 2q8, HDq12, and HDq16, respectively).  
However, under the current hierarchical testing procedure, using the same 
assumptions as indicated above, a total sample size of 640 patients for 3 
groups provides 98% power for rejecting the null hypothesis H10, and 
subsequently 92% power for rejecting the null hypothesis H30, for the 
primary endpoint assessing non-inferiority, with a 1-sided t-test at 
significance level of 0.025.  
The primary hypotheses (null vs. alternative) are stated as below. 
H10: μ1 ≤ μ0 – 4 vs. H11:  μ1 > μ0 – 4 (ie, HDq12 vs. 2q8) 
H30: μ2 ≤ μ0 – 4 vs. H31:  μ2 > μ0 – 4 (ie, HDq16 vs. 2q8) 
where μ0, μ1, μ2, are the mean change from baseline in BCVA at week 48 
for 2q8, HDq12, and HDq16, respectively. The primary efficacy analysis 
will be based on a mixed model for repeated measurements (MMRM) with 
baseline BCVA as a covariate, treatment, baseline CRT, prior DME 
treatment, geographical region and visit as fixed effects, and interaction 
terms for treatment by visit and baseline BCVA by visit; this model will use 
the full analysis set (FAS). Full analysis set is defined as all randomized 
patients who received at least 1 dose of study drug. 
In addition, the HDq12 and HDq16 treatment groups will be tested for non-
inferiority against the control group of 2q8 with respect to the following key 
secondary endpoints: change from baseline in BCVA at week 60 (non-
inferiority with NI margin of 4 letters) (only for regulatory requirements for 
European Medicines Agency [EMA] and Pharmaceuticals and Medical 
Devices Agency [PMDA] of Japan) and proportion of patients with a ≥2 
step improvement in DRSS at week 48 (non-inferiority with NI margin of 
15%).  The key secondary endpoint of change from baseline in BCVA at 
week 60 (SAP for EMA, PMDA [EP-SAP] only) will be analyzed with a 
model matching the one for the primary endpoint.  The proportion of patients 
with a ≥2 step improvement in DRSS at week 48 will be analyzed using the 
Cochran-Mantel-Haenszel (CMH) method, stratified by baseline CRT, prior 
DME treatment, and geographical region. 
The change from baseline in BCVA at week 48 and week 60 (for the EP-
SAP) will also be tested for superiority to compare the HDq12 and HDq16 
treatment groups against the control group of 2q8. 
The overall family-wise type 1 error will be controlled at 0.025 one-sided 
level for testing the primary and key secondary endpoints. Adjustment for 
multiple comparisons in the primary and key secondary endpoints will be 
made with a hierarchical testing procedure.  For safety analysis, all 
treatment-emergent adverse events (TEAEs) will be summarized for each 
treatment group by the primary system organ class (SOC) and preferred 
terms (PT) using the Medical Dictionary for Regulatory Activities 
dictionary (MedDRA®).  Severity and relationship to treatment will also be 
presented by SOC and PT.  Deaths, serious adverse events (SAEs), and 
TEAEs leading to permanent treatment discontinuation will also be listed 
and summarized by treatment group.  In addition, vital signs and laboratory 
tests results will be descriptively tabulated and/or graphically presented as 
well as patient listings provided.  Treatment exposure will be summarized 
in terms of total number of treatments, duration of treatment, and proportion 
of patients maintaining, shortening, or extending the dosing interval. 
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1. 
INTRODUCTION  
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes.  Diabetic 
macular edema (DME), a manifestation of diabetic retinopathy, is the primary cause of vision loss 
and blindness in patients with diabetes (Klein, 1984) (Moss, 1994) (Moss, 1998) 
(Sivaprasad, 2012) and the most frequent cause of blindness in young and middle-aged adults 
(Klein, 1984) (Moss, 1998).  If left untreated, approximately half of patients with DME will lose 
2 or more lines of visual acuity (VA) within 2 years (Bandello, 2012) (Ciulla, 2003).  Among 
patients with diabetes, the prevalence of clinically significant macular edema (CSME) ranges from 
2.77% to 7.6% (Giuffrè, 2004) (Gulliford, 2010) (Ling, 2002) (McKay, 2000) (Minassian, 2012). 
The World Health Organization (WHO) reported the number of people with diabetes at 422 million 
in 2014, and a global prevalence of diabetes among adults at 8.5% in 2014, increased from 4.7% 
in 1980, with a continued rise in these numbers expected in coming years (Danaei, 2011) 
(NCD Risk Factor Collaboration, 2016). 
Treatment options for DME include laser photocoagulation and pharmacologic interventions, 
specifically vascular endothelial growth factor (VEGF) inhibitors and steroids.  Surgery is also 
performed in some cases as a fall-back therapeutic option, particularly for those refractory to 
treatment or with vitreomacular traction. 
However, anti-VEGF compounds have become the standard of care for the treatment of DME.  
This approach is highly attractive as it directly targets VEGF, one of the main mediators of DR 
and DME.  Vascular endothelial growth factor is a protein growth factor that both stimulates 
angiogenesis and increases vascular permeability, playing a key role in the pathophysiology of 
DME (Ferrara, 2000) (Nguyen, 2006) (Bhagat, 2009).  Hypoxia and other metabolic factors trigger 
VEGF release.  VEGF induces vascular leakage and neovascularization.  While neovascularization 
is the most severe manifestation of DR, vascular leakage leading to macular edema is an important 
cause of reduced visual acuity. 
EYLEA (also known as intravitreal aflibercept injection) is a VEGF antagonist currently approved 
in over 100 countries for the treatment of DME at a dosage level of 2 mg (administered at a 
concentration of 
 injected intravitreally [IVT]).  EYLEA is currently approved in at least 
100 countries for additional indications that include neovascular age-related macular degeneration 
(nAMD), macular edema following central retinal vein occlusion (CRVO) and branch retinal vein 
occlusion (BRVO), and in 99 countries for the treatment of myopic choroidal neovascularization 
(mCNV). EYLEA is also approved in the United States for the treatment of diabetic retinopathy. 
(See the Investigator’s Brochure for additional details). 
Ranibizumab (LUCENTIS®, Novartis AG), a VEGF inhibitor, has been approved in the US and 
in the European Union for the treatment of DME.  The results of the pivotal studies used to support 
the approval of LUCENTIS (Massin, 2010) (Mitchell, 2011) (Nguyen, 2012) and aflibercept 
(Brown, 2015) (Korobelnik, 2014), as well as data from large, randomized trials sponsored by the 
Diabetic Retinopathy Clinical Research (DRCR) Network (Elman, 2010) (Wells, 2015) using 
ranibizumab, bevacizumab, and aflibercept, support the assertion that anti-VEGF therapy may be 
the treatment option of choice, leading to vision gains for a significant number of patients.  
Additionally, in the 1-year data from DRCR Protocol T that compared aflibercept, bevacizumab, 
and ranibizumab, aflibercept demonstrated superior efficacy in the overall population with a more 
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pronounced benefit in patients with baseline best-corrected visual acuity (BCVA) worse than 
20/40 (Wells, 2015). 
Despite available treatments, there remains an unmet medical need for the development of 
therapies with the potential to improve important clinical outcomes.  This unmet need includes 
decreasing the treatment burden via a reduction in the required frequency of intravitreal injections, 
improving visual and anatomic outcomes over currently available standards of care, and slowing 
or even reversing the underlying pathophysiology of the disease itself, specifically retinal 
ischemia.  
Increasing the drug product concentration of aflibercept allows a greater amount of drug to be 
delivered IVT and thus has the potential to increase aflibercept’s pharmacological duration of 
action, and thereby provide additional benefit to patients with DME.  The resulting extension of 
treatment intervals to every 12 weeks or 16 weeks, early after the initiation of treatment, would 
reduce the number of injections in the first treatment year.  A potential decrease in injection-related 
treatment burden and safety events could be a significant contribution to patient care and healthcare 
services. 
This study will investigate the safety and efficacy of a high-dose aflibercept with the intent of 
extending the dosing interval, with at least similar functional and potentially improved anatomic 
outcomes compared to 2 mg aflibercept.  
 
  
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to determine if treatment with high-dose aflibercept (HD) at 
intervals of 12 or 16 weeks provides noninferior BCVA compared to 2 mg aflibercept dosed every 
8 weeks.  
2.2. 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• To determine the effect of HD vs. 2 mg aflibercept on anatomic and other visual 
measures of response 
• To evaluate the safety, immunogenicity, and pharmacokinetics (PK) of aflibercept   
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
• To determine the effect of HD vs. 2 mg aflibercept on additional anatomic measures of 
response 
• To study molecular drivers of DME or related diseases, the mechanism of action of 
afIibercept, and the VEGF pathway 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Treatment with high-dose aflibercept with longer treatment intervals of at least 12 weeks will result 
in noninferior changes from baseline in BCVA at week 48 compared to 2 mg aflibercept dosed 
every 8 weeks. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
There remains an unmet medical need in the treatment of DME.  Although many patients benefit 
from treatment with currently available anti-VEGF agents, a sizable proportion of patients still 
need frequent IVT injections.  Long-term data suggest that visual benefits may be lost if regular 
dosing is not maintained.  In addition, dosing at an insufficient frequency may result in fluctuations 
in visual and anatomic manifestations of the disease, leading ultimately to irreversible loss of 
vision below certain visual thresholds, eg driving vision.  Longer treatment intervals will lead to 
better treatment compliance and improved long-term clinical benefit. 
Increasing the drug product concentration of aflibercept allows a greater amount of drug to be 
delivered intravitreally, with the potential for both added efficacy and an increase in aflibercept’s 
pharmacological duration of action, thereby providing additional benefit to patients with DME 
while reducing burden on both patients and physicians.  In addition, higher intravitreal aflibercept 
concentrations sustained over a longer period of time may provide better control of the anatomic 
features of DME. 
Anatomic measures of retinal thickness and retinal fluid are well-known markers of disease 
activity.  These parameters are used by clinicians to determine treatment success and/or the timing 
of further retreatment. These measures will be used as secondary and exploratory endpoints in this 
phase 2/3 study, as these endpoints will help determine the timing and degree to which HD can 
extend the dosing interval relative to 2 mg aflibercept.  
The study aims to investigate the efficacy and safety of HD with the objectives of achieving 
noninferior BCVA with an extended dosing interval and potential improvements in anatomic 
outcomes vs. 2 mg aflibercept.  The study is designed to investigate HD dosed every 12 or 16 
weeks after 3 initial monthly injections vs. 2 mg aflibercept dosed every 8 weeks (2q8) after 
5 initial monthly injections in patients diagnosed with DME.   
3.2.2. 
Rationale for Dose Selection  
Based on considerations of manufacturing capabilities, formulation, stability, and the likelihood 
of achieving a meaningful extension of the duration of pharmacological effect, an 8 mg IVT dose 
was selected for evaluation in the present study.  
In a nonclinical rabbit model of chronic retinal neovascularization and vascular leak, dose-
dependent duration of leak suppression was observed after single IVT doses equivalent of up to 8 
mg in humans.  Pharmacokinetic simulations of free aflibercept concentration-time profiles in 
human vitreous using a 1-compartment ocular model predicted 
 
 
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Studies with intravenous (IV) aflibercept indicated that blood pressure (BP) increase was the 
earliest pharmacodynamic indicator of systemic effect.  Two studies (PDY6655 and PDY6656) 
evaluated the effects of IV and subcutaneous aflibercept on BP via 24-hour ambulatory 
BP monitoring in healthy subjects.  At the lowest IV dose tested in these studies (1 mg/kg; 
PDY6656), a maximal increase of ~5 mmHg in 24-hour mean change from baseline in systolic BP 
(SBP) occurred by day 6 after a single dose, SBP returning to baseline by ~30 days post-dose.  
Assuming linear PK and extrapolating Cmax and AUClast values (for both mean and maximum 
individual patient values) from 2 mg IVT, estimated free aflibercept systemic Cmax and AUClast for 
an 8 mg IVT dose are approximately 60-142x and 98-221x lower, respectively, than the 
corresponding values associated with a 1 mg/kg IV dose.  Although systemic concentrations of 
free aflibercept at these IVT doses are appreciably lower than those required to saturate the target-
mediated elimination pathway, linear extrapolation may overestimate the exposure margins for an 
8 mg IVT dose.  A threshold dose and/or concentration of free aflibercept associated with BP 
increase has not yet been determined. 
In phase 1 and 2 clinical trials, doses up to 4 mg per eye in monthly intervals, with injection 
volumes up to 100 µl, were generally well tolerated in patients with both DME and nAMD.  In a 
small number of patients with nAMD, isolated cases of unintentional dosing with 8 mg per eye 
occurred and were also well tolerated.  It is expected that an 8 mg IVT dose will extend the dosing 
interval relative to 2 mg IVT, thereby reducing the number of injections needed for successful 
treatment.  Hence, with the expectation of both a longer dosing interval resulting in a lower 
annualized number of injections, and similar safety profile, the 8 mg dose was selected for 
evaluation in this study. 
3.3. 
Risk-Benefit 
Benefits of Treatment with HD:  
High-dose aflibercept for IVT injection may provide improved patient benefit through:  
• Longer treatment intervals of every 12 weeks or longer for all patients 
• Potential for improved functional and anatomic efficacy  
• Less injection-related risk over time  
• Increased compliance by reducing the treatment burden on patients, caregivers, 
physicians, and healthcare systems 
Extrapolated safety margins for free aflibercept after an 8 mg IVT dose, derived from linear 
extrapolation of available PK data for 2 mg IVT aflibercept, suggest an acceptable systemic safety 
profile of HD aflibercept 8 mg.  Robust generation of safety data is further planned in the phase 2 
and phase 3 trials. 
 
 
 
  
 
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Risks and Risk Management of Treatment with HD: 
The safety profile of aflibercept 2 mg has been thoroughly investigated in a comprehensive clinical 
trial program including 9 phase 3 studies in the indications nAMD, CRVO, BRVO, mCNV, DME, 
and DR.  Overall, more than 4900 patients were treated with aflibercept in clinical trials.  Patients 
were treated for up to 148 weeks with aflibercept during these phase 3 studies.  No new safety 
findings were observed with long-term treatment with aflibercept. 
The safety profile of HD is anticipated to be similar to that of 2 mg aflibercept, and includes 
identified risks such as intraocular inflammation/infection, retinal tear, retinal detachment, 
transient increase in intraocular pressure (IOP), traumatic cataract, and hypersensitivity. 
Other safety topics that are known to be associated with the systemic administration of anti-VEGF 
medications for cancer treatment include arteriothromboembolic events (ATEs), embryo-
fetotoxicity, and an increase in BP.  However, pharmacokinetic and clinical safety data of IVT 
2 mg aflibercept have indicated that the known potential risks from systemic administration of 
anti-VEGF treatments in oncology indications were not identified with IVT dosing of 2 mg.  
Studies performed with IV administration of aflibercept demonstrated that increases in BP were 
the earliest pharmacodynamic (PD) indicator of systemic effects.  Based on the estimated exposure 
margins for free aflibercept after an 8 mg IVT dose for a 5 mmHg mean increase in SBP as 
described above, a meaningful increase in BP is not anticipated for the 8 mg IVT dose.   
An objective of this study in DME patients is to assess patient safety.  Robust generation of safety 
data is planned in this phase 2/3 trial to evaluate potential systemic exposure-related adverse events 
(AEs) such as changes in BP and incidence of ocular safety events.  Safety will be assessed by 
collection of vital signs (including careful monitoring of blood pressure, heart rate, and 
temperature), ocular assessments, AEs, laboratory assessments, and sparse PK sampling.  
Additionally, the aflibercept PK profile (via dense sampling for drug concentration and PK 
evaluation) and PD effects (ie, BP changes) will be evaluated in a dense PK substudy.  
As risk minimization measures, patients and investigators will be informed about the anticipated 
safety profile of HD and exclusion criteria will be applied to account for safety topics such as 
hypersensitivity, pregnancy, ATEs, and uncontrolled hypertension. 
Overall Risk-Benefit Balance: 
Based on the available preclinical and clinical data, the benefit-risk assessment of HD aflibercept 
is considered as positive and supports the participation of patients with DME in the clinical trial 
program. 
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 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.  Site initiation visits will then be determined based on the sites’ 
ability to proceed. 
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4. 
ENDPOINTS  
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
The primary endpoint is the change from baseline in BCVA at week 48. 
4.1.2. 
Key Secondary Endpoints 
The key secondary efficacy endpoints are:  
• Proportion of patients with a ≥2 step improvement in Diabetic Retinopathy Severity 
Scale (DRSS) at week 48 
• Change from baseline in BCVA at week 60 (for EMA/PMDA [European Medicines 
Agency/Pharmaceuticals and Medical Devices Agency] Analysis Plan only, see 
Section 11)  
4.1.3. 
Additional Secondary Endpoints 
The secondary efficacy endpoints are: 
• Proportion of patients gaining ≥15 letters at week 48 
• Proportion of patients with BCVA ≥69 letters at week 48 
• Proportion of patients without fluid at foveal center at week 48 
• Change from baseline in central retinal thickness (CRT) at week 48  
• Proportion of patients without leakage on fluorescein angiography (FA) at week 48 
• Change from baseline in National Eye Institute Visual Function Questionnaire (NEI-
VFQ) total score at week 48 
• Systemic PK of aflibercept as assessed from baseline through week 48 
• Assessment of immunogenicity to aflibercept through end of study (EOS) week 
(week 96).   
The secondary safety endpoint is: 
• Safety evaluation by assessment of AEs and serious adverse events (SAEs) through 
weeks 48, 60, 96, 
 
4.1.4. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Proportion of patients without retinal fluid (total fluid, intraretinal fluid [IRF] and/or 
subretinal fluid [SRF]) at the foveal center and in center subfield at week 48 and 
week 96 
• Time to fluid-free retina over 48 weeks and 96 weeks (total fluid, IRF and/or SRF at 
foveal center and in the center subfield) 
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• Proportion of patients with sustained fluid-free retina over 48 weeks and 96 weeks 
(total fluid, IRF and/or SRF at foveal center and in the center subfield) 
• Proportion of patients without CSME at week 48 and week 96 
• Proportion of patients with a ≥3 step improvement in DRSS at week 48 and week 96 
• Change from baseline in BCVA averaged over the period from week 36 to week 48  
• Change from baseline in BCVA averaged over the period from week 48 to week 60  
• Proportions of patients gaining and losing 5 or 10 letters at week 48 and week 96 
• Proportion of patients losing 15 letters at week 48 and week 96 
• Proportion of patients randomized to HDq16 maintaining q16 dosing interval or longer 
through weeks 48, 60, and 96  
• Proportion of patients randomized to HDq12 maintaining q12 dosing interval or longer 
through weeks 48, 60 and 96 
• Proportion of patients with an assigned injection interval of ≥16 or ≥20 weeks based 
on assessment at the last injection visit 
In addition to those specified above, all primary, secondary, and exploratory endpoints may be 
analyzed in an exploratory manner at weeks 60 and 96. 
 
 
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5. 
STUDY VARIABLES  
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics, medical history, and medication history. 
5.2. 
Efficacy Variables 
The efficacy variable relevant to the primary efficacy endpoint is visual acuity. 
The efficacy variables relevant to the secondary endpoints are: 
• BCVA 
• Assessment of retinal fluid levels and retinal thickness on spectral domain optical 
coherence tomography (SD-OCT) 
• Dosing interval 
• Quality of life using the NEI VFQ-25  
• Diabetic retinopathy severity level using the DRSS  
The efficacy variables relevant to the exploratory endpoints are: 
• Assessment of retinal fluid levels and retinal thickness on SD-OCT 
• BCVA 
• Dosing interval 
5.3. 
Safety Variables 
Safety will be evaluated by assessment of AEs and SAEs, ocular exams, IOP, vital signs (including 
BP, heart rate, and temperature), and clinical laboratory values. 
5.4. 
Pharmacokinetic Variables 
The PK variables are the concentrations of free, bound, adjusted bound, and total aflibercept in 
plasma at each time point (Table 2). 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are anti-drug antibody (ADA) status, titer, and neutralizing 
antibody (NAb) status at each study visit time point (Table 2).  
 
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6. 
STUDY DESIGN  
6.1. 
Study Description and Duration 
This phase 2/3, multi-center, randomized, double-masked study in patients with DME involving 
the center of the macula will investigate the efficacy and safety of HD aflibercept versus 
2 mg aflibercept (through week 96; year 2) 
 
 
The study consists of a screening/baseline period, a treatment period, and an EOS visit at week 96. 
 
A total of approximately 640 eligible patients will be randomized into 3 treatment groups in a 1:2:1 
ratio as follows: 1) 2q8: 2 mg aflibercept every 8 weeks, following 5 initial monthly doses (n=160), 
2) HDq12: HD aflibercept every 12 weeks, following 3 initial monthly doses (n=320), 3) HDq16: 
HD aflibercept every 16 weeks following 3 initial monthly doses (n=160) (Figure 1). 
Patients will be stratified based on baseline CRT (<400µm, ≥400 µm), prior DME treatment (yes, 
no), and geographical region (Rest of world, Japan).  Sham injections will be given at all visits 
when an active injection is not planned.  All patients will be followed every 4 weeks through week 
96. 
The primary analysis will take place once all patients have completed week 48 (or prematurely 
discontinued), with additional analyses after all patients have completed week 60, and after all 
patients have completed the study at week 96.   
Safety will be assessed by ophthalmic exams, collection of vital signs (including heart rate, BP, 
and temperature), AEs, and laboratory assessments.  All AEs reported in this study will be coded 
using the currently available version of the Medical Dictionary for Regulatory Activities 
(MedDRA®).  
Approximately 24 patients will be included in a dense PK substudy (n=8 per group, with half 
Japanese and half non-Japanese per group).  For details refer to Table 3. 
In all patients, blood samples for measurement of drug concentrations (PK) and ADA will be 
obtained prior to the first treatment and at prespecified time points throughout the course of the 
study (see Schedule of Events, Table 2).  In addition, a DNA sample will be collected from those 
who sign the informed consent form (ICF) for the optional genomic substudy.   
Dosing schedules appear in Figure 2 and 
 are described below. 
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Figure 1: 
Study Flow Diagram  
 
 
Figure 2: 
Dosing Schedule  
 
 
 
 
 
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Figure 3 
 
Dose Regimen Modifications/Rescue Regimen 
For masking purposes, assessments for dose regimen modifications (DRMs) will be performed in 
all participants at all visits (through the IWRS) beginning at week 16.  Based on these assessments, 
patients in the HD groups may have their treatment intervals shortened (year 1 and year 2) or 
extended (year 2).  The minimum interval between injections will be 8 weeks which is considered 
a rescue regimen for patients randomized to HD aflibercept and unable to tolerate a dosing interval 
greater than every 8 weeks.  Patients in the aflibercept 2 mg group will remain on fixed q8 dosing 
throughout the study (ie, will not have modifications of their treatment intervals regardless of the 
outcomes of the DRM assessments).  
Year 1: Baseline to Week 52 
Beginning at week 16, patients in the HD groups will have the dosing interval shortened (at the 
visits described below) if BOTH of the following criteria are met:  
1. >10 letter loss in BCVA from week 12 in association with persistent or worsening DME 
AND 
2. >50 µm increase in CRT from week 12  
(It should be noted that the change in CRT for these criteria will be assessed at the site.) 
If a patient in the HDq12 group or the HDq16 group meets both criteria at week 16 or week 20, 
the patient will be dosed with 8 mg aflibercept at that visit and will continue on a rescue regimen 
(aflibercept 8 mg, every 8 weeks).  If a patient in the HDq16 group who has not met the criteria at 
week 16 or 20 meets both criteria at week 24, the patient will be dosed with 8 mg aflibercept at 
that visit and will continue on q12 week dosing.  
For patients whose interval was not shortened to q8 dosing at or before week 24, the interval will 
be shortened if the DRM criteria are met at a subsequent dosing visit.  Patients in the HDq12 group 
who meet the criteria will receive the planned dose at that visit and will then continue on a rescue 
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regimen (aflibercept 8 mg, every 8 weeks).  Patients in the HDq16 group who meet these criteria 
will receive the planned dose at that visit and will then continue to be dosed every 12 weeks if they 
were on a 16-week interval, or switch to the rescue regimen (aflibercept 8mg, every 8 weeks) if 
they were previously shortened to a 12-week interval.  Therefore, a patient randomized to HDq16 
whose injection interval has been shortened to q12 will have their injection interval further 
shortened to q8 if these criteria are met at any subsequent dosing visit. 
Year 2: Week 52 to Week 96 (End of Study) 
From week 52 through the end of study (year 2), all patients in the HD groups will continue to 
have the interval shortened in 4-week intervals if the DRM criteria for shortening are met at dosing 
visits using the DRM criteria described above for year 1.  As in year 1, the minimum dosing 
interval for patients in all treatment groups is every 8 weeks. 
In addition to shortening of the interval, all patients in the HD groups (including patients whose 
interval was shortened during year 1) may be eligible for interval extension (by 4-week 
increments), if BOTH the following criteria are met at dosing visits in year 2: 
1. <5 letter loss in BCVA from week 12 AND 
2. CRT <300 µm on SD-OCT (or <320 µm on Spectralis SD-OCT)  
For patients who do not meet the criteria for shortening or extension of the interval, the dosing 
interval will be maintained.  
As in year 1, all patients in all treatment groups (including the 2q8 group) will be evaluated against 
both DRM criteria at all visits through the IWRS for masking purposes.  However, changes to 
dosing schedule will only be implemented as described above for those patients randomized to 
HDq12 or HDq16 treatment groups. No changes to the dosing schedule will be made to the 2q8 
treatment group at any time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
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6.2. 
Planned Interim Analysis  
No formal interim analysis is planned.  However, the primary analysis for this study will be 
performed once all patients reach week 48, with a subsequent analysis performed when all patients 
reach week 60.  The study will continue through week 96 for the main phase 
 
  
Another analysis will be conducted after all patients have completed the main phase of study at 
week 96 (or prematurely discontinued).  
 
 
 
 
A description of the statistical methods to be employed is in Section 11.4 and masking implications 
are discussed in Section 8.5. 
6.3. 
Study Committees  
6.3.1. 
Study Steering Committee 
A study steering committee (SC) will be established to help guide the study in regard to safety and 
efficacy.  All members of the SC are masked with regard to treatment assignments throughout the 
study.   
6.3.2. 
Anti-Platelet Trialists Collaboration Adjudication Committee 
Potential ATEs will be evaluated by a masked adjudication committee according to criteria 
formerly applied and published by the Anti-Platelet Trialists’ Collaboration (APTC) prior to 
database unmasking (Antithrombotic Trialists’ Collaboration 1994; Antithrombotic Trialists’ 
Collaboration 2002).  Arterial thromboembolic events as defined by the APTC criteria include 
nonfatal myocardial infarction, nonfatal ischemic stroke, nonfatal hemorrhagic stroke, or death 
resulting from vascular or unknown causes.  The committee will include at least 2 cardiologist-
equivalent adjudicators, and the activities of the committee will be governed by a charter. 
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6.3.3. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will meet periodically to review the ongoing 
safety of patients in the study and provide recommendations to continue or terminate the study 
depending upon these reviews.  The operation of the IDMC is governed by a charter that describes 
the group’s frequency of meeting, procedures (including but not limited to periodic safety 
monitoring), and requirements for reporting its observations to the sponsor.  The IDMC oversight 
will continue through the last patient’s completion of visit 26 EOS visit (week 96) 
 
  
During the course of the study, the SC and the IDMC keep each other informed in order to assess 
all relevant safety information in a timely and efficient manner.  Communications between SC and 
IDMC will only include masked data. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
The study will enroll approximately 640 patients to be randomized 1:2:1 (160 patients each in the 
2q8 and the HDq16 groups, and 320 patients in the HDq12 group).  
 
 
7.2. 
Study Population  
The study population will comprise patients with DME with central involvement.  
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria at both the screening and randomization visits (except 
where indicated) to be eligible for inclusion in the study: 
1. Men or women ≥18 years of age (or country’s legal age of adulthood if the legal age is >18 
years) with type 1 or type 2 diabetes mellitus 
2. DME with central involvement in the study eye with CRT ≥300 µm (or ≥320 µm on 
Spectralis) as determined by the reading center at the screening visit  
3. BCVA early treatment diabetic retinopathy study (ETDRS) letter score of 78 to 24 
(approximate Snellen equivalent of 20/32 to 20/320) in the study eye with decreased vision 
determined to be primarily the result of DME  
4. Willing and able to comply with clinic visits and study-related procedures 
5. Provide informed consent signed by study patient or legally acceptable representative 
 
 
 
 
 
  
7.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria at either the screening or randomization visits 
will be excluded from the study: 
1. Evidence of macular edema due to any cause other than diabetes mellitus in either eye 
2. Active proliferative diabetic retinopathy in the study eye  
3. Panretinal laser photocoagulation (PRP) or macular laser photocoagulation in the study eye 
within 12 weeks (84 days) of the screening visit 
4. IVT anti-VEGF treatment (aflibercept, ranibizumab, bevacizumab, brolucizumab, 
pegaptanib sodium) in the study eye within 12 weeks (84 days) of the screening visit 
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5. Prior IVT investigational agents in either eye (eg, anti-ang-2/anti-VEGF bispecific 
monoclonal antibodies, gene therapy, etc.) at any time 
6. Treatment with ocriplasmin (JETREA®) in the study eye at any time 
7. Previous use of intraocular or periocular corticosteroids in the study eye within 16 weeks 
(112 days) of the screening visit, or ILUVIEN® or OZURDEX® IVT implants at any time 
8. History of vitreoretinal surgery (including scleral buckle) in the study eye 
9. Any other intraocular surgery within 12 weeks (84 days) before the screening visit 
10. Yttrium-aluminum-garnet (YAG) laser capsulotomy in the study eye within 4 weeks 
(28 days) of the screening visit 
11. IOP ≥25 mmHg in the study eye 
12. History of glaucoma filtration surgery in the past, or likely to need filtration surgery in the 
future in the study eye 
13. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye within 
4 weeks (28 days) of the screening visit  
14. Any intraocular inflammation/infection in either eye within 12 weeks (84 days) of the 
screening visit 
15. History of idiopathic or autoimmune uveitis in the study eye  
16. Vitreomacular traction or epiretinal membrane in the study eye evident on biomicroscopy 
or OCT that is thought to affect central vision  
17. Preretinal fibrosis involving the macula in the study eye  
18. Any history of macular hole of stage 2 and above in the study eye 
19. Current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment 
visible at the screening assessments in the study eye 
20. History of corneal transplant or corneal dystrophy in study eye 
21. Any concurrent ocular condition in the study eye which, in the opinion of the investigator, 
could either increase the risk to the patient beyond what is to be expected from standard 
procedures of IVT injections, or which otherwise may interfere with the injection 
procedure or with evaluation of efficacy or safety 
22. Only 1 functional eye, even if that eye was otherwise eligible for the study (eg, BCVA of 
counting fingers or less in the eye with worse vision) 
23. Structural damage to the center of the macula in the study eye that is likely to preclude 
improvement in BCVA following the resolution of macular edema including atrophy of 
the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia, or 
organized hard exudates 
24. Ocular conditions with poorer prognosis in the fellow eye 
25. Inability to obtain photographs, FA, or SD-OCT in the study eye, eg, due to media opacity, 
allergy to fluorescein dye, or lack of venous access 
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26. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that might affect interpretation of the results of the 
study or render the patient at high risk for treatment complications  
27. Any prior systemic (IV) anti-VEGF administration 
28. Uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) > 12%  
29. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg).  
Patients may be treated with up to 3 agents known to have anti-hypertensive effects for 
arterial hypertension to achieve adequate blood pressure control.  This limit applies to 
drugs that could be used to treat hypertension even if their primary indication in the patient 
was not for blood pressure control.  Any recent changes in medications known to affect 
blood must be stable for 12 weeks (84 days) prior to screening. 
30. History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) 
of screening visit 
31. Renal failure, dialysis, or history of renal transplant 
32. Known sensitivity to any of the compounds of the study formulation 
33. Participation in an investigational study within 30 days prior to screening visit that involved 
treatment with any drug (excluding vitamins and minerals) or device 
34. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the sponsor 
35. Pregnant or breastfeeding women 
36. Men or women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the initial dose/start of the first treatment, during the study, 
and for at least 4 months after the last dose.  Highly effective contraceptive measures 
include:  
a. stable use of combined (estrogen and progestogen-containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS) 
c. bilateral tubal ligation 
d. vasectomy** 
e. condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive 
sponge, foam, or jelly  
f. and/or sexual abstinence†, ‡. 
*Postmenopausal women must be amenorrhoeic for at least 12 months without an 
alternative medical cause in order not to be considered of childbearing potential.  
Pregnancy testing and contraception are not required for women with documented 
hysterectomy or tubal ligation. 
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**Vasectomized partner or vasectomized study participant must have received medical 
assessment of the surgical success. 
†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are 
not acceptable methods of contraception.  Female condom and male condom should 
not be used together.  
Additional Exclusion Criteria for the PK Substudy: 
1. Prior treatment with IVT aflibercept in the fellow eye within 12 weeks (84 days) of the 
screening visit 
2. Other IVT anti-VEGF treatment (ranibizumab, bevacizumab, brolucizumab, pegaptanib 
sodium) in the fellow eye within 4 weeks (28 days) of the screening visit 
3. Patients with SBP >140 mmHg or diastolic blood pressure (DBP) >90 mmHg 
4. Patients with known cardiac arrhythmia 
5. Patients who, in the opinion of the investigator, are unlikely to have stable BP over the 
course of the study (eg, due to known or suspected non-compliance with medication)  
6. Variation by more than 10% in the 3 pre-randomization BP measures recorded at the 
screening visits and at randomization  
7.3. 
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 the early 
termination visit (EOS visit, [visit 26] 
 as described in Section 9.1.4.  
Rules for discontinuation of the study or study treatment (permanent or temporary) are discussed 
in Section 8.3.2. 
7.4. 
Replacement of Patients  
Patients prematurely discontinued from study/study drug will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
The HD drug product will be supplied for this study as an aqueous solution in sterile, sealed, single-
use vials for IVT administration at a concentration of 114.3 mg/mL aflibercept which will be 
delivered in an injection volume of 70 µl (0.07 mL). 
Intravitreal aflibercept injection 2 mg will be supplied for this study as an aqueous solution in 
sterile, sealed, single-use vials for IVT administration at a concentration of 40 mg/mL delivered 
in an injection volume of 50 μL (0.05 mL).  
Empty vials will be supplied in sham injection kits. 
Instructions on dose preparation are provided in the pharmacy manual. 
Fellow eye treatment will be allowed with 2 mg aflibercept, throughout the main study phase 
 
, at the investigator’s discretion for indications approved by governing authorities. 
The treated fellow eye will not be considered an additional study eye. 
8.2. 
Rescue Treatment 
There is no alternative rescue treatment defined for this study.  However, patients in the HDq12 
and HDq16 groups meeting the DRM criteria for shortening may be shortened to intervals as short 
as every 8 weeks, which is considered a rescue regimen.  See Section 6.1.  
8.3. 
Dosing Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dosing Modification 
Dosing modification for an individual patient is not allowed. 
8.3.2. 
Study and Study Drug Discontinuation 
A patient may withdraw from study drug or the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
Patients must be withdrawn if any of the following occurs: 
• Relevant laboratory abnormality or SAEs, if the sponsor or investigator sees this as 
medical reason to warrant withdrawal. 
• AE (ocular or nonocular) that, from the patient’s or the investigator’s view, is severe 
enough to require withdrawal from the study. The investigator must notify the sponsor 
immediately if a patient is withdrawn because of an AE/SAE.  
• At the discretion of the treating investigator. The development of conditions, which 
would have prevented a patient’s entry into the study according to the selection criteria, 
is no reason per se for withdrawal. However, the withdrawal in such cases remains at 
the discretion of the treating investigator.  
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• Decision by the investigator or sponsor that termination is in the patient’s best medical 
interest or administrative decision for a reason other than an AE/SAE.  
• A female patient becomes pregnant (see Section 10.1.3). 
• Lost to follow-up. 
• Decision by the sponsor to halt the entire study.  
Patients may be withdrawn if any of the following occurs: 
• If any treatment for DME other than study interventions is given in the study eye.  
• Systemic anti-angiogenic agents are taken by the patient during the study.  
• If, in the investigator's opinion, continuation in the study would be harmful to the 
patient’s well-being. 
• At the specific request of the sponsor and in liaison with the investigator (eg, obvious 
noncompliance or safety concerns). 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study.  Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 9.1.3. 
8.4. 
Method of Treatment Assignment 
Approximately 640 patients will be randomized into 3 treatment groups in a ratio of 1:2:1 to 
receive either 2 mg aflibercept every 8 weeks following 5 initial monthly doses (2q8), HD every 
12 weeks following 3 initial monthly doses (HDq12), or HD every 16 weeks following 3 initial 
monthly doses (HDq16), according to a central randomization scheme provided by an interactive 
web response system (IWRS) to the designated, unmasked investigator or study coordinator (or 
unmasked qualified designee).  Randomization will be stratified according to baseline CRT 
(<400 µm, ≥400 µm), prior treatment for DME (yes, no) and geographic region 
(Rest of world, Japan). 
8.5. 
Masking  
The study will be conducted in double-masked fashion.  Study patients and masked study site 
personnel will remain masked to all randomization assignments throughout the main study.  The 
Regeneron Medical/Study Director, study monitor, and any other Regeneron and contract research 
organization (CRO) personnel who are in regular contact with the study site will remain masked 
to all patient randomization assignments.   
To preserve masking, sham injections will be performed for all patients at treatment visits in which 
patients do not receive an active injection through week 92.  
A masked physician will be assigned to do the following:  1) assess AEs, 2) perform all study 
procedures except those related to study drug injection, and 3) perform the masked assessment of 
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efficacy.  A separate, unmasked physician will administer treatment in the study eye (ie, perform 
study drug injection or sham injection) (Table 1). 
The unmasked physician or designee will not have any role in the study beyond the receipt, 
tracking, preparation, destruction, and administration of study drug, and assessing safety during 
the observation period following study drug administration.  The masked physician will provide 
assessments for the IWRS to determine whether the patient has met DRM criteria for shortening 
or extending the interval.     
Every effort must be made to ensure that all other study site personnel other than those designated 
as unmasked remain masked to treatment assignment. 
Masked and unmasked roles will be assumed for the entire study, and switching from an unmasked 
to a masked role after the first patient is randomized at a site is not permitted.  Any deviation to 
the roles above must first be approved by the sponsor.  This must be properly documented before 
any patients are treated, and the site signature and delegation log must be maintained as new 
personnel are added to the study team. 
 
 
 
 
 
 
 
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Table 1: 
Responsibilities of the Masked and Unmasked Personnel 
Masked or Unmasked Personnel 
• Performs all screening procedures up until randomization 
• Assesses inclusion/exclusion criteria 
• Obtains medical/ophthalmic history 
• Obtains informed consent 
• Collects samples for laboratory testing and antibody sampling  
• Performs electrocardiograms (ECGs) and transfers to reading center 
Masked Personnel 
• Assesses AEs, including severity and relationship  
• Assesses efficacy 
• Performs ophthalmic examinations, including IOP, at all study visits (except post-dose examinations 
immediately after treatment) 
• Evaluates all safety, including vital signs and review of images for safety concerns (except those immediately 
after IVT injection)  
• May perform fellow eye injections at any unscheduled visits where only the fellow eye is treated 
• Tests refraction and BCVA (no exceptions will be granted) 
• Performs and assesses OCT, fundus photography (FP), and FA images and transfers them to reading centers 
Unmasked Personnel 
• Coordinates randomization  
• Performs receipt and accountability of study drug 
• Performs study drug (HD or 2 mg aflibercept) or sham injections in study eye 
• Performs fellow eye injection (if treatment is administered bilaterally/in conjunction with study eye treatment) 
• Observes safety through the end of the observation period (approximately 30 minutes following study 
treatment) 
• Checks IOP post-dose (study eye) before the end of the approximately 30-minute observation period 
• Checks indirect ophthalmoscopy post-dose (study eye) 
8.6. 
Emergency Unmasking  
Unmasking of treatment assignment for a patient may be necessary due to a medical emergency 
or any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient’s treatment assignment.  Study drug will be discontinued for patients whose 
treatment has been unmasked (Section 8.3.2). 
• If unmasking is required: 
− Only the investigator will make the decision to unmask the treatment assignment. 
− Only the affected patients will be unmasked. 
− Unmasking is performed using the IWRS which will notify Regeneron. 
− The investigator will also notify Regeneron and/or designee as soon as possible 
after unmasking the patient. 
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Treatment assignment is not to be provided to site personnel, other than the unmasked site 
personnel, at any time during the conduct of the study, except in the case of a true emergency and 
when a treatment decision is contingent on knowing the patient’s treatment assignment.   
8.7. 
Treatment Logistics and Accountability 
8.7.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used to label investigational study drug.  Lists linking 
medication numbers with product lot numbers will be maintained by the groups (or companies) 
responsible for study drug packaging.  In order to maintain the mask, these lists will not be 
accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.7.2. 
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. 
8.7.3. 
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. 
8.7.4. 
Treatment Compliance 
Study drug treatments will be administered by clinical personnel during study visits.  All drug 
compliance records must be kept current and made available for inspection by the sponsor and 
regulatory agency inspectors. 
8.8. 
Concomitant Medications and Procedures  
Any treatment administered from time of informed consent to the end of final study visit will be 
considered concomitant medication.  This includes medications that were started before the study 
and are ongoing during the study. 
If a pretreatment concomitant medication is administered in the study eye before injection (eg, 
antibiotic or anesthetic), it must be administered for sham and fellow eye injections as well. 
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8.8.1. 
Prohibited Medications and Procedures  
Study Eye: 
Patients are not allowed to receive any standard or investigational treatment for DME in the study 
eye other than their assigned study treatment with HD or 2 mg aflibercept, as specified in the 
protocol.  This includes medications administered locally (eg, IVT, topical, juxtascleral, or 
periorbital routes) with the intent of treating DME in the study eye. 
Fellow Eye: 
If the fellow eye has DME, or any other approved indication, 2 mg aflibercept will be allowed and 
supplied through the IWRS.  Once the fellow eye receives aflibercept 2 mg therapy during the 
study, AEs/SAEs will be assessed as related/not related to aflibercept 2 mg treatment in the fellow 
eye in addition to being assessed as related/not related to the study drug (delivered to the study 
eye), IVT injection-procedure, and other protocol-specified procedures.  Patients are not allowed 
to receive any other anti-VEGF agent in the fellow eye. 
Patients enrolled in the dense PK substudy cannot receive 2 mg aflibercept in the fellow eye before 
providing a PK sample at visit 3, week 4. 
Non-Ocular (Systemic): 
Non-ocular (systemic) standard or investigational treatments for DME of the study or fellow eye 
are not permitted.   
8.8.2. 
Permitted Medications and Procedures  
Any other medications or procedures that are considered necessary for the patient’s welfare, and 
that are not expected to interfere with the evaluation of the study drug, are allowed. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
9.1.1. 
Schedule of Events for the Study 
Study assessments and procedures are presented by study period and visit in Table 2. 
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 2: 
Schedule of Events 
Baseline to Week 48 
Study Procedure 
Screen-
ing 
Visit 1 
Base-
line 
Visit 2 
Visit 
3 
Visit 
4 
Option
al Visit 
4.11 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit
12 
Visit 
13 
Visit 
14 
Week 
 
0  
4 
8 
 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Day 
-21 to 
 -1 
1 
29 
57 
60-64 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Window (day) 
 
 
±5 
±5 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Screening/Baseline: 
Informed consent 
form(ICF) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dense PK substudy 
ICF2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic substudy 
ICF3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research ICF4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug5 
Study drug (active or 
sham) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DRM assessment 
 
 
 
 
 
 
X6 
X6  
X6 
X6 
X6 
X6 
X6 
X6 
X6 
Ocular Efficacy and Safety (bilateral unless indicated): 
 
BCVA (ETDRS) and 
Refraction7 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP8 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp examination 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Indirect 
ophthalmoscopy9 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FA, FP10 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
SD-OCT10 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 2: 
Schedule of Events 
Baseline to Week 48 (continued) 
Study Procedure 
Screen-
ing 
Visit 1 
Base-
line 
Visit 2 
Visit 
3 
Visit 
4 
Optional 
Visit 
4.11 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit
12 
Visit 
13 
Visit 
14 
Week 
 
0  
4 
8 
 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Day 
-21 to 
 -1 
1 
29 
57 
60-64 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Window (day) 
 
 
±5 
±5 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
OCTA substudies11 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
NEI-VFQ-25 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Nonocular Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs12 
X 
X 
X 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test (women 
of childbearing potential)14 
X 
Serum 
X 
Urine 
X 
Urine 
X 
Urine 
 
X 
Urine 
X 
Urine  
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
Urinalysis/UPCR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacokinetics and Other Sampling 
 
PK samples (Dense)15, 17 
 
See schedule 
below 
X  
 
X1 
X 
 
 
 
X 
 
 
 
 
X 
PK samples (Sparse)16, 17 
 
X 
X 
 
X1 
X 
 
 
 
X 
 
 
 
 
X 
Genomic DNA sample3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
sample16, 17 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Table 2 continued: Schedule of Events 
Week 52 to Week 96 
Study Procedure 
Visit 
15  
Visit 
16 
Visit 
17 
Visit 
18 
Visit 
19 
Visit 
20 
Visit 
21 
Visit 
22 
Visit 
23 
Visit 
24 
Visit 
25 
EOS 
Visit18 
26 
Week 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
Day 
365 
393 
421 
449 
477 
505 
533 
561 
589 
617 
645 
673 
Window (day) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer Study Drug5 
Study Drug (active or 
sham) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
DRM assessment 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
 
Ocular Efficacy and Safety (bilateral unless indicated): 
BCVA (ETDRS) and 
refraction7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Indirect 
ophthalmoscopy9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FA, FP10  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
SD-OCT10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCTA Substudies11 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
NEI VFQ-25  
 
 
X 
 
 
 
 
 
 
 
 
X 
Nonocular Safety: 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing13 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood chemistry 
 
 
 
 
 
 
 
 
 
 
 
X 
HbA1c 
 
 
 
 
 
 
 
 
 
 
 
X 
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Study Procedure 
Visit 
15  
Visit 
16 
Visit 
17 
Visit 
18 
Visit 
19 
Visit 
20 
Visit 
21 
Visit 
22 
Visit 
23 
Visit 
24 
Visit 
25 
EOS 
Visit18 
26 
Week 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
Day 
365 
393 
421 
449 
477 
505 
533 
561 
589 
617 
645 
673 
Pregnancy test (women 
of childbearing 
potential)14 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
 
Urinalysis/UPCR 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacokinetics and Other Sampling 
PK samples(Dense)15,17 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples(Sparse)16,17 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic DNA sample3 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
sample16, 17 
 
 
 
 
 
 
 
 
 
 
 
X 
BCVA=Best corrected visual acuity, DRM = Dose regimen modification, ECG=electrocardiogram, ETDRS=Early Treatment Diabetic Retinopathy Study, 
FA=fluorescein angiography, FP=fundus photography, IOP=Intraocular pressure, OCTA = optical coherence tomography angiography, PK=pharmacokinetics, 
SD-OCT=spectral domain optical coherence tomography, UPCR=urine protein:creatinine ratio. 
 
 
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9.1.1.1. 
Footnotes for the Schedule of Events Table 
1. An optional visit for all patients on days 60 to 64 (after the third injection) to collect a PK 
sample and assess heart rate and BP (no temperature measures required) as well as 
concomitant medications and AEs.   
2. Signed only by patients participating in the dense PK substudy and in addition to the study 
ICF. 
3. The optional genomic substudy ICF should be presented to patients at the screening visit 
and may be signed at any subsequent visit at which the patient chooses to participate after 
screening.  The genomic DNA sample should be collected on day 1/baseline (pre-dose) or 
at any study visit from patients who have signed the substudy ICF. 
4. The optional future biomedical research substudy ICF should be presented to patients and 
signed at the screening visit.   
5. Refer to pharmacy manual for study drug injection guidelines.  Following study drug 
injection, patients will be observed for approximately 30 minutes. 
6. Assessments for DRM criteria will occur in all patients at all visits for masking purposes 
beginning at week 16.  Actual DRMs will be implemented as described in Section 6.1. 
7. Patients enrolled at sites participating in the optional visual function substudy may undergo 
additional visual function tests.  See study procedure manual for details. 
8. Intraocular pressure will be measured at all study visits (bilateral).  On days when study 
drug is administered, IOP should be measured pre-dose (bilaterally) by the masked 
investigator (or designee) and approximately 30 minutes after administration of study drug 
(study eye only) by the unmasked investigator (or designee). IOP will be measured using 
Goldmann applanation tonometry or Tono-pen™ and the same method of measurement 
must be used in each patient throughout the study. 
9. Indirect ophthalmoscopy will be performed bilaterally at all visits by the masked 
investigator.  On days when study drug is administered, it should also be performed 
immediately after administration of study drug (study eye only) by the unmasked 
investigator. 
10. The same SD-OCT/FA/FP imaging system used at screening and day 1 must be used at all 
follow-up visits in each patient.  Images will be taken in both eyes before dosing at each 
required visit.  For FA, the study eye will be the transit eye and images should be collected 
using the widest field available.  If available, sites should also submit an optional ultra-
widefield color photograph.   
11. Details on an optional substudy evaluating OCTA are provided in study procedure manual.  
Images will be collected at the same time points as FA/FP.  
12. Vital signs (BP, heart rate, temperature) should be measured prior to injection and any 
blood sampling.  When possible, timing of all BP assessments should be within 2 hours of 
clock time of dosing on day 1.  Table 3 shows additional measurements for patients 
enrolled in the dense PK substudy. 
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13. All samples collected for laboratory assessments should be obtained prior to administration 
of fluorescein and prior to administration of study drug. 
14. For women of childbearing potential, a negative serum pregnancy test at screening is 
required for eligibility.  A negative urine pregnancy test is required before treatment is 
administered at subsequent visits. 
15. Dense PK sampling will be performed in approximately 24 patients (n=8/group) as 
indicated in Table 2.  Additional samples will be drawn according to the dense PK substudy 
schedule defined in Table 3.  On dosing visits, PK sampling should be performed prior to 
the administration of study drug and within 2 hours of the clock time of dosing on day 1.   
16. On dosing visits, PK and ADA sampling will be performed prior to dosing.  
17. PK and ADA samples may also be drawn at any non-specified scheduled visit or any 
unscheduled visit if a patient experiences an unexpected SAE. 
18. The EOS will also represent the early termination visit.  
9.1.2. 
Schedule of Events for the Dense PK Substudy 
Additional study assessments and procedures for the Dense PK Substudy are presented by study 
period and visit in Table 3.  
Table 3: 
Schedule of Events: (Dense PK Substudy) 
Visit 
Dose 
Assessment 
Day 
Assessment Time 
(h) 
PK Sample  
Heart Rate and 
Blood Pressure3 
Screening 21 
 
-20 to -1 
±2h 
 
X2 
Visit 2 
 
1 
Predose3 
X 
X2 
X 
4h ±30min 
X 
 
 
8h ±2h 
X 
 
 
 
2 
±2h3 
X 
X2 
 
3 
±2h3 
X 
X2 
 
5 
±2h3 
X 
X2 
 
8 
±2h3 
X 
X2 
 
15 
±2h3 
X 
X2 
  
22 
±2h3 
X 
X2 
9.1.2.1. 
Footnotes for the Dense PK Substudy Schedule of Events Table 3 
1. Additional BP assessment to confirm eligibility for patients in the dense PK substudy 
between screening and baseline 
2. Timing of all BP assessments must be within 2 hours of the clock time of dosing on day 1.  
Blood pressure assessments for patients in the dense PK substudy will be obtained prior to 
blood sample collection, using automated office blood pressure (AOBP) measurement with 
the Omron Model HEM 907XL (or comparable).  Measures displayed by the device will 
be recorded in the electronic data capture (EDC).  Detailed instructions can be found in the 
study procedure manual. 
3. PK sampling is to be performed within ±2 hours of the clock time of dosing on day 1. 
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9.1.3. 
 
 
 
 
 
 
 
 
 
 
 
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Table 4: 
 
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9.1.3.1. 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.1.4. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic for an early 
termination visit consisting of the end of study assessments described in Table 2 (EOS, visit 26) 
 
9.1.5. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
9.2. 
Study Procedures 
9.2.1. 
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, demographics, and physical 
examination.  Signatures for ICFs will also be obtained. 
9.2.2. 
Ocular Study Procedures (Efficacy and Safety)  
 
 
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9.2.2.1. 
Intraocular Pressure 
Intraocular pressure of the study eye will be measured in both eyes at every visit using Goldmann 
applanation tonometry or Tono-pen®, as specified in Table 2 and Table 4.  The same method of 
IOP measurement must be used throughout the study for each individual patient.  Intraocular 
pressure will be measured pre-dose (bilateral) by the masked physician (or designee), and at 
approximately 30 minutes post-dose (study eye) by the unmasked physician (or designee). 
9.2.2.2. 
Slit Lamp Examination 
Patients’ anterior eye structure and ocular adnexa will be examined bilaterally pre-dose at each 
study visit using a slit lamp by the masked investigator, as specified in Table 2 and Table 4.   
9.2.2.3. 
Indirect Ophthalmoscopy 
Patients’ posterior pole and peripheral retina will be examined by indirect ophthalmoscopy at each 
study visit pre-dose (bilateral) by the masked investigator and post-dose (study eye) by the 
unmasked investigator, as specified in Table 2 and Table 4.  Post-dose evaluation must be 
performed immediately after injection. 
9.2.2.4. 
Fundus Photography/Fluorescein Angiography 
The anatomical state of the retinal vasculature, including the DRSS level, leakage, and perfusion 
status will be evaluated by FP and FA as specified in Table 2 and Table 4.  Fundus photography 
and FA will be captured and transmitted to an independent reading center for both eyes.  For FA, 
the study eye will be the transit eye and images should be collected using the widest field available.  
If available, sites should also submit an optional ultra-widefield color photograph.   
Fundus and angiographic images will be sent to an independent reading center where images will 
be read by masked readers.  All FPs and FAs will be archived at the site as part of the source 
documentation.  Photographers must be masked to treatment assignment and must be certified by 
the reading center to ensure consistency and quality in image acquisition.  A detailed protocol for 
image acquisition and transmission can be found in the study procedure manual.   
Details on an optional substudy evaluating an exploratory OCT-angiography procedure are 
provided in the study procedure manual. 
9.2.2.5. 
Spectral Domain Optical Coherence Tomography 
Retinal characteristics will be evaluated at each study visit specified in Table 2 and Table 4 using 
SD-OCT.  Images will be captured and transmitted for both eyes.  Images will be sent to an 
independent reading center where they will be read by masked readers.  All OCTs will be 
electronically archived at the study site as part of the source documentation.  Optical coherence 
tomography technicians must be masked to treatment assignment and must be certified by the 
reading center to ensure consistency and quality in image acquisition. A detailed protocol for 
acceptable OCT machines and OCT image acquisition/transmission can be found in the study 
procedure manual.  
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9.2.2.6. 
Best Corrected Visual Acuity 
Visual function of the study eye and the fellow eye will be assessed using the ETDRS protocol 
(Early Treatment Diabetic Retinopathy Study Research Group, 1985) at 4 meters at each study 
visit specified in Table 2 and Table 4.  Visual acuity examiners must be certified to ensure 
consistent measurement of BCVA. They must remain masked per Section 8.5, but whenever 
possible, should also remain masked to prior BCVA measures and study eye.  Best corrected visual 
acuity should be assessed before any other ocular procedures are performed.  A detailed protocol 
for conducting visual acuity testing and refraction can be found in the study procedure manual.  
Patients enrolled at sites participating in the optional visual function substudy may undergo 
additional visual function tests.   
9.2.2.7. 
Quality of Life Questionnaire 
Vision-related quality of life (QoL) will be assessed using the NEI VFQ-25 (see study procedure 
manual) in the interviewer-administered format at visits specified in Table 2 and Table 4.  The 
NEI VFQ-25 will be administered by masked certified personnel.   
9.2.3. 
Safety Procedures (non-ocular) 
Safety procedures to assess AEs and SAEs include: 
9.2.3.1. 
Vital Signs 
Vital signs, including BP, heart rate, and temperature, will be collected pre-dose at designated time 
points according to Table 2 and Table 4. 
 
 
When possible, BP assessments will be obtained using AOBP measurement with the Omron Model 
HEM 907XL (or comparable).  Measures will be taken in triplicate and a mean measure as 
displayed by the device will be recorded in the EDC.  Detailed instructions can be found in the 
study procedure manual. 
9.2.3.2. 
Physical Examination 
A physical examination, including height and weight, will be performed at the screening visit.  
9.2.3.3. 
Electrocardiogram 
A standard 12-lead ECG measurement will be measured at visits specified in Table 2.  Heart rate 
will be recorded from the ventricular rate and the PR, QRS, RR, and QT intervals will be recorded.  
The ECG strips or report will be retained with the source documentation.  Electrocardiograms will 
be forwarded to a central reader. 
9.2.3.4. 
Laboratory Testing 
Hematology, blood chemistry, HbA1c, urinalysis, and serum pregnancy testing samples will be 
analyzed by a central laboratory.  All samples collected for laboratory assessments will be obtained 
prior to administration of study drug.  At visits at which FA is performed, urinalysis samples must 
be collected before FA to avoid false elevations in urine protein values.  Detailed instructions for 
blood sample collection are in the laboratory manual provided to study sites. 
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Samples for laboratory testing will be collected at visits according to Table 2 (main study) and 
Table 4 
  Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Urine protein:creatinine ratio 
(UPCR) 
 
 
Other Laboratory Tests 
Hemoglobin A1c will be measured at time points according to Table 2. 
Women of childbearing potential must have a documented negative serum pregnancy test before 
randomization.  Urine pregnancy tests will be performed at every treatment visit, and a negative 
result must be documented before study eye treatment (active or sham) or fellow eye treatment can 
be administered.   
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the masked investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality.  When necessary, appropriate ancillary investigations 
should be initiated.  If the abnormality fails to resolve or cannot be explained by events or 
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conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.   
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the masked investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.4. 
Drug Concentration and Measurements 
Blood samples for concentrations of free, bound, adjusted bound, and total aflibercept in plasma 
will be collected at the visits and time points listed in Table 2 and Table 3.  Instructions for PK 
blood sample collection will be included in the laboratory manual provided to study sites.  
9.2.5. 
Immunogenicity Measurements and Samples 
Serum samples for ADA and NAb assessment will be collected at time points listed in Table 2.   
9.2.6. 
Future Biomedical Research (Optional) 
Additional analyses may be performed on leftover PK and ADA samples from patients who 
consent to participate in the optional future biomedical research substudy.  Samples will be banked 
in long-term storage.  The unused PK/ADA samples will be stored for up to 15 years after the final 
date of the database lock.  The unused samples may be utilized for future biomedical research of 
DME, related diseases or pathways blocked by study treatment, and any adverse reactions that 
may emerge.  These samples may also be used for assay development and assay validation 
purposes.  After 15 years, any residual samples will be destroyed.  The results of these future 
biomedical research analyses will not be presented in the clinical study report.  
9.2.6.1. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics substudy will be required to consent to this 
optional substudy before collection of the samples.  Whole blood samples for DNA extraction 
should be collected on day 1/baseline (predose) but can be collected at a later study visit.  
DNA samples will be collected for pharmacogenomics analyses to understand the genetic 
determinants of efficacy and safety associated with the treatments in this study and the molecular 
basis of DME and related diseases.  These samples will be single-coded as defined by the 
International Council on Harmonisation (ICH) guideline E15.  Samples will be stored for up to 15 
years after the final date of the database lock.  If there are specific site or country requirements 
involving the pharmacogenomic analyses which the sponsor is unable to comply with, samples 
will not be collected at those sites.   
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to aflibercept, other DME clinical outcome measures, and possible AEs.  In 
addition, associations between genomic variants and prognosis or progression of DME as well as 
related diseases may also be studied.  These data may be used or combined with data collected 
from other studies to identify and validate genomic markers related to the study drug, target 
pathway, or DME and related diseases.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions.  Other methods including whole-exome 
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sequencing, whole-genome sequencing, and DNA copy number variation may also be 
performed.  The list of methods may be expanded to include novel methodology that may be 
developed during the course of this study or sample storage period.  Results from the genomic 
analyses will not be reported in the CSR.   
10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events  
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data collection 
period from the time of signing of the ICF to the end of the on-treatment period (defined as the 
time from signing of the ICF to the last dose of study drug (active or sham) plus 30 days, or to the 
last study visit (week 96 
 (see Section 11.4.5.1).  
Medical conditions that existed or were diagnosed prior to the first dose of study drug will be 
recorded as part of medical history.  Abnormal laboratory values and vital signs observed at the 
time of informed consent should also be recorded as medical history.  Any subsequent 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 should also be recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient.  Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit.  Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms.  The masked investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 10.2.  The masked investigator’s assessment must be clearly documented in the site’s 
source documentation with the masked investigator’s signature.  The investigator should follow 
up on SAEs until they have resolved or are considered clinically stable; AEs should be followed 
until they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE.   
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
masked investigator to determine their clinical significance.  Isolated abnormal laboratory results, 
vital sign findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be 
reported as AEs if they are symptomatic, lead to study drug discontinuation or dose reduction, 
require corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to first dose of study 
drug) procedures, treatments requiring hospitalization for pre-existing conditions that do not 
worsen in severity, and admission for palliative or social care should not be reported as SAEs (see 
Section 10.2 for Definitions).   
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For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any SAE that may occur subsequent to the reporting period (after the end of the on-treatment 
period) that the masked investigator assesses as related to study drug should also be reported. 
All AEs, SAEs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.   
10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with masked investigator’s assessment of 
the event’s seriousness, severity, and causality to the study drug, study conduct, and/or injection 
procedure.  For SAEs, a detailed narrative summarizing the course of the event, including its 
evaluation, treatment, and outcome should be provided on the AE case report form (CRF).  Specific 
or estimated dates of event onset, treatment, and resolution should be included, when available.  
Medical history, concomitant medications, and laboratory data that are relevant to the event should 
also be summarized in the narrative.  For fatal events, the narrative should state whether an autopsy 
was or will be performed and include the results if available.  Information not available at the time 
of the initial report must be documented in a follow-up report.  Source documents (including 
hospital or medical records, diagnostic reports, etc.) will be summarized in the narrative on the 
AE CRF, and retained at the study center and available upon request.   
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs 
• 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. 
10.2. 
Definitions 
10.2.1. 
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 (ICH 
E2A Guideline.  Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
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10.2.2. 
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 (any duration) 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). 
An ocular important medical event may include the following: 
• An AE that requires either surgical or medical intervention to prevent permanent loss 
of vision 
• Substantial, unexplained vision loss or an AE that causes substantial vision loss 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild: Does not interfere in a significant manner with the patient’s normal functioning level.  It 
may be an annoyance.  Prescription drugs are not ordinarily needed for relief of symptoms but may 
be given because of personality of the patient. 
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 patient’s health.  Treatment for symptom may be given and/or patient hospitalized. 
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If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates (see Section 9.2.3.4 and Section 10.1.1 for further 
information regarding the assessment of laboratory values as AEs). 
10.2.4. 
Causality 
The masked investigator must provide causality assessment as to whether or not there is a 
reasonable possibility that the drug caused the adverse event, based on evidence or facts, his/her 
clinical judgment, and the following definitions.  The causality assessment must be made based on 
the available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs. time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug and same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction, when applicable  
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
Causality to the study drug: 
The relationship of AEs to study drug will be assessed by the masked investigator, and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug?  
The possible answers are: 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
condition (eg, disease under study, concurrent diseases, concomitant medications), 
or other external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
• Not Related: 
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− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
For patients receiving fellow eye injections, AEs will also be assessed as related/ not related to 
“aflibercept 2mg (fellow eye)”. 
Causality to the Injection Procedure 
The relationship of AEs to the injection procedure will be assessed by the masked investigator, 
and is 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: 
• Related:  There is a reasonable possibility that the event may have been caused by the 
injection procedure. 
• Not Related:  There is no reasonable possibility that the event may have been caused 
by the injection procedure. 
Causality to the other protocol-specified procedures (excluding injection procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol-specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical condition (eg, disease under study, concurrent diseases, 
concomitant medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol-specified procedure, 
or can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
10.3. 
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; 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.  In addition, the IDMC will review the ongoing safety of 
patients in the study and provide recommendations to continue or terminate the study depending 
upon these reviews (see Section 6.3.3).   
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10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, ECs/Institutional 
Review Boards (IRBs), and the participating investigators of any SUSARs (suspected unexpected 
serious adverse reactions) occurring in other study centers or other studies of the active study drug 
(HD), as appropriate per local reporting requirements.  In addition, the sponsor and/or CRO will 
comply with any additional local safety reporting requirements.  All notifications to investigators 
will contain only masked information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the ECs/IRBs unless delegated to the sponsor. 
Event expectedness for high-dose and for 2 mg aflibercept is assessed against the reference safety 
information section of the current Investigator’s Brochure that is effective for expedited safety 
reporting.   
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 ECs/IRBs as appropriate. 
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11. 
STATISTICAL PLAN 
Due to differing requirements for the submission to various global regulatory authorities, 
2 different testing strategies will be described in the statistical analysis plan (SAP):  a global plan 
(G-SAP), and a plan that specifically addresses requirements from EMA and PMDA (EP-SAP).  
This section provides the basis for these plans which will be used to govern the detailed analysis 
of the study.  The G-SAP will constitute the primary analysis for the study.  The EP-SAP will be 
used for submission to the EMA/PMDA regulatory authorities.  
11.1. 
Statistical Hypothesis  
The 2 primary hypotheses to be tested are the non-inferiority (NI) of HDq12 vs. 2q8 (control) and 
HDq16 vs. 2q8 (control) with respect to the primary endpoint of change from baseline in BCVA 
at week 48.  The non-inferiority margin is set at 4 letters for each of the primary hypotheses.   
Justification of Non-inferiority Margin: 
Based on the pooled data analysis of VIVID and VISTA studies in patients with DME treated with 
aflibercept 2q8, the mean change from baseline in BCVA at week 48 was 10.4 (95% CI: 9.41 to 
11.4) letters.  Using the lower limit of this confidence interval, a non-inferiority (NI) margin of 4 
letters would preserve greater than 50% (57.5%) of the treatment effect of aflibercept 2q8 when 
compared to a putative placebo. The assumption that mean change in vision for a placebo group 
would be 0 letters is considered conservative as studies that included sham/placebo treatment 
demonstrated larger proportions of patients losing vision compared to laser treated groups 
(Blankenship, 1979) (Early Treatment Diabetic Retinopathy Study Research Group, 1985).  This 
provides justification of the NI margin based on statistical considerations. 
Regarding clinical relevance of the NI margin for the BCVA endpoint, previous studies with anti-
VEGF therapies in other indications regarded a difference of 5 letters as clinically relevant.  For 
example, the CLARITY (Sivaprasad, 2017) study in diabetic retinopathy (comparing aflibercept 
to panretinal photocoagulation) and the CATT study (CATT Research Group, 2011) in nAMD 
(comparing ranibizumab and bevacizumab), used a non-inferiority margin of 5 letters in BCVA. 
Recently, controlled phase 3 clinical trials studying nAMD (HARBOR study [Ho, 2014] and 
HAWK and HARRIER study [Dugel, 2019]) were based on a reduced margin of 4 letters. 
Null and Alternative Hypotheses: 
The primary family of hypotheses (null vs. alternative) are stated as below. 
H10: μ1 ≤ μ0 – 4 vs. H11:  μ1 > μ0 – 4 (ie, HDq12 vs. 2q8) 
H30: μ2 ≤ μ0 – 4 vs. H31:  μ2 > μ0 – 4 (ie, HDq16 vs. 2q8) 
where μ0, μ1, μ2, are the mean change from baseline in BCVA at week 48 for 2q8, HDq12, and 
HDq16, respectively.   
In addition, the HDq12 and HDq16 treatment groups will be tested for non-inferiority against the 
control group of 2q8 with respect to the following key secondary endpoints.  The hypotheses (null 
vs. alternative) are, respectively, stated as below. 
1. Change from baseline in BCVA at week 60 (non-inferiority) (included as part of the 
primary family of hypotheses only for the EP-SAP) 
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H20: μ1 ≤ μ0 – 4 vs. H21: μ1 > μ0 – 4 (ie, HDq12 vs. 2q8) 
H40: μ2 ≤ μ0 – 4 vs. H41: μ2 > μ0 – 4 (ie, HDq16 vs. 2q8) 
where μ0, μ1, μ2, are the mean change from baseline in BCVA at week 60 for 2q8, HDq12, and 
HDq16, respectively.  The non-inferiority margin is set at 4 letters. 
2. Proportion of patients with a ≥2 step improvement in DRSS at week 48 (non-inferiority) 
H50: p1 ≤ p0 – 0.15 vs. H51: p1 > p0 – 0.15 (ie, HDq12 vs. 2q8) 
H60: p2 ≤ p0 – 0.15 vs. H61: p2 > p0 – 0.15 (ie, HDq16 vs. 2q8) 
where p0, p1, p2, are the proportion of patients with ≥2 step improvement in DRSS at week 48 
for 2q8, HDq12, and HDq16, respectively.  The non-inferiority margin is set at 15%. 
The change from baseline in BCVA at week 48 and week 60 (for the EP-SAP) will also be tested 
for superiority to compare the HDq12 and HDq16 treatment groups against the control group of 
2q8.  
3. Change from baseline in BCVA at week 48 (superiority) 
H70: μ1 ≤ μ0 vs. H71:  μ1 > μ0 (ie, HDq12 vs. 2q8) 
H90: μ2 ≤ μ0 vs. H91:  μ2 > μ0 (ie, HDq16 vs. 2q8) 
where μ0, μ1, μ2, are the mean change from baseline in BCVA at week 48 for 2q8, HDq12, and 
HDq16, respectively.   
4.  Change from baseline in BCVA at week 60 (superiority) (included only for the EP-SAP) 
H80: μ1 ≤ μ0 vs. H81: μ1 > μ0 (ie, HDq12 vs. 2q8) 
H100: μ2 ≤ μ0 vs. H10_1: μ2 > μ0 (ie, HDq16 vs. 2q8) 
where μ0, μ1, μ2, are the mean change from baseline in BCVA at week 60 for 2q8, HDq12, and 
HDq16, respectively.   
11.2. 
Justification of Sample Size 
The sample size calculation is based on the primary endpoint, the change from baseline in BCVA 
at week 48 in 2 pairwise comparisons: (1) HDq12 vs. 2q8; (2) HDq16 vs. 2q8. The non-inferiority 
margin is defined to be 4 letters.  
Under the original testing strategy (prior to Amendment 4), assuming a standard deviation of 9.07 
letters for each treatment group (Brown, 2015), a sample size of 129 patients per group will provide 
90% power using a two-sample t-test to demonstrate non-inferiority with one-sided alpha=0.0125 
(=0.025/2) for each comparison. The overall family-wise type I error rate of 0.025 (one-sided) will 
be preserved. Allowing for a dropout rate of 19%, 160 patients per group will be required to 
provide 90% power for each pairwise comparison. However, the sample size in the HDq12 group 
has been doubled to meet regulatory requirements for the safety database. This results in a total of 
640 patients for 3 groups (160, 160, and 320 patients for groups 2q8, HDq16, and HDq12, 
respectively). Therefore, with these sample sizes, the power for the pairwise comparisons will be: 
90% for HDq16 vs. 2q8, and approximately 97% for HDq12 vs. 2q8. The power to reject each of 
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the primary hypotheses with the proposed multiple testing procedure will be at least as high. 
Sample size/power calculations were performed using East 6 software. 
However, under the current hierarchical testing procedure, using the same assumptions as 
indicated above, a total sample size of 640 patients for 3 groups provides 98% power for rejecting 
the null hypothesis H10, and subsequently 92% power for rejecting the null hypothesis H30, for the 
primary endpoint assessing non-inferiority, with a 1-sided t-test at significance level of 0.025. 
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients  who received at least 1 dose of study 
drug.  Analysis of the FAS will be done according to the treatment assigned to the patient at 
baseline (as randomized).  All efficacy endpoints will be analyzed using the FAS.  The FAS will 
be used for primary analysis (statistical evaluation of non-inferiority) and the analysis of key 
secondary hypotheses. 
The per protocol set (PPS) includes all patients in the FAS who had a baseline and at least 1 post-
baseline assessment of BCVA, and do not have any relevant important protocol violations that 
affect the primary efficacy endpoint.  Treatment assignment is based on the treatment received (as 
treated). The final determination on the exclusion of patients from the PPS will be made on the 
masked data prior to the first database lock. The PPS will be used for supplementary analyses of 
change from baseline in BCVA (non-inferiority only) at week 48 (primary endpoint) and week 60 
(key secondary endpoint, under the EP-SAP). 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study treatment; 
it is based on the treatment received (as treated).  Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF.  The safety analysis will be performed on 
the observed safety data. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug.  Patients will be analyzed based on 
actual treatment received. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received study drug and had at least 1 non-missing 
result in the ADA assay following the first study dose.  Samples positive in the ADA assay will be 
analyzed in the NAb assay. 
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or with at least 1 non-missing result in the NAb assay.  Patients who are ADA 
negative are set to negative in the NAb analysis set. 
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11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Subgroups will be defined by key baseline factors (ie, demographics, disease characteristics, and 
medical history).  Subgroup analyses will be performed on efficacy and safety endpoints.  Details 
will be described in the SAPs. 
All statistical analyses will be performed using Statistical Analysis Software (SAS), version 9.4 or 
higher. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients who have signed the ICF 
• The total number of randomized patients: received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
• The FAS (defined in Section 11.3.1) 
• The PPS (defined in Section 11.3.1) 
• The SAF (defined in Section 11.3.2) 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.  No formal comparison between treatment groups will be conducted. 
11.4.3. 
Efficacy Analyses 
Efficacy analyses will be conducted using the FAS population.  
The primary analysis is based on the estimand concept.  The estimand of primary interest will be 
mainly based on a hypothetical strategy (ICH E9 [R1], 2017).  It describes the change from 
baseline for all patients who started treatment, assuming all patients have stayed on treatment until 
week 48. 
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The estimand is specified through the following definitions of population, variable, treatment 
condition, intercurrent events, and population-level summary: 
• Population: Defined by the inclusion/exclusion criteria  
• Variable: Change from baseline to week 48 in BCVA 
• Treatment condition:  HD aflibercept administered every 12 weeks (HDq12) after 
3 initial monthly injections or every 16 weeks (HDq16) after 3 initial monthly 
injections versus aflibercept 2 mg administered every 8 weeks (2q8) after 5 initial 
monthly injections; dose regimen may be modified as detailed in Section 6.1.  For 
primary analysis, data for patients will be analyzed according to their randomized 
treatment group regardless of dose regimen modifications. 
• Intercurrent events: Premature discontinuation from treatment;  
• shortening/extension of the interval (DRM / rescue regimen) will not be considered 
an intercurrent event but as part of the randomized treatment regimen. 
• Population-level summary: Difference in least squares (LS) mean change from baseline 
to week 48 in BCVA between HDq12 and 2q8 (and HDq16 and 2q8) resulting from a 
mixed-model for repeated measurements (MMRM). 
11.4.3.1. Primary Efficacy Analysis 
Primary Efficacy Analysis: 
The primary efficacy analysis will be a multiple-comparison between the following 2 comparative 
arms: 1) HDq12 vs. 2q8; and 2) HDq16 vs. 2q8.  The primary efficacy variable (change in BCVA 
from baseline to week 48) will be analyzed using FAS with an MMRM analysis model.  The model 
is specified below and includes baseline BCVA as a covariate, treatment group, baseline CRT 
category, prior DME treatment, geographical region and visit as fixed effects, and interaction terms 
for treatment by visit and baseline BCVA by visit.  A Kenward-Roger approximation will be used 
for the denominator degrees of freedom. More details (including the handling of missing data as 
well as the missing at random assumption) will be in the SAP. 
𝑌𝑖𝑗𝑘= 𝛽0 + 𝛽𝑏𝑎𝑠𝑒𝐵𝐶𝑉𝐴𝑥𝑖+ 𝛽𝑡𝑘+ 𝛽𝑏𝑎𝑠𝑒𝐶𝑅𝑇𝑛+ 𝛽𝑝𝐷𝑀𝐸𝑙+ 𝛽𝑟𝑒𝑔𝑖𝑜𝑛𝑚 + 𝛽𝑣𝑖𝑠𝑖𝑡𝑗+ 𝛽𝑡𝑘 * 𝑣𝑖𝑠𝑖𝑡𝑗
+ 𝛽𝑏𝑎𝑠𝑒𝐵𝐶𝑉𝐴∗𝑣𝑖𝑠𝑖𝑡𝑗𝑥𝑖 + 𝜀𝑖𝑗𝑘, 
where: 
  𝑌𝑖𝑗𝑘 is the change from baseline BCVA at week 48 for 𝑖𝑡ℎ patient at 
𝑗𝑡ℎ visit for kth treatment group, 
𝛽0 is an intercept term,  
𝛽𝑏𝑎𝑠𝑒𝐵𝐶𝑉𝐴 is the regression coefficient of the covariate,  
𝑥𝑖 for the baseline BCVA of 𝑖𝑡ℎ patient, 
𝛽𝑡𝑘 is the fixed effect of treatment group 𝑘,𝛽𝑏𝑎𝑠𝑒𝐶𝑅𝑇𝑛 is the fixed effect of categorized  baseline CRT n, 
𝛽𝑝𝐷𝑀𝐸𝑙 is the fixed effect of prior DME treatment l,  
𝛽𝑣𝑖𝑠𝑖𝑡𝑗 is the fixed effect of visit 𝑗, 
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𝛽𝑟𝑒𝑔𝑖𝑜𝑛𝑚 is the fixed effect of region m,  
𝛽𝑡𝑘 * 𝑣𝑖𝑠𝑖𝑡𝑗, 𝛽𝑏𝑎𝑠𝑒𝐵𝐶𝑉𝐴∗𝑣𝑖𝑠𝑖𝑡𝑗 are the interaction terms for treatment by visit and baseline BCVA by visit, and 
𝜀𝑖𝑗𝑘 is the residual error term. 
In terms of the model parameters, the estimand of interest, ie, treatment effect can be expressed, 
for example, as (𝛽𝑡1 + 𝛽𝑡1 * 𝑊𝑒𝑒𝑘 48) −(𝛽𝑡2 + 𝛽𝑡2 * 𝑊𝑒𝑒𝑘 48). 
A supplementary analysis of the primary endpoint will be conducted using the MMRM model 
using the PPS.   
Superiority testing for change from baseline in BCVA at week 48 will be performed as described 
in Section 11.1  and placed in hierarchy as described in Section 11.4.4. Further details will be 
described in the SAP. 
11.4.3.2. Secondary Efficacy Analysis 
Analysis for Key Secondary Endpoints: 
The key secondary endpoint of change from baseline in BCVA at week 60 (EP-SAP only) will be 
analyzed with a model matching the one for the primary endpoint.  The other key secondary 
efficacy endpoint (proportion of patients with ≥2 step improvement in DRSS at week 48) will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) method, stratified by baseline CRT, prior 
DME treatment, and geographical region as specified for the primary endpoint.  The key secondary 
hypotheses for non-inferiority (see Section 11.1) will be tested according to the multiplicity 
adjustment method specified in Section 11.4.4.  In addition, two-sided 95% confidence intervals 
will be reported. 
Superiority testing for the change from baseline in BCVA at week 60 will be performed as 
described in Section 11.1 and placed in hierarchy as described in Section 11.4.4. Further details 
will be described in the SAP. 
Analysis for Additional Secondary and Exploratory Endpoints: 
All additional efficacy variables (see Section 4.1.3 and Section 4.1.4) will be analyzed 
descriptively at each scheduled visit from baseline to week 48, week 60, week 96, 
 
  These descriptive analyses may include statistical tests (with nominal p-
values) for the efficacy variables and two-sided 95% confidence intervals, in the same way as 
described for the primary and secondary efficacy variable analyses (see Section 11.4.3.1 and 
Section 11.4.3.2).  Time-to-event variables will be analyzed using the Kaplan-Meier method.  No 
multiplicity adjustments will be made for the additional efficacy analyses.  Further details will be 
described in the SAP. 
11.4.4. 
Control of Multiplicity 
The overall family-wise type 1 error will be controlled at 0.025 one-sided level for testing the 
primary and key secondary endpoints. Adjustment for multiple comparisons in the primary and 
key secondary endpoints will be made with the hierarchical testing procedure. This approach 
allows the confirmatory testing of a hypothesis at the full alpha level of 0.025 after successful 
rejection of the hypotheses which are ranked higher in the hierarchy. The testing hypotheses will 
be tested in the order as specified in Table 5 for G-SAP and EP-SAP, respectively.  
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Table 5: 
The Testing Order of Hierarchical Testing Procedure in G-SAP and EP-SAP 
G-SAP 
EP-SAP 
H10 : Q12 BCVA Week 48 non-inferiority 
H10 : Q12 BCVA Week 48 non-inferiority 
 
H20 : Q12 BCVA Week 60 non-inferiority 
H30 : Q16 BCVA Week 48 non-inferiority 
H30 : Q16 BCVA Week 48 non-inferiority 
 
H40 : Q16 BCVA Week 60 non-inferiority 
H50 : Q12 DRSS Week 48 non-inferiority 
H50 : Q12 DRSS Week 48 non-inferiority 
H60 : Q16 DRSS Week 48 non-inferiority 
H60 : Q16 DRSS Week 48 non-inferiority 
H70 : Q12 BCVA Week 48 superiority 
H70 : Q12 BCVA Week 48 superiority 
 
H80 : Q12 BCVA Week 60 superiority 
H90 : Q16 BCVA Week 48 superiority 
H90 : Q16 BCVA Week 48 superiority 
 
H100 : Q16 BCVA Week 60 superiority 
11.4.5. 
Safety Analysis 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period (to determine treatment-emergent adverse events [TEAEs]) is 
defined as the time from first dose of study drug to the last dose of study drug (active 
or sham) plus 30 days.   
• The post-treatment period is defined as after the end of the on-treatment period. 
Treatment-emergent adverse events 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 MedDRA®. 
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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 10.2.3), 
presented by SOC and PT 
• All treatment-related TEAEs, presented by SOC and PT 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (BP, heart rate, and temperature) will be summarized by baseline and change from 
baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out-of-laboratory range values. 
11.4.5.3. Treatment Exposure 
Exposure to study drug will be examined for each patient.  The total number of treatments 
administered to each patient and the duration of treatment will be analyzed and summarized using 
descriptive statistics by treatment group in the SAF and FAS populations.  Proportions of patients 
maintaining, shortening, or extending the dosing interval at various time points will be summarized 
as well.   
11.4.5.4. Treatment Compliance 
Compliance with protocol-defined study medication will be calculated as follows: 
Treatment compliance = (number of received injections through a given week)/(number of planned 
injections during the period of participation in the study through the given week)x100%. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
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Main Study: 
The concentrations of free, bound, adjusted bound, and total aflibercept over time will be 
summarized by descriptive statistics for each treatment group. Concentrations may be further 
grouped by factors such as age, renal function, HbA1c level, hepatic function, concomitant 
medications, body weight, ethnicity, etc. No formal statistical hypothesis testing will be performed.  
Dense PK Substudy: 
The PK parameters to be determined after the first dose for free, adjusted bound, and total 
aflibercept may include, but are not limited to: 
• Cmax 
• Cmax/Dose 
• tmax   
• tlast 
• Clast 
• AUClast 
• AUCinf    
• AUCinf/Dose   
• t1/2    
• Ctrough 
After repeat dosing in the dense PK substudy, PK parameters to be determined may include, but 
are not limited to, Ctrough, time to reach steady-state, and accumulation ratio.  PK parameters will 
be summarized by descriptive statistics by treatment group, and geographical region as 
appropriate.  This descriptive statistical assessment may include the geometric means and ratios of 
the geometric means for selected PK parameters, as deemed appropriate.  No formal statistical 
hypothesis testing will be performed. 
11.4.6.2. Pharmacokinetics/Pharmacodynamics Analyses 
Dose- and/or exposure-response analyses for efficacy and safety endpoints may be performed, as 
appropriate. 
11.4.7. 
Analysis of Immunogenicity Data  
Incidence of treatment-emergent ADA response will be provided by treatment groups, including 
characterization of the response with titers and neutralizing antibody status.  
Plots of drug concentrations may be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated.  Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
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11.5. 
Interim Analysis  
No formal interim analysis is planned.  The primary analysis for this study will be performed once 
all patients reach week 48, with a subsequent analysis when all patients reach week 60.  The study 
will continue through week 96 for the main phase 
  
Another analysis will be conducted after all patients have completed the main phase of the study 
at week 96 (or prematurely discontinued).  
 
 
 
  
11.6. 
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 15.1. 
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12. 
QUALITY CONTROL AND 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 described in this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
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 Pharmaceuticals, Inc. (sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history/ophthalmic 
history) will be done using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an EDC system (Medidata RAVE). 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata RAVE 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring  
12.2.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, [CRO] monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study.  This study will use the principles of risk-based 
monitoring (ICH).  This means that the number of visits for any given site may vary based on site 
risk indicators.  The investigator must allow study-related monitoring. 
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. 
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12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents).  The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate, and complete. 
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. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel.  All required CRFs must be completed for each and 
every patient enrolled in the study.  The investigator must ensure the accuracy, completeness, and 
timeliness of the data reported to the sponsor in the CRFs.  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. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
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/EC 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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12.4. 
Study Documentation 
12.4.1. 
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 
eCRFs that will be provided to the sponsor. 
12.4.2. 
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.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-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 the 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, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately.  All study patients must be informed of the new information and provide their 
written consent if they wish to continue in the study.  The original, signed revised ICF must be 
maintained in the patient’s study record and a copy must be given to the patient. 
13.2.1. 
 
 
 
13.3. 
Patients 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. 
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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. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patient 
(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/EC 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/EC 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/EC approval letter with a current list of the IRB/EC 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/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site after 
study completion. 
14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment.  Where required per local legislation, regulatory authority approval 
will also be sought.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-
OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
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/EC and health authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
REFERENCES 
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Bhagat N, Grigorian RA, Tutela A, and Zarbin MA. Diabetic macular edema: pathogenesis and 
treatment. Surv Ophthalmol 2009;54;1-32. 
Blankenship GW. Diabetic macular edema and argon laser photocoagulation: a prospective 
randomized study.Ophthalmology. 1979 Jan;86(1):69-78. 
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches for 
multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. Biom J 
2011;Nov 53(6):894-913. 
Brown DM, Schmidt-Erfurth U, Do DV, HolzFG, Boyer DS, Midena E, et al. Intravitreal 
aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. 
Ophthalmology 2015;122(10):2044-52. 
CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, et al. 
Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 
2011 May 19;364(20):1897-908. 
Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: 
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Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ. et al. National, regional, and 
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Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, et al. HAWK and 
HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for 
Neovascular Age-Related Macular Degeneration. Ophthalmology. 2019 Apr 12. pii: S0161-
6420(18)33018-5. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic 
macular edema: Early treatment diabetic retinopathy study report Number 1. Arch Ophthalmol 
1985;103(2):1796-1806. 
Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, et al. Randomized trial 
evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for 
diabetic macular edema. Ophthalmology 2010;117:1064-1077. 
Ferrara N. VEGF: an update on biological and therapeutic aspects. Curr Opin Biotechnol 2000;11; 
617-24. 
Giuffrè G, Lodato G, Dardanoni G. Prevalence and risk factors of diabetic retinopathy in adult and 
elderly subjects: The Casteldaccia Eye Study. Graefes Arch Clin Exp Ophthalmol, 2004; 
242(7):535-40. 
Gulliford MC, Dodhia H, Chamley M, McCormick K, Mohamed M, Naithani S, et al., Socio-
economic and ethnic inequalities in diabetes retinal screening. Diabet Med 2010;27(3); 282-8. 
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Ho AC, Busbee BG, Regillo CD, Wieland MR, Van Everen SA, Li Z, et al. Twenty-four-month 
efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-
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of Confirmatory Clinical Trials. In Biopharmaceutical Applied Statistics Symposium. Singapore: 
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ICH E9 (R1) addendum on estimands and Sensitivity Analysis in Clinical Trials to the guideline 
on 
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for 
clinical 
trials. 
European 
Medicines 
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https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-e9-r1-addendum-
estimands-sensitivity-analysis-clinical-trials-guideline-statistical_en.pdf. 
August 
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aflibercept for diabetic macular edema. Ophthalmology 2014;121:2247-54. 
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Massin P, Bandello F, Garweg JG, Hansen LL, Harding SP, Larsen M, et al. Safety and efficacy 
of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, 
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Minassian DC, Owens DR, Reidy A. Prevalence of diabetic macular oedema and related health 
and social care resource use in England. Br J Ophthalmol 2012;96(3): 345-49. 
Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The 
RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for 
diabetic macular edema. Ophthalmology 2011;118(4):615-25. 
Moss SE, Klein R, Klein BE. Ten-year incidence of visual loss in a diabetic population. 
Ophthalmology 1994;101:1061-70. 
Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. 
Ophthalmology 1998;105:998-1003. 
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analysis of 751 population-based studies with 4.4 million participants. Lancet 2016;387:1513-30. 
Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic 
macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 
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Photocoagulation for Diabetic Macular Edema: Early Treatment Diabetic Retinopathy Study 
Report Number 1 Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol. 
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Rohmeyer K, Klinglmueller F. gMCP: Graph Based Multiple Test Procedures. R package version 
0.8. 10. URL http://CRAN.R-project.org/package=gMCP 2015.  
Sivaprasad S, Gupta B, Crosby-Nwaobi R, Evans J. Prevalence of diabetic retinopathy in various 
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Sobha Sivaprasad, A Toby Prevost, Joana C Vasconcelos, Amy Riddell, Caroline Murphy, Joanna 
Kelly, James Bainbridge, Rhiannon Tudor-Edwards, David Hopkins, Philip Hykin, on behalf of 
the CLARITY Study Group* Clinical efficacy of intravitreal aflibercept versus panretinal 
photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy 
at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-
inferiority trial  Lancet 2017; 389: 2193–203. Published Online May 7, 2017 
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Wells JA, Glassman AR, Ayala AR., Jampol LM, Aiello LP, Antoszyk AN, et al. Aflibercept, 
bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015;372(13):1193-203. 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol:  A Randomized, Double-Masked, Active-Controlled Phase 2/3 
Study of the Efficacy and Safety of High-Dose Aflibercept in Patients with Diabetic Macular 
Edema, 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/EC.  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 Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 A Randomized, Double-Masked, Active-Controlled Phase 2/3 Study of the 
Efficacy and Safety of High-Dose Aflibercept in Patients with Diabetic Macular Edema  
Protocol Number: 
VGFTe-HD-DME-1934  
Protocol Version:   
VGFTe-HD-DME-1934 Amendment 6 
 
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 Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
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-2023 21:12:42 GMT+0000
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